No retraction, correction or concern found when last checked on Oct 19, 2026.

Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation—Driven Liver and Colorectal Cancers

Lara Kern, Melanie Mittenbühler, Anna Vesting and 3 more

Cancers · 2018 · Review · CC BY

Abstract

Obesity promotes the development of numerous cancers, such as liver and colorectal cancers, which is at least partly due to obesity-induced, chronic, low-grade inflammation. In particular, the recruitment and activation of immune cell subsets in the white adipose tissue systemically increase proinflammatory cytokines, such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). These proinflammatory cytokines not only impair insulin action in metabolic tissues, but also favor cancer development. Here, we review the current state of knowledge on how obesity affects inflammatory TNFα and IL-6 signaling in hepatocellular carcinoma and colorectal cancers.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Obesity-Induced Inflammation Impairs Insulin Action

1More than two decades ago, Hotamisligil and colleagues discovered the negative impact of tumor necrosis factor α (TNFα) on insulin sensitivity in obesity. Since then, numerous research articles have been published, reviewed elsewhere (e.g.,), that support the view of obesity-induced, low-grade inflammation in the development of insulin resistance.

2In obesity, the enlargement of the white adipose tissue (WAT) induces mechanical as well as endoplasmatic reticulum (ER) stress in adipocytes, leading to the release of free fatty acids (FFA) and inflammatory cytokines (Figure 1). Subsequently, recruitment of immune cells to the obese WAT enhances local and systemic inflammation. This obesity-driven, low-grade, chronic inflammation affects insulin sensitivity of all metabolic organs such as WAT, liver, muscle, pancreas, and even the central nervous system.

3The obese WAT differs from that of lean individuals regarding immune cell composition and numbers. In particular, cell types of innate and adaptive immunity have been shown to infiltrate the obese WAT (Figure 1). One major subset of infiltrating innate immune cells are macrophages that, depending on their polarization, can exert variable functions in WAT. In detail, Mantovani et al., defined polarized macrophages in two classes: M1 proinflammatory and M2 anti-inflammatory macrophages.

4In the obese WAT, proinflammatory M1 macrophages form crown-like structures around dead adipocytes and thereby contribute to the obesity-induced, low-grade inflammation. The elevated number of M1 macrophages in the obese WAT is the main source of TNFα and interleukin-6 (IL-6) (Figure 1). In contrast, lean WAT contains more M2 macrophages that mediate anti-inflammatory functions. At the front between innate and adaptive immunity, natural killer cells (NK) are activated and proliferate in the obese WAT to trigger M1 macrophage accumulation and polarization. Furthermore, obesity promotes the expansion of a distinct IL-6 receptor α (IL-6Rα) positive NK cell subpopulation, which is also present in the blood of obese patients, expressing myeloid lineage markers to contribute to the obesity-induced inflammation. Besides innate immune cells, adaptive immunity mediated by T and B cells are also involved in WAT inflammation. In line, cluster of differentiation (CD)4 and CD8-positive effector T cells both contribute to the obesity-induced inflammation. While in lean WAT, regulatory T cells (Treg) are anti-inflammatory, the percentage of these cells is reduced in the obese WAT. Although not fully understood, B cells were reported to control Treg numbers in the WAT. Obese B-cell-deficient mice have increased WAT-resident Tregs and, consequently, a reduction in inflammation as well as improved insulin sensitivity. Thus, both innate and adaptive immune cells contribute to obesity-induced inflammation and the development of insulin resistance.

5However, other cytokines, such as IL-1, monocyte chemoattractant protein 1 (MCP1), IL-10, and IL-17, are also altered upon obesity and have been extensively examined. IL-6 signaling is not only required to induce IL-10 expression, but is also involved in T cell differentiation to IL-17-expressing T cells, thereby further complicating the exact definition of cell type specific contributions of inflammatory mediators in obesity and its associated disorders.

6The contribution of TNFα and IL-6 signaling to obesity-associated insulin resistance is well studied in conditional mouse models, but still reveals contradictory outcomes. TNFα the IR- substrate 1 (IRS1) required for downstream activation of insulin signaling. On the one hand, TNFα activates spingomyelinase to produce ceramides that convert IRS1 into an inhibitor of the intrinsic tyrosine kinase of IR. On the other hand, TNFα activates intracellular c-JUN N-terminal kinase (JNK) 1 and IκB kinase (IKK) that blunt insulin signaling via inhibitory phosphorylation of IRS1 at serine 307, which is a read-out of TNFα’s negative impact on insulin sensitivity (Figure 2). Consistently, JNK1 but not JNK2 deficiency retained insulin sensitivity in diet-induced obesity. However, exchanging S307 in IRS1 to a nonphosphorylatable amino acid fails to protect against the development of obesity-induced insulin resistance, and instead impairs insulin sensitivity, indicating that the impact of TNFα on insulin signaling might be context- and cell-type-dependent.

7In contrast to TNFα, IL-6 exerts both pro- and anti-inflammatory effects. IL-6-mediated STAT3 activation leads to the expression of the negative regulator of IL-6 signaling, suppressor of cytokine signaling (SOCS), which in turn destabilizes IRS1, thereby blunting insulin action (Figure 2). While hepatic SOCS3 deficiency initially prevents impaired insulin action in diet-induced obesity, these mice have accelerated inflammation at later stages. This suggests a fine-tuned balance between anti- and proinflammatory actions of IL-6. Contradictory to its role as a proinflammatory cytokine, inactivation of classical membrane-bound IL-6Rα signaling in hepatocytes and macrophages shows impaired insulin sensitivity. Otherwise, mice with IL-6Rα deficiency in T cells exhibit improved insulin sensitivity at the onset of diet-induced obesity. Taken together, TNFα and IL-6 signaling in obesity-associated inflammation point towards complex, temporal, and cell-type-specific functions in the development of insulin resistance.

8However, TNFα and IL-6 not only impact systemic insulin sensitivity in obesity, but also promote cancer, since these cytokines are also produced from cells of the tumor microenvironment. In line, TNFα and IL-6 levels are elevated in the serum of cancer patients. In fact, most cancer types show a positive correlation between cancer incidence and body mass index. While multiple factors contribute to obesity-associated cancers, we will only focus on the role of obesity-induced TNFα and IL-6 signaling in the promotion and development of hepatocellular carcinoma (HCC) and colorectal cancer (CRC) within this review.

9Insulin binding to the insulin receptor (IR) results in the activation of the intrinsic tyrosine kinase of IR and subsequent tyrosine phosphorylation of the IRS1, ultimately causing protein kinase B (AKT) activation. Obesity increases systemic levels of tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). TNFα signaling activates intracellular c-JUN N terminal kinase (JNK) and IκB kinase (IKK). Both blunt insulin signaling by inhibitory phosphorylation of IRS1 at serine 307. TNFα signaling triggers the production of ceramides through the sphingomyelin phosphodiesterase (SM). Ceramides suppress the phosphorylation of IR, thereby inhibiting the insulin signaling pathway. IL-6 binds to the IL-6 receptor α (IL-6Rα), which recruits two glycoprotein 130 (GP130) receptor molecules to activate janus kinase (JAK). JAK phosphorylates tyrosine residues of the GP130 receptor and thereby induces activation of signal transducer and activator of transcription 3 (STAT3). Phosphorylated STAT3 translocates into the nucleus and induces target gene expression. In turn, suppressor of cytokine signaling 3 (SOCS3) is expressed and inhibits the IL-6 signaling pathway and ubiquitinates IRS1, resulting in its degradation.

2. TNFα and Its Bivalent Role in Liver Homeostasis

10TNFα is one of the master regulators of liver homeostasis. It mediates hepatocyte proliferation, but also controls hepatocyte apoptosis and necroptosis. Secreted TNFα binds either TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2). However, the main signal transduction occurs via TNFR1. TNFR activates proinflammatory nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinase pathways rapidly through signaling complex I, which is composed of the adaptor molecule TNF type 1-associated DEATH domain protein (TRADD), the kinase receptor interacting serine/threonine-protein kinase 1 (RIP1), as well as TNFR-associated factor 2 (TRAF2). The NF-κB heterodimer composed of p65 and p50 is sequestered in the cytosol by inhibitor of κBα (IκBα), when cells are not exposed to TNFα. TNFα-mediated activation of the IKK complex, which is comprised of the two catalytic subunits, IKK1 and IKK2, as well as the regulatory subunit NF-κB essential modulator (NEMO), induces classical NF-κB pathway activation through IKK-mediated phosphorylation and degradation of IκBα (Figure 2). Degradation of IκBα leads to nuclear translocation of the p65/p50 heterodimer and subsequently the induction of NF-κB-dependent target gene expression such as proinflammatory and cell survival genes. NF-κB induces transcription of antiapoptotic target genes such as cellular inhibitors of apoptosis (cIAPs), cIAP1, cIAP2, X-linked inhibitor of apoptosis protein (XIAP), and B cell lymphoma 2 (Bcl2) family members.

11In addition to IKK complex/NF-κB signaling, the JNK pathway has emerged as one of the key regulators of hepatic inflammation (Figure 2). Here, TNFR activation leads to the formation of complex I and activation of transforming growth factor β-activated kinase 1 (TAK1). TAK1 further activates mitogen-activated protein kinase kinase 4 (MKK4) and MKK7, which subsequently leads to JNK activation and downstream cJUN activation.

3. TNFα: A Key Driver of Hepatocellular Carcinoma (HCC) Development

12The obesity-induced, nonresolving, inflammatory microenvironment is a major driver of tumor progression, especially of HCC, characterized by the presence of immune cells and proinflammatory cytokines such as TNFα. The main source of TNFα is liver-resident Kupffer cells and macrophages, which are anatomically in close proximity to hepatocytes. A key step in tumor initiation is compensatory proliferation of hepatocytes. Recruited macrophages secrete TNFα and IL-6 to block hepatocyte apoptosis and in turn induce hepatocyte survival and proliferation. Permanent proliferating hepatocytes accumulate DNA damage and proliferation-induced mutations, which promote HCC development. Consistently, genetic mouse models revealed that inactivation of TNFR1 decreases the incidence of liver tumors. TNFR1-knockout mice fed a high fat diet show an ablation of obesity-enhanced HCC, as well as reduced obesity-induced hepatosteatosis. Further, multidrug resistance protein 2 (MDR2)-deficient mice, a model of inflammation-associated HCC, develop spontaneous HCC in a TNFα-dependent manner. In this model, the increased production of TNFα by endothelial and inflammatory cells activates hepatocyte-specific NF-κB signaling, thus highlighting the role of TNFα signaling in orchestrating spontaneous HCC development. Moreover, in major urinary protein (MUP)-urokinase-type plasminogen activator (uPA) transgenic mice, a model for ER and transient liver stress, blocking of TNFα and hepatic TNFR1 signaling prevents nonalcoholic steatohepatitis (NASH) in obese mice. Notably, the progression of NASH to HCC is driven by TNFR1 signaling within hepatocytes, which activate protumorigenic NF-κB signaling.

13During obesity-driven, low-grade inflammation, hepatic NF-κB serves as an antiapoptotic survival factor, which promotes the proliferation of HCC progenitor cells and HCC development. In contrast, hepatic inactivation of IKK2 increases diethylnitrosamine (DEN)-induced HCC burden. In line with this evidence, hepatic NEMO deficiency causes spontaneous progression of TNFα-mediated chronic hepatitis to HCC. This detrimental effect of hepatic NEMO deficiency is potentiated under obese conditions presumably by enhanced liver inflammation and hepatic lipid accumulation. This supports the notion that NEMO acts as a tumor suppressor in the liver. Surprisingly, hepatic NEMO-deficient mice are protected against diet-induced obesity and exhibit improved insulin sensitivity. A recent report demonstrated that NEMO prevents hepatocarcinogenesis via inhibiting RIP1 kinase-activity-driven hepatocyte apoptosis.

14Another TNFα-induced NF-κB activator is interferon gamma (IFNγ). It was shown that TNFα and IFNγ synergistically induce the expression of ubiquitous antiapoptotic B7-H1 receptors on HCC cells via JAK/STAT/interferon regulatory factor 1 signaling, thereby enhancing adaptive immune resistance and facilitating HCC growth.. Importantly, A20, also known as TNFα-induced protein 3 (TNFAIP3), a key regulator of inflammation and terminator of NF-κB signaling, reduces hepatic inflammation and cancer onset by protecting hepatocytes from TNFα-induced apoptosis under obese conditions. Thus, hepatic NF-κB signaling might play a dual role in hepatocarcinogenesis. While in principle, NF-κB in hepatocytes is required for protection against TNFα-induced cell death, which is accelerated in obesity, the compensatory proliferation of neighboring hepatocytes promotes hepatocarcinogenesis presumably via activation of other TNFα-activated signaling pathways such as JNK.

15JNKs are not only activated by TNFα, but also by FFA, which are highly abundant during overnutrition or as a consequence of excessive ceramide synthesis. Thereby, JNK induces hepatocyte lipoapoptosis by activating proapoptotic Bcl-2 proteins and triggering the mitochondrial apoptotic pathway. Hui and colleagues reported that cancer cell proliferation decreases significantly in JNK1-deficient mice and that this reduction requires JNK-dependent p21 downregulation. Interestingly, HCC progression seems to require JNK function in nonparenchymal liver cells, whereas compound deficiency of hepatocyte JNK1 and JNK2 did not prevent HCC development. This finding is further emphasized by a study demonstrating that myeloid-specific JNK deficiency reduces the expression of inflammatory cytokines and hepatic infiltration of immune cells, thereby suppressing the development of HCC. In line with these findings, hepatic NF-κB blockade and hepatic TAK1 deficiency lead to spontaneous progression from hepatic inflammation to liver tumors. This implicates tightly controlled feedback mechanisms of both TNFα-activated pathways to prevent cancer. Taken together, TNFα-activated IKK and JNK signaling are increased in the liver upon obesity, thereby revealing their dysregulation and combined oncogenic potential in obese patients.

16TNFα and NF-κB signaling promote cancer progression by facilitating cell migration, invasion, and metastasis. Metastasis requires extracellular matrix degradation and basement membrane destruction executed by matrix metalloproteinases (MMP), namely MMP-3 and MMP-13. TNFα increases the expression of MMP-3 and MMP-13 in HepG2 cells and enhances cancer cell migration by activation of the extracellular signal-regulated kinase/ NF-κB pathways. Furthermore, reactive oxygen species (ROS) such as superoxide anion, a byproduct of respiration and a secondary messenger, have been demonstrated to drive migration. In addition, disruption of the equilibrium between ROS generation and antioxidant defense leads to oxidative stress, which induces liver DNA damage and promotes neoplastic transformations of hepatocytes TNFα-induced ROS production by complex I and complex III of the mitochondrial respiratory chain activates NF-κB signaling, thereby enhancing cell migration. Metastasis is promoted by activated macrophages in the tumor microenvironment releasing TNFα and thereby driving metastasis. Finally, NF-κB is accompanied by vascular endothelial growth factor (VEGF) expression, which drives cancer progression by inducing vascularization. In summary, the interplay of all these factors creates a tumor microenvironment that supports the transformation of hepatocytes, which ensures their survival and evasion from immune surveillance via antiapoptotic pathways.

4. Hepatic IL-6 Signaling: Cytokine with Versatile Functions

17The pleiotropic glycoprotein IL-6 is an important signaling molecule in the activation of the immune system in response to infections and systemic inflammation. IL-6 activates T cells, promotes B cell differentiation, and regulates the acute-phase response in the liver. It also affects lipid metabolism, insulin resistance, and mitochondrial activity. IL-6 further plays a role in vascular diseases, the neuroendocrine system, as well as neuropsychological behavior, hence, emphasizing the pleiotropic characteristics of this cytokine. Moreover, IL-6 was shown to maintain chronic inflammation and thus promotes disease progression, for example, autoimmune encephalomyelitis, arthritis, pristine-induced lupus, plasmacytomas, and various cancers including HCC.

18The expression of IL-6 is induced by TNFα and IL-1. Furthermore, the Toll-like receptors, prostaglandins, adipokines, stress responses, and others are also involved in the induction of IL-6 expression. The canonical IL-6 signaling pathway is transduced through the IL-6Rα (Figure 2), a transmembrane receptor found on hepatocytes, macrophages, T-lymphocytes, and endothelial cells. For signal transduction, the IL-6Rα alone is not sufficient, but the ubiquitously expressed GP130 receptor molecule is necessary to induce downstream signaling. Binding of IL-6 to the IL-6Rα chain recruits two GP130 chains, which activates JAK/STAT pathways. JAK phosphorylates five tyrosine residues of GP130 and thereby induces intracellular signaling cascades including STAT3, phosphoinositide-3-kinase (PI3K)/ protein kinase B (AKT), and mitogen-activated protein kinase (MAPK). Besides the membrane-bound IL-6Rα, a soluble form (sIL-6Rα), which induces IL-6 trans-signaling, has been described. In humans, the sIL-6Rα is either produced by alternative splicing or by A disintegrin and metalloproteinase domain 10 (ADAM10)- and ADAM17-mediated shedding of the membrane-bound receptor; the latter has also been seen in mice. Through association of IL-6 with sIL-6Rα, this complex can directly bind to ubiquitously expressed GP130 receptors on the cell membrane, enabling IL-6 stimulation of cells, which do not express the membrane-bound IL-6Rα.

19Various cell types express the IL-6Rα, but the cell-specific effects of IL-6 signaling differ depending on the target cells. Under nonpathological conditions, deficiency of hepatic IL-6 signaling was shown to impair insulin sensitivity and glucose tolerance via accelerated TNFα expression. Moreover, previous studies focusing on IL-6 signaling in immune cells attribute IL-6 an important role in the control of macrophage polarization, favoring the anti-inflammatory M2 state. IL-6 signaling in NK cells was shown to drive their reprogramming into cells with myeloid gene expression and thereby impair insulin action in obesity.

5. IL-6 Signaling: A Fatal Player in Obesity-Induced HCC

20Lack of IL-6 results in impaired immune responses after viral, parasitic, and bacterial infections, as well as impaired liver regeneration after injury. Thus, IL-6 regulates, amongst others, acute phase responses and liver regeneration, resulting in dramatically increased IL-6 serum levels upon states of infection, inflammation, and liver damage.

21IL-6 is increased in diabetes, obesity, and various cancers. Elevated IL-6 serum levels strongly correlate with increased risk to develop HCC and vice versa; serum IL-6 and sIL-6Rα levels are elevated in patients suffering from HCC. The risk of developing HCC is decreased in female mice due to increased estrogen receptor signaling, which inhibits IL-6 expression, emphasizing an important role of IL-6 signaling in HCC. In consistency, whole body IL-6, IL-6Rα, and hepatic GP130 deficiency result in a significant decrease in DEN-induced HCC burden in mice. In these knockout animals, reduced STAT3 activation is observed which results in altered gene expression of various genes involved in the regulation of proliferation, apoptosis, and fibrosis. Park and colleagues demonstrated that IL-6-deficient animals are protected from DEN-induced HCC under lean and obese conditions due to accelerated hepatic apoptosis. In line with this evidence, deficiency of the IL-6Rα causes destabilization of the antiapoptotic molecule myeloid leukemia cell differentiation protein (MCL1), thereby resulting in reduced HCC burden in lean mice. Specifically, IL-6 signaling inhibits the expression of molecules like protein phosphatase 1 catalytic subunit alpha (PP1CA), which is required for the activation of glycogen synthase kinase 3 beta (GSK3β). GSK3β marks MCL1 for degradation, resulting in the activation of apoptosis. Gene expression of Mcl1 ubiquitin ligase E3 is also inhibited by STAT3. Therefore, inhibition of IL-6 signaling induces apoptosis through degradation of MCL1. However, IL-6Rα deficiency only sensitized lean, but not obese, livers to apoptosis. Therefore, obesity might induce another STAT3-activating factor that compensates for IL-6Rα deficiency. Recently, we have shown that hepatocytes from obese and from IL-6Rα-deficient mice increase their leptin receptor (Lepr) expression, implying a compensatory role of leptin signaling. Ultimately, deletion of hepatic LepR in IL-6Rα-deficient mice further ameliorates DEN-induced HCC development, implicating that downstream STAT3 inhibition might be a pivotal strategy to prevent hepatocarcinogenesis in humans. In line with our results, a recent study by Grohmann and colleagues demonstrated increased hepatic pSTAT3 levels in obese mice and humans. Importantly, they identified STAT3 as the driver of HCC progression in obesity, whereas obesity-driven NASH and fibrosis depend on STAT1. Taken together, these results highlight the crucial role of STAT3 signaling in obesity-associated HCC development and progression.

22In addition to classical IL-6 signaling, IL-6 trans-signaling was identified as a major driver of HCC through blocking p53-induced apoptosis and enhancing angiogenesis by inducing endothelial cell proliferation and tumor development. Besides blocking apoptosis, IL-6 promotes HCC progression by upregulating osteopontin (OPN), a secretory extracellular matrix protein involved in stem cell maintenance and metastasis.

23Another important factor in tumor development is angiogenesis, which ensures the required nutrient supply during tumor growth. IL-6 downstream signaling through STAT3 activates hypoxia-inducible factor 1- α (HIF-1α) and VEGF. Niu et al., reported that tumor cells transfected with a constitutive active STAT3 mutant increases Vegf expression and enhances tumor angiogenesis after implantation into mice. Thus, the pleiotropic nature of IL-6-induced STAT3 activation sets multiple starting points for therapeutic intervention.

24IL-6 downstream signaling also involves activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade and Villanueva and colleagues observed overactivated mTOR signaling in 50% of human HCC samples. In line with this evidence, another study in human HCC linked activated mTOR signaling to poor prognosis and survival of HCC patients, suggesting an important role of PI3K/AKT/mTOR signaling in HCC progression. Supporting the importance of mTOR activation during HCC progression, a previous study in mice showed that chronic activation of mTOR causes HCC. mTOR indirectly activates eukaryotic translation initiation factor 4E (eIF4e), a molecule that is part of the eIF4F complex. eIF4e regulates translational control of mRNAs involved in proliferation and antiapoptotic pathways and is thereby highly associated with tumorigenesis. However, whether these effects can also be linked directly to upstream IL-6 signaling remains to be elucidated. Taken together, IL-6 signaling has a pivotal role in HCC development and progression. However, given the complex downstream signaling pathways, which are activated by IL-6, some contributing factors still remain elusive.

6. Obesity Disturbs the Balance of Inflammatory Effectors and Inhibitors

25The activation of the IL-6 signaling pathway in hepatocytes is tightly regulated and the reaction to acute IL-6 signaling is quickly diminished due to negative feedback loops. Consequently, deficiencies in these negative feedback loops lead to an aberrant STAT3 activation to promote oncogenic transformation. Chronic inflammation in obesity disturbs the balance of inflammation effectors and their inhibitors, which might play a fundamental role in HCC development. In line with this, obese mice exhibit elevated basal activation of STAT3, but react poorly to acute IL-6.

26Excessive IL-6 signaling can be controlled through JAK/STAT degradation or inhibition by at least three different protein families. Besides SOCS proteins and src-homology 2 (SH2)-containing phosphatase (SHP-1), protein inhibitors of activated STAT (PIAS) inhibit STAT signal transduction. Chung et al., identified PIAS3 as a specific and direct inhibitor of STAT3, but not STAT1. PIAS proteins are constitutively expressed in the cell and do not terminate cytokine-induced signaling. Thus, it is assumed that PIAS3 rather fine-tunes STAT3 activation instead of serving as a classic negative feedback regulator. In contrast, SHP-1 acts in a classical negative feedback loop: upon JAK2 activation through IL-6, JAK2 phosphorylates GP130 at tyrosine residues that serve as docking sites for STAT3. However, the phosphorylation sites within GP130 are also recognized and dephosphorylated by SHP-1 to reduce the catalytic activity of JAK2 directly. In fact, SHP-1 is known to exert tumor-suppressive function in HCC. While SHP-1 seems to be constitutively expressed in cells and instantly inhibits JAK-mediated signaling, SOCS protein expression is directly induced via STAT transcription factors and consequently its suppressive effect is delayed. This allows for time-restricted, IL-6-induced signaling. Furthermore, SHP-1 is involved in the regulation of other signaling pathways, whereas SOCS proteins act more specifically.

27SOCS1-7 and cytokine-induced SH2-containing protein (CIS) are the eight members of the classic SOCS protein family. However, IL-6 signaling induces only the expression of SOCS1 and SOCS3. Overexpression studies discovered a crucial role for SOCS3 and SOCS1 in IL-6 signaling regulation in vitro. In contrast, Croker et al., claim that SOCS1 and SOCS3 are functionally not redundant in terms of IL-6 regulation in vivo. In particular, SOCS1 regulates IFNγ activity and SOCS3 specifically controls IL-6 signaling. Despite little sequence similarities of the N-terminal region, SOCS1 and SOCS3 share multiple common features. All eight members share the central SH2 domain, a conserved carboxyl-terminal region, and a conserved SOCS box. However, a unique feature of SOCS1 and SOCS3 is the kinase inhibitor region (KIR) that acts as a noncompetitive suppressor of the JAK2 tyrosine kinase. Through their SH2 domain, SOCS1 and SOCS3 mediate the direct inhibition of JAK activity or competitively block the access of STAT to phosphorylated tyrosines on the GP130 receptor. SOCS3 binds to phosphorylated tyrosine Y757 on the receptor subunit GP130 through its SH2 domain. Based on a three-dimensional model, SOCS1 is predicted to directly interact with JAK2 and inhibit its catalytic activity. Furthermore, the SOCS box of SOCS1 and SOCS3 mediates the interaction with elongins B and C to connect them with the ubiquitin transferase system. Therefore, SOCS proteins can act as E3 ubiquitin ligases and mediate the degradation of their target proteins such as IRS1 (Figure 2). Phosphorylation of the SOCS box leads to the degradation of SOCS protein itself, which is necessary to resensitize the IL-6 signaling pathway for acute signaling.

28A disturbance in the balance of inflammatory effectors and their inhibitors can have severe consequences. Mice lacking SOCS1 die before weaning due to dysregulated IFNγ signaling, which causes severe systemic inflammation. Conventional deletion of SOCS3 leads to lethality within 11–13 days of gestation as a result of placental defects. In HCC cell lines and HCC patient samples, SOCS1 and SOCS3 expression is reduced, caused by aberrant methylation of CpG island in their loci. Moreover, hepatic SOCS3 deletion results in enhanced chemical-induced fibrosis due to elevated STAT3 activation, which is accompanied with increased TGF-β1 promoting fibrosis. Besides beneficial effects, chronic activation of STAT3 in obesity leads to constant expression of its own inhibitor, SOCS3, disrupting the homeostasis of the IL-6 signaling pathway. Elevated SOCS1 and SOCS3 protein levels impair insulin action by mediating the ubiquitination of IRS1 and its degradation. This in turn contributes to the development of obesity-associated insulin resistance in peripheral organs. In consistency, we identified increased basal activation of STAT3 in hepatocytes from obese mice causing a diminished responsiveness to acute IL-6. Thus, elevated hepatic SOCS3 levels in obesity impair both insulin and IL-6 signaling, thereby inducing a vicious cycle that might ultimately lead to cancer.

29Collectively, obesity-associated increases of systemic TNFα and IL-6 might impact HCC initiation and progression via redundant and opposing functions of downstream signaling molecules. Therefore, further detailed analyses of signaling capacities in obesity and HCC are required to develop novel approaches to combat this fatal disease.

7. Obesity-Induced Inflammation and CRC

30Besides HCC, cancer entities of the colon and rectum, colorectal cancer (CRC), also display an elevated burden in obese patients. CRC is the third most common diagnosed cancer type in males and in females, accounting for 9% and 8% of all cancer-related deaths, respectively. Up to 95% of newly diagnosed CRC patients do not carry genetic predispositions, but share common risk factors including age, inflammatory bowel diseases (IBD), and an unhealthy Western lifestyle. In IBD patients, the risk to develop colitis-associated colorectal cancer (CAC) is increased up to 20%, indicating a correlation between the degree of colonic inflammation and CAC risk. A Western lifestyle, characterized by low physical activity, high caloric intake, and excessive smoking, as well as alcohol consumption, favors the development of CRC. Epidemiological studies established a strong correlation between obesity and incidence, as well as morbidity of CRC. Remarkably, all risk factors—age, IBDs, Western lifestyle—elevate the inflammatory tone not only systemically but also locally in the colon. This inflammation can not only enable but also promote tumor development by causing genomic instability and mutations.

31The capacity of obesity to induce spontaneous CRC development has been supported by genetic mouse models of CRC development. In the commonly used adenomatosis polyposis coli (APC) model for spontaneous and inherited CRC development, obese APCMin/+ mice developed significantly higher numbers of colorectal carcinomas than lean APCMin/+ mice. Furthermore, activated K-rat sarcoma (K-ras) signaling led to increased tumor burden in obese KrasG12Dint mice, due to a shift in microbiota composition. This was accompanied by increased invasiveness and metastasizing capacities.

32Long-term, high-fat diet-feeding alone is already sufficient to induce spontaneous CRC development in C57BL/6 mice. Additionally, diet-induced obesity elevates the tumor burden after chemical induction of CAC. Gulhane et al., showed that diet-induced obesity was accompanied with disruption of the intestinal barrier function by reduced expression of mucus-encoding genes and decreased expression of genes encoding tight junctional proteins. Moreover, Ahmad et al., reported an expression switch of Claudin genes, integral components of the tight junctions, that resulted in increased permeability of the colonic epithelium in high-fat diet-fed C57BL/6 mice. In the colon, the cell junctional network generates a physical barrier against invading commensal bacteria. Impairment of the intestinal barrier function due to decreased expression of tight junctional proteins results in increased paracellular permeability and translocation of commensal bacteria into the underlying lamina propia, where they evoke an inflammatory response and elevated expression of proinflammatory cytokines. Specifically, diet-induced obesity increases the expression of Tnfα in the colons of mice, most likely as a direct consequence of intestinal barrier defects. In line, obese patients exhibit higher circulating endotoxin levels together with higher circulating proinflammatory cytokines, like TNFα and IL-6. Increased levels of circulating proinflammatory cytokines can ultimately drive CRC development and progression. Data from patients suffering from IBD, such as colitis ulcerosa and Crohn‘s disease, support the link between inflammation and CRC/CAC development via increased circulating TNFα and IL-6 levels. Of note, Izano et al., failed to find a significant association between CRC and increased IL-6 and TNFα levels.

33Supporting the importance of increased TNFα and IL-6 in CRC/CAC, TNFR1-, IL-6-, IL-6Rα-deficient mice have reduced mucosal damage, infiltration of macrophages and neutrophils, and consequently less tumors. This indicates that TNFα and IL-6 signaling promote carcinogenesis and CRC progression in the colon. In contrast, genetic ablation of Tnf in APCMin/+ mice exposed to dextran sulfate sodium in the drinking water does not lead to less tumor development. Although, under acute colitis conditions induced by dextran sulfate sodium, TNF-deficient mice and mice treated with anti-TNF exhibit enhanced intestinal inflammation, whereas, in mice with chronic inflammation, anti-TNF treatment reduces colitis.

34However, caloric restriction or reduction of TNFα and IL-6 leads to reduced tumor development in humans and mice by reducing colorectal inflammation. In line, recent CAC studies in mice demonstrate that enriching high-fat diets with TNF- and IL-6-inhibiting supplements leads to the reduction of inflammation and mucosal injury in the colons of mice and ultimately to less tumor development. Similar effects on tumor burden are seen by reducing obesity-induced inflammation via natural substances in the diets of obese APCMin/+ mice.

35Increased TNFα levels are detected in the microenvironment of CRC and vice versa in mouse models for CAC development; TNFα levels are linked with increased leukocyte infiltration and tumor formation. Inactivation of TNFR1 results in reduced tumor burden and transplantation of TNF-Rp55-deficent bone marrow into wild type recipients leads to less tumor development in the CAC model. This indicates that it is not the tumor cells which depend on TNFα signaling, but rather immune cells derived from the bone marrow. In this line, depletion of IKKβ in myeloid cells reduces tumor size and inflammation in CAC. TNFα and TNFR1 are mainly expressed by infiltrating immune cells, but not in the epithelial cells, supporting that TNFα activates NF-κB in inflammatory cells causing colonic inflammation and thereby promoting carcinogenesis.

36Interestingly, the effects of obesity promoting cancer can even be transmitted to the next generation. Maternal high-fat diet consumption enhances offspring susceptibility to dextran sulfate sodium-induced colitis in mice accompanied with upregulated NF-κB signaling, enhanced neutrophil infiltration, and elevated IL-6 levels, thereby further revealing TNFα and IL-6 as ideal targets for CRC therapies.

37In contrast to TNFα, IL-6 is a TNFα/ NF-κB-regulated cytokine that acts on epithelial and immune cells. IL-6 is increased in the serum of CRC patients and impacts tumor grade and survival rate. Moreover, IL-6 promotes CAC development partly via its action on intestinal epithelial cells. Consistently, a higher number of pSTAT3-expressing epithelial cells are found in CAC patients. Inactivation of IL-6 or the IL-6Rα in mice reduces tumor formation in the CAC mouse model. However, mice deficient in intestinal IL-6Rα have a similar tumor load compared to control mice. This indicates that IL-6 is not the major signaling pathway in the intestinal epithelium promoting intrinsic tumor growth via STAT3. Rather, IL-6 acts on immune cells in the tumor microenvironment to promote inflammation and tumor growth. Blunting of IL-6 signaling in macrophages reduces tumor development in the CAC mouse model. We and others have shown that IL-6Rα-deficient macrophages stay in the proinflammatory M1 state, while obesity-induced IL-6 shifts macrophage polarization towards the tumor-promoting M2 state. In turn, these M2 macrophages secrete the chemokine CC-chemokine ligand-20 (CCL-20). In detail, CCL-20 recruits CC-chemokine receptor-6 (CCR-6)-expressing immune cells via chemotaxis into the tumor microenvironment, further driving colonic inflammation and CAC development.

38Taken together, these studies demonstrate that TNFα and IL-6, either induced by obesity or the colonic tumor microenvironment, exert their function mainly on infiltrating immune cells and, to a lesser extent, on intestinal cells to promote CRC. Therefore, future studies will be required to pinpoint exact signaling pathways in obesity and cancer that are amenable for cancer therapy.

8. Conclusions

39The obesity epidemic is expected to still rise during the next years, and the prevalence of obesity-associated cancer, as well as its treatment expenses, will increase, representing enormous socioeconomic efforts. Given that inflammatory pathways can exert redundant or opposing functions depending on context and cell type, future studies will be required to define exact signaling pathways that contribute to obesity and cancer and are amenable for anticancer therapies.

References 208

1.
Hotamisligil G.S., Shargill N.S., Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science. 1993;259:87-91.
Not in our library10.1126/science.7678183
2.
Hotamisligil G.S., Peraldi P., Budavari A., Ellis R., White M.F., Spiegelman B.M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271:665-668.
Not in our library10.1126/science.271.5249.665
3.
Wellen K.E., Hotamisligil G.S. Inflammation, stress, and diabetes. J. Clin. Investig. 2005;115:1111-1119.
Not in our library10.1172/jci25102
4.
Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L., Ferrante A.W. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 2003;112:1796-1808.
Not in our library10.1172/jci200319246
5.
Xu H., Barnes G.T., Yang Q., Tan G., Yang D., Chou C.J., Sole J., Nichols A., Ross J.S., Tartaglia L.A., et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Investig. 2003;112:1821-1830.
Not in our library10.1172/jci200319451
6.
Jais A., Bruning J.C. Hypothalamic inflammation in obesity and metabolic disease. J. Clin. Investig. 2017;127:24-32.
Not in our library10.1172/jci88878
7.
Cancello R., Tordjman J., Poitou C., Guilhem G., Bouillot J.L., Hugol D., Coussieu C., Basdevant A., Bar Hen A., Bedossa P., et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes. 2006;55:1554-1561.
Not in our library10.2337/db06-0133
8.
Caspar-Bauguil S., Cousin B., Bour S., Casteilla L., Penicaud L., Carpene C. Adipose tissue lymphocytes: Types and roles. J. Physiol. Biochem. 2009;65:423-436.
Not in our library10.1007/bf03185938
9.
Macrophage function in obesity-induced inflammation and insulin resistance · 2017
No notice
10.
Murano I., Barbatelli G., Parisani V., Latini C., Muzzonigro G., Castellucci M., Cinti S. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J. Lipid Res. 2008;49:1562-1568.
Not in our library10.1194/jlr.m800019-jlr200
11.
Mantovani A., Sica A., Sozzani S., Allavena P., Vecchi A., Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677-686.
Not in our library10.1016/j.it.2004.09.015
12.
Revelo X.S., Luck H., Winer S., Winer D.A. Morphological and inflammatory changes in visceral adipose tissue during obesity. Endocr. Pathol. 2014;25:93-101.
Not in our library10.1007/s12022-013-9288-1
13.
Wensveen F.M., Jelencic V., Valentic S., Sestan M., Wensveen T.T., Theurich S., Glasner A., Mendrila D., Stimac D., Wunderlich F.T., et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 2015;16:376-385.
Not in our library10.1038/ni.3120
14.
Theurich S., Tsaousidou E., Hanssen R., Lempradl A.M., Mauer J., Timper K., Schilbach K., Folz-Donahue K., Heilinger C., Sexl V., et al. IL-6/Stat3-Dependent Induction of a Distinct, Obesity-Associated NK Cell Subpopulation Deteriorates Energy and Glucose Homeostasis. Cell Metab. 2017;26:171-184.e6.
Not in our library10.1016/j.cmet.2017.05.018
15.
Nishimura S., Manabe I., Nagasaki M., Eto K., Yamashita H., Ohsugi M., Otsu M., Hara K., Ueki K., Sugiura S., et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 2009;15:914-920.
Not in our library10.1038/nm.1964
16.
Winer S., Chan Y., Paltser G., Truong D., Tsui H., Bahrami J., Dorfman R., Wang Y., Zielenski J., Mastronardi F., et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 2009;15:921-929.
Not in our library10.1038/nm.2001
17.
Feuerer M., Herrero L., Cipolletta D., Naaz A., Wong J., Nayer A., Lee J., Goldfine A.B., Benoist C., Shoelson S., et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 2009;15:930-939.
Not in our library10.1038/nm.2002
18.
DeFuria J., Belkina A.C., Jagannathan-Bogdan M., Snyder-Cappione J., Carr J.D., Nersesova Y.R., Markham D., Strissel K.J., Watkins A.A., Zhu M., et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc. Natl. Acad. Sci. USA. 2013;110:5133-5138.
Not in our library10.1073/pnas.1215840110
19.
Lee M.K., Yvan-Charvet L., Masters S.L., Murphy A.J. The modern interleukin-1 superfamily: Divergent roles in obesity. Semin. Immunol. 2016;28:441-449.
Not in our library10.1016/j.smim.2016.10.001
20.
Rajbhandari P., Thomas B.J., Feng A.C., Hong C., Wang J., Vergnes L., Sallam T., Wang B., Sandhu J., Seldin M.M., et al. IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure. Cell. 2018;172:218-233.e7.
Not in our library10.1016/j.cell.2017.11.019
21.
Garidou L., Pomie C., Klopp P., Waget A., Charpentier J., Aloulou M., Giry A., Serino M., Stenman L., Lahtinen S., et al. The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORgammat and Controls Metabolic Disease. Cell Metab. 2015;22:100-112.
Not in our library10.1016/j.cmet.2015.06.001
22.
Chang E.Y., Guo B., Doyle S.E., Cheng G. Cutting edge: Involvement of the type I IFN production and signaling pathway in lipopolysaccharide-induced IL-10 production. J. Immunol. 2007;178:6705-6709.
Not in our library10.4049/jimmunol.178.11.6705
23.
T cell-intrinsic role of IL-6 signaling in primary and memory responses · 2014
No notice
24.
Peraldi P., Hotamisligil G.S., Buurman W.A., White M.F., Spiegelman B.M. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J. Biol. Chem. 1996;271:13018-13022.
Not in our library10.1074/jbc.271.22.13018
25.
Vandenabeele P., Declercq W., Beyaert R., Fiers W. Two tumour necrosis factor receptors: Structure and function. Trends Cell Biol. 1995;5:392-399.
Not in our library10.1016/s0962-8924(00)89088-1
26.
Aguirre V., Uchida T., Yenush L., Davis R., White M.F. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J. Biol. Chem. 2000;275:9047-9054.
Not in our library10.1074/jbc.275.12.9047
27.
Gao Z., Hwang D., Bataille F., Lefevre M., York D., Quon M.J., Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J. Biol. Chem. 2002;277:48115-48121.
Not in our library10.1074/jbc.m209459200
28.
Hirosumi J., Tuncman G., Chang L., Gorgun C.Z., Uysal K.T., Maeda K., Karin M., Hotamisligil G.S. A central role for JNK in obesity and insulin resistance. Nature. 2002;420:333-336.
Not in our library10.1038/nature01137
29.
Copps K.D., Hancer N.J., Opare-Ado L., Qiu W., Walsh C., White M.F. Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab. 2010;11:84-92.
Not in our library10.1016/j.cmet.2009.11.003
30.
Rui L., Yuan M., Frantz D., Shoelson S., White M.F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 2002;277:42394-42398.
Not in our library10.1074/jbc.c200444200
31.
Sachithanandan N., Fam B.C., Fynch S., Dzamko N., Watt M.J., Wormald S., Honeyman J., Galic S., Proietto J., Andrikopoulos S., et al. Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity. Hepatology. 2010;52:1632-1642.
Not in our library10.1002/hep.23861
32.
Mauer J., Chaurasia B., Goldau J., Vogt M.C., Ruud J., Nguyen K.D., Theurich S., Hausen A.C., Schmitz J., Bronneke H.S., et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 2014;15:423-430.
Not in our library10.1038/ni.2865
33.
Wunderlich F.T., Strohle P., Konner A.C., Gruber S., Tovar S., Bronneke H.S., Juntti-Berggren L., Li L.S., van Rooijen N., Libert C., et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 2010;12:237-249.
Not in our library10.1016/j.cmet.2010.06.011
34.
Xu E., Pereira M.M.A., Karakasilioti I., Theurich S., Al-Maarri M., Rappl G., Waisman A., Wunderlich F.T., Bruning J.C. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nat. Commun. 2017;8:14803.
Not in our library10.1038/ncomms14803
35.
Chronic Inflammation and Cytokines in the Tumor Microenvironment · 2014
No notice
36.
Bhaskaran K., Douglas I., Forbes H., dos-Santos-Silva I., Leon D.A., Smeeth L. Body-mass index and risk of 22 specific cancers: A population-based cohort study of 5.24 million UK adults. Lancet. 2014;384:755-765.
Not in our library10.1016/s0140-6736(14)60892-8
37.
Calle E.E., Rodriguez C., Walker-Thurmond K., Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003;348:1625-1638.
Not in our library10.1056/nejmoa021423
38.
Calle E.E., Kaaks R. Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer. 2004;4:579-591.
Not in our library10.1038/nrc1408
39.
Van T.M., Polykratis A., Straub B.K., Kondylis V., Papadopoulou N., Pasparakis M. Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis. J. Clin. Investig. 2017;127:2662-2677.
Not in our library10.1172/jci92508
40.
Ehlken H., Krishna-Subramanian S., Ochoa-Callejero L., Kondylis V., Nadi N.E., Straub B.K., Schirmacher P., Walczak H., Kollias G., Pasparakis M. Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout. Cell Death Differ. 2014;21:1721-1732.
Not in our library10.1038/cdd.2014.83
41.
Lang I., Fullsack S., Wyzgol A., Fick A., Trebing J., Arana J.A., Schafer V., Weisenberger D., Wajant H. Binding Studies of TNF Receptor Superfamily (TNFRSF) Receptors on Intact Cells. J. Biol. Chem. 2016;291:5022-5037.
Not in our library10.1074/jbc.m115.683946
42.
Micheau O., Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181-190.
Not in our library10.1016/s0092-8674(03)00521-x
43.
NF-κB signaling in inflammation · 2017
No notice
44.
Luedde T., Schwabe R.F. NF-kappaB in the liver—Linking injury, fibrosis and hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2011;8:108-118.
Not in our library10.1038/nrgastro.2010.213
45.
The complexity of NF-κB signaling in inflammation and cancer · 2013
No notice
46.
Lin A. Activation of the JNK signaling pathway: Breaking the brake on apoptosis. Bioessays. 2003;25:17-24.
Not in our library10.1002/bies.10204
47.
Sun B., Karin M. Inflammation and liver tumorigenesis. Front. Med. 2013;7:242-254.
Not in our library10.1007/s11684-013-0256-4
48.
Yoshioka Y., Hashimoto E., Yatsuji S., Kaneda H., Taniai M., Tokushige K., Shiratori K. Nonalcoholic steatohepatitis: Cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J. Gastroenterol. 2004;39:1215-1218.
Not in our library10.1007/s00535-004-1475-x
49.
Fausto N. Mouse liver tumorigenesis: Models, mechanisms, and relevance to human disease. Semin. Liver Dis. 1999;19:243-252.
Not in our library10.1055/s-2007-1007114
50.
Knight B., Yeoh G.C., Husk K.L., Ly T., Abraham L.J., Yu C., Rhim J.A., Fausto N. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J. Exp. Med. 2000;192:1809-1818.
Not in our library10.1084/jem.192.12.1809
51.
Park E.J., Lee J.H., Yu G.Y., He G., Ali S.R., Holzer R.G., Osterreicher C.H., Takahashi H., Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197-208.
Not in our library10.1016/j.cell.2009.12.052
52.
Pikarsky E., Porat R.M., Stein I., Abramovitch R., Amit S., Kasem S., Gutkovich-Pyest E., Urieli-Shoval S., Galun E., Ben-Neriah Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461-466.
Not in our library10.1038/nature02924
53.
Nakagawa H., Umemura A., Taniguchi K., Font-Burgada J., Dhar D., Ogata H., Zhong Z., Valasek M.A., Seki E., Hidalgo J., et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26:331-343.
Not in our library10.1016/j.ccr.2014.07.001
54.
Kucharczak J., Simmons M.J., Fan Y., Gelinas C. To be, or not to be: NF-kappaB is the answer--role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene. 2003;22:8961-8982.
Not in our library10.1038/sj.onc.1207230
55.
Maeda S., Kamata H., Luo J.L., Leffert H., Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121:977-990.
Not in our library10.1016/j.cell.2005.04.014
56.
Cubero F.J., Singh A., Borkham-Kamphorst E., Nevzorova Y.A., Al Masaoudi M., Haas U., Boekschoten M.V., Gassler N., Weiskirchen R., Muller M., et al. TNFR1 determines progression of chronic liver injury in the IKKgamma/Nemo genetic model. Cell Death Differ. 2013;20:1580-1592.
Not in our library10.1038/cdd.2013.112
57.
Wunderlich F.T., Luedde T., Singer S., Schmidt-Supprian M., Baumgartl J., Schirmacher P., Pasparakis M., Bruning J.C. Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc. Natl. Acad. Sci. USA. 2008;105:1297-1302.
Not in our library10.1073/pnas.0707849104
58.
Kondylis V., Polykratis A., Ehlken H., Ochoa-Callejero L., Straub B.K., Krishna-Subramanian S., Van T.M., Curth H.M., Heise N., Weih F., et al. NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. Cancer Cell. 2015;28:830.
Not in our library10.1016/j.ccell.2015.11.007
59.
Wesemann D.R., Benveniste E.N. STAT-1 alpha and IFN-gamma as modulators of TNF-alpha signaling in macrophages: Regulation and functional implications of the TNF receptor 1:STAT-1 alpha complex. J. Immunol. 2003;171:5313-5319.
Not in our library10.4049/jimmunol.171.10.5313
60.
Li N., Wang J., Zhang N., Zhuang M., Zong Z., Zou J., Li G., Wang X., Zhou H., Zhang L., et al. Cross-talk between TNF-alpha and IFN-gamma signaling in induction of B7-H1 expression in hepatocellular carcinoma cells. Cancer Immunol. Immunother. CII. 2018;67:271-283.
Not in our library10.1007/s00262-017-2086-8
61.
Chen H., Hu L., Luo Z., Zhang J., Zhang C., Qiu B., Dong L., Tan Y., Ding J., Tang S., et al. A20 suppresses hepatocellular carcinoma proliferation and metastasis through inhibition of Twist1 expression. Mol. Cancer. 2015;14:186.
Not in our library10.1186/s12943-015-0454-6
62.
Catrysse L., Farhang Ghahremani M., Vereecke L., Youssef S.A., Mc Guire C., Sze M., Weber A., Heikenwalder M., de Bruin A., Beyaert R., et al. A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death. Cell Death Dis. 2016;7:e2250.
Not in our library10.1038/cddis.2016.154
63.
Malhi H., Bronk S.F., Werneburg N.W., Gores G.J. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J. Biol. Chem. 2006;281:12093-12101.
Not in our library10.1074/jbc.m510660200
64.
Holland W.L., Brozinick J.T., Wang L.P., Hawkins E.D., Sargent K.M., Liu Y., Narra K., Hoehn K.L., Knotts T.A., Siesky A., et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 2007;5:167-179.
Not in our library10.1016/j.cmet.2007.01.002
65.
Hui L., Zatloukal K., Scheuch H., Stepniak E., Wagner E.F. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J. Clin. Investig. 2008;118:3943-3953.
Not in our library10.1172/jci37156
66.
Das M., Garlick D.S., Greiner D.L., Davis R.J. The role of JNK in the development of hepatocellular carcinoma. Genes Dev. 2011;25:634-645.
Not in our library10.1101/gad.1989311
67.
Han M.S., Barrett T., Brehm M.A., Davis R.J. Inflammation Mediated by JNK in Myeloid Cells Promotes the Development of Hepatitis and Hepatocellular Carcinoma. Cell Rep. 2016;15:19-26.
Not in our library10.1016/j.celrep.2016.03.008
68.
Bettermann K., Vucur M., Haybaeck J., Koppe C., Janssen J., Heymann F., Weber A., Weiskirchen R., Liedtke C., Gassler N., et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell. 2010;17:481-496.
Not in our library10.1016/j.ccr.2010.03.021
69.
Wen J., Wu Y., Wei W., Li Z., Wang P., Zhu S., Dong W. Protective effects of recombinant human cytoglobin against chronic alcohol-induced liver disease in vivo and in vitro. Sci. Rep. 2017;7:41647.
Not in our library10.1038/srep41647
70.
Kastl L., Sauer S.W., Ruppert T., Beissbarth T., Becker M.S., Suss D., Krammer P.H., Gulow K. TNF-alpha mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-kappaB activation in liver cells. FEBS Lett. 2014;588:175-183.
Not in our library10.1016/j.febslet.2013.11.033
71.
The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages · 2013
No notice
72.
Themanns M., Mueller K.M., Kessler S.M., Golob-Schwarzl N., Mohr T., Kaltenecker D., Bourgeais J., Paier-Pourani J., Friedbichler K., Schneller D., et al. Hepatic Deletion of Janus Kinase 2 Counteracts Oxidative Stress in Mice. Sci. Rep. 2016;6:34719.
Not in our library10.1038/srep34719
73.
Role of nonresolving inflammation in hepatocellular carcinoma development and progression · 2018
No notice
74.
Sakurai T., Maeda S., Chang L., Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl. Acad. Sci. USA. 2006;103:10544-10551.
Not in our library10.1073/pnas.0603499103
75.
Barton B.E. The biological effects of interleukin 6. Med. Res. Rev. 1996;16:87-109.
Not in our library10.1002/(sici)1098-1128(199601)16:1<87::aid-med3>3.0.co;2-q
76.
Yasukawa K., Hirano T., Watanabe Y., Muratani K., Matsuda T., Nakai S., Kishimoto T. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J. 1987;6:2939-2945.
Not in our library10.1002/j.1460-2075.1987.tb02598.x
77.
Yoshizaki K., Nakagawa T., Fukunaga K., Tseng L.T., Yamamura Y., Kishimoto T. Isolation and characterization of B cell differentiation factor (BCDF) secreted from a human B lymphoblastoid cell line. J. Immunol. 1984;132:2948-2954.
Not in our library
78.
Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A., et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986;324:73-76.
Not in our library10.1038/324073a0
79.
Mauer J., Denson J.L., Bruning J.C. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015;36:92-101.
Not in our library10.1016/j.it.2014.12.008
80.
Pedersen B.K., Steensberg A., Fischer C., Keller C., Keller P., Plomgaard P., Febbraio M., Saltin B. Searching for the exercise factor: Is IL-6 a candidate? J. Muscle Res. Cell Motil. 2003;24:113-119.
Not in our library10.1023/a:1026070911202
81.
Jones S.A., Scheller J., Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Investig. 2011;121:3375-3383.
Not in our library10.1172/jci57158
82.
Kraakman M.J., Kammoun H.L., Allen T.L., Deswaerte V., Henstridge D.C., Estevez E., Matthews V.B., Neill B., White D.A., Murphy A.J., et al. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 2015;21:403-416.
Not in our library10.1016/j.cmet.2015.02.006
83.
McInnes I.B., Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol. 2007;7:429-442.
Not in our library10.1038/nri2094
84.
Schett G., Elewaut D., McInnes I.B., Dayer J.M., Neurath M.F. How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat. Med. 2013;19:822-824.
Not in our library10.1038/nm.3260
85.
Eugster H.P., Frei K., Kopf M., Lassmann H., Fontana A. IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur. J. Immunol. 1998;28:2178-2187.
Not in our library10.1002/(sici)1521-4141(199807)28:07<2178::aid-immu2178>3.0.co;2-d
86.
Alonzi T., Fattori E., Lazzaro D., Costa P., Probert L., Kollias G., De Benedetti F., Poli V., Ciliberto G. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 1998;187:461-468.
Not in our library10.1084/jem.187.4.461
87.
Ohshima S., Saeki Y., Mima T., Sasai M., Nishioka K., Nomura S., Kopf M., Katada Y., Tanaka T., Suemura M., et al. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc. Natl. Acad. Sci. USA. 1998;95:8222-8226.
Not in our library10.1073/pnas.95.14.8222
88.
Richards H.B., Satoh M., Shaw M., Libert C., Poli V., Reeves W.H. Interleukin 6 dependence of anti-DNA antibody production: Evidence for two pathways of autoantibody formation in pristane-induced lupus. J. Exp. Med. 1998;188:985-990.
Not in our library10.1084/jem.188.5.985
89.
Lattanzio G., Libert C., Aquilina M., Cappelletti M., Ciliberto G., Musiani P., Poli V. Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB/c mice. Am. J. Pathol. 1997;151:689-696.
Not in our library
90.
Rose-John S., Heinrich P.C. Soluble receptors for cytokines and growth factors: Generation and biological function. Biochem. J. 1994;300:281-290.
Not in our library10.1042/bj3000281
91.
Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989;58:573-581.
Not in our library10.1016/0092-8674(89)90438-8
92.
Gilbert L.A., Hemann M.T. DNA damage-mediated induction of a chemoresistant niche. Cell. 2010;143:355-366.
Not in our library10.1016/j.cell.2010.09.043
93.
Grivennikov S.I., Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21:11-19.
Not in our library10.1016/j.cytogfr.2009.11.005
94.
Gruber S., Straub B.K., Ackermann P.J., Wunderlich C.M., Mauer J., Seeger J.M., Buning H., Heukamp L., Kashkar H., Schirmacher P., et al. Obesity promotes liver carcinogenesis via Mcl-1 stabilization independent of IL-6Ralpha signaling. Cell Rep. 2013;4:669-680.
Not in our library10.1016/j.celrep.2013.07.023
95.
Johnson C., Han Y., Hughart N., McCarra J., Alpini G., Meng F. Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Transl. Gastrointest. Cancer. 2012;1:58-70.
Not in our library10.3978/j.issn.2224-4778.2011.11.02
96.
Li N., Grivennikov S.I., Karin M. The unholy trinity: Inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell. 2011;19:429-431.
Not in our library10.1016/j.ccr.2011.03.018
97.
Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.Y., Vallabhapurapu S., Scheller J., Rose-John S., Cheroutre H., Eckmann L., et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103-113.
Not in our library10.1016/j.ccr.2009.01.001
98.
Hunter C.A., Jones S.A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 2015;16:448-457.
Not in our library10.1038/ni.3153
99.
Lutticken C., Wegenka U.M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpur A.G., Wilks A.F., Yasukawa K., Taga T., et al. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994;263:89-92.
Not in our library10.1126/science.8272872
100.
Stahl N., Boulton T.G., Farruggella T., Ip N.Y., Davis S., Witthuhn B.A., Quelle F.W., Silvennoinen O., Barbieri G., Pellegrini S., et al. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994;263:92-95.
Not in our library10.1126/science.8272873
101.
Darnell J.E., Kerr I.M., Stark G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415-1421.
Not in our library10.1126/science.8197455
102.
Stahl N., Farruggella T.J., Boulton T.G., Zhong Z., Darnell J.E., Yancopoulos G.D. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995;267:1349-1353.
Not in our library10.1126/science.7871433
103.
Gerhartz C., Heesel B., Sasse J., Hemmann U., Landgraf C., Schneider-Mergener J., Horn F., Heinrich P.C., Graeve L. Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation. J. Biol. Chem. 1996;271:12991-12998.
Not in our library10.1074/jbc.271.22.12991
104.
Ihle J.N. The Janus protein tyrosine kinase family and its role in cytokine signaling. Adv. Immunol. 1995;60:1-35.
Not in our library10.1016/s0065-2776(08)60582-9
105.
Wegiel B., Bjartell A., Culig Z., Persson J.L. Interleukin-6 activates PI3K/Akt pathway and regulates cyclin A1 to promote prostate cancer cell survival. Int. J. Cancer. 2008;122:1521-1529.
Not in our library10.1002/ijc.23261
106.
Hirano T., Nakajima K., Hibi M. Signaling mechanisms through gp130: A model of the cytokine system. Cytokine Growth Factor Rev. 1997;8:241-252.
Not in our library10.1016/s1359-6101(98)80005-1
107.
Novick D., Engelmann H., Wallach D., Rubinstein M. Soluble cytokine receptors are present in normal human urine. J. Exp. Med. 1989;170:1409-1414.
Not in our library10.1084/jem.170.4.1409
108.
Lust J.A., Donovan K.A., Kline M.P., Greipp P.R., Kyle R.A., Maihle N.J. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine. 1992;4:96-100.
Not in our library10.1016/1043-4666(92)90043-q
109.
Mullberg J., Schooltink H., Stoyan T., Gunther M., Graeve L., Buse G., Mackiewicz A., Heinrich P.C., Rose-John S. The soluble interleukin-6 receptor is generated by shedding. Eur. J. Immunol. 1993;23:473-480.
Not in our library10.1002/eji.1830230226
110.
Blindenbacher A., Wang X., Langer I., Savino R., Terracciano L., Heim M.H. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology. 2003;38:674-682.
Not in our library10.1053/jhep.2003.50378
111.
Dienz O., Rud J.G., Eaton S.M., Lanthier P.A., Burg E., Drew A., Bunn J., Suratt B.T., Haynes L., Rincon M. Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol. 2012;5:258-266.
Not in our library10.1038/mi.2012.2
112.
Hoge J., Yan I., Janner N., Schumacher V., Chalaris A., Steinmetz O.M., Engel D.R., Scheller J., Rose-John S., Mittrucker H.W. IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling. J. Immunol. 2013;190:703-711.
Not in our library10.4049/jimmunol.1201044
113.
Kopf M., Baumann H., Freer G., Freudenberg M., Lamers M., Kishimoto T., Zinkernagel R., Bluethmann H., Kohler G. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994;368:339-342.
Not in our library10.1038/368339a0
114.
Longhi M.P., Wright K., Lauder S.N., Nowell M.A., Jones G.W., Godkin A.J., Jones S.A., Gallimore A.M. Interleukin-6 is crucial for recall of influenza-specific memory CD4 T cells. PLoS Pathog. 2008;4:e1000006.
Not in our library10.1371/journal.ppat.1000006
115.
Neveu W.A., Allard J.B., Dienz O., Wargo M.J., Ciliberto G., Whittaker L.A., Rincon M. IL-6 is required for airway mucus production induced by inhaled fungal allergens. J. Immunol. 2009;183:1732-1738.
Not in our library10.4049/jimmunol.0802923
116.
Cressman D.E., Greenbaum L.E., DeAngelis R.A., Ciliberto G., Furth E.E., Poli V., Taub R. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379-1383.
Not in our library10.1126/science.274.5291.1379
117.
Waage A., Brandtzaeg P., Halstensen A., Kierulf P., Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J. Exp. Med. 1989;169:333-338.
Not in our library10.1084/jem.169.1.333
118.
Kado S., Nagase T., Nagata N. Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol. 1999;36:67-72.
Not in our library10.1007/s005920050147
119.
Van Greevenbroek M.M., Schalkwijk C.G., Stehouwer C.D. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: Causes and consequences. Neth. J. Med. 2013;71:174-187.
Not in our library
120.
Soresi M., Giannitrapani L., D’Antona F., Florena A.M., La Spada E., Terranova A., Cervello M., D’Alessandro N., Montalto G. Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma. World J. Gastroenterol. 2006;12:2563-2568.
Not in our library10.3748/wjg.v12.i16.2563
121.
Aleksandrova K., Boeing H., Nothlings U., Jenab M., Fedirko V., Kaaks R., Lukanova A., Trichopoulou A., Trichopoulos D., Boffetta P., et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology. 2014;60:858-871.
Not in our library10.1002/hep.27016
122.
Porta C., De Amici M., Quaglini S., Paglino C., Tagliani F., Boncimino A., Moratti R., Corazza G.R. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann. Oncol. 2008;19:353-358.
Not in our library10.1093/annonc/mdm448
123.
Jang J.W., Oh B.S., Kwon J.H., You C.R., Chung K.W., Kay C.S., Jung H.S. Serum interleukin-6 and C-reactive protein as a prognostic indicator in hepatocellular carcinoma. Cytokine. 2012;60:686-693.
Not in our library10.1016/j.cyto.2012.07.017
124.
Naugler W.E., Sakurai T., Kim S., Maeda S., Kim K., Elsharkawy A.M., Karin M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317:121-124.
Not in our library10.1126/science.1140485
125.
Hatting M., Spannbauer M., Peng J., Al Masaoudi M., Sellge G., Nevzorova Y.A., Gassler N., Liedtke C., Cubero F.J., Trautwein C. Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model. Cell Death Dis. 2015;6:e1667.
Not in our library10.1038/cddis.2014.590
126.
Mittenbuhler M.J., Sprenger H.G., Gruber S., Wunderlich C.M., Kern L., Bruning J.C., Wunderlich F.T. Hepatic leptin receptor expression can partially compensate for IL-6Ralpha deficiency in DEN-induced hepatocellular carcinoma. Mol. Metab. 2018;17:122-133.
Not in our library10.1016/j.molmet.2018.08.010
127.
Grohmann M., Wiede F., Dodd G.T., Gurzov E.N., Ooi G.J., Butt T., Rasmiena A.A., Kaur S., Gulati T., Goh P.K., et al. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell. 2018;175:1289-1306 e1220.
Not in our library10.1016/j.cell.2018.09.053
128.
Bergmann J., Muller M., Baumann N., Reichert M., Heneweer C., Bolik J., Lucke K., Gruber S., Carambia A., Boretius S., et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology. 2017;65:89-103.
Not in our library10.1002/hep.28874
129.
Wang C.Q., Sun H.T., Gao X.M., Ren N., Sheng Y.Y., Wang Z., Zheng Y., Wei J.W., Zhang K.L., Yu X.X., et al. Interleukin-6 enhances cancer stemness and promotes metastasis of hepatocellular carcinoma via up-regulating osteopontin expression. Am. J. Cancer Res. 2016;6:1873-1889.
Not in our library
130.
Xu Q., Briggs J., Park S., Niu G., Kortylewski M., Zhang S., Gritsko T., Turkson J., Kay H., Semenza G.L., et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 2005;24:5552-5560.
Not in our library10.1038/sj.onc.1208719
131.
Niu G., Wright K.L., Huang M., Song L., Haura E., Turkson J., Zhang S., Wang T., Sinibaldi D., Coppola D., et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002;21:2000-2008.
Not in our library10.1038/sj.onc.1205260
132.
Villanueva A., Chiang D.Y., Newell P., Peix J., Thung S., Alsinet C., Tovar V., Roayaie S., Minguez B., Sole M., et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972-1983.e11.
Not in our library10.1053/j.gastro.2008.08.008
133.
Zhou L., Huang Y., Li J., Wang Z. The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med. Oncol. 2010;27:255-261.
Not in our library10.1007/s12032-009-9201-4
134.
Menon S., Yecies J.L., Zhang H.H., Howell J.J., Nicholatos J., Harputlugil E., Bronson R.T., Kwiatkowski D.J., Manning B.D. Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice. Sci. Signal. 2012;5:ra24.
Not in our library10.1126/scisignal.2002739
135.
Pelletier J., Graff J., Ruggero D., Sonenberg N. Targeting the eIF4F translation initiation complex: A critical nexus for cancer development. Cancer Res. 2015;75:250-263.
Not in our library10.1158/0008-5472.can-14-2789
136.
Wendel H.G., De Stanchina E., Fridman J.S., Malina A., Ray S., Kogan S., Cordon-Cardo C., Pelletier J., Lowe S.W. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature. 2004;428:332-337.
Not in our library10.1038/nature02369
137.
Epigenetic Activation of a Subset of mRNAs by eIF4E Explains Its Effects on Cell Proliferation · 2007
No notice
138.
Jiang M., Zhang W.W., Liu P., Yu W., Liu T., Yu J. Dysregulation of SOCS-Mediated Negative Feedback of Cytokine Signaling in Carcinogenesis and Its Significance in Cancer Treatment. Front. Immunol. 2017;8:70.
Not in our library10.3389/fimmu.2017.00070
139.
Niwa Y., Kanda H., Shikauchi Y., Saiura A., Matsubara K., Kitagawa T., Yamamoto J., Kubo T., Yoshikawa H. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene. 2005;24:6406-6417.
Not in our library10.1038/sj.onc.1208788
140.
Fan L.C., Shiau C.W., Tai W.T., Hung M.H., Chu P.Y., Hsieh F.S., Lin H., Yu H.C., Chen K.F. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. Oncogene. 2017;36:5768-5769.
Not in our library10.1038/onc.2017.251
141.
Chung C.D., Liao J., Liu B., Rao X., Jay P., Berta P., Shuai K. Specific inhibition of Stat3 signal transduction by PIAS3. Science. 1997;278:1803-1805.
Not in our library10.1126/science.278.5344.1803
142.
Hilton D.J. Negative regulators of cytokine signal transduction. Cell. Mol. Life Sci. 1999;55:1568-1577.
Not in our library10.1007/s000180050396
143.
Tai W.T., Shiau C.W., Chen P.J., Chu P.Y., Huang H.P., Liu C.Y., Huang J.W., Chen K.F. Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Hepatology. 2014;59:190-201.
Not in our library10.1002/hep.26640
144.
Krebs D.L., Hilton D.J. SOCS proteins: Negative regulators of cytokine signaling. Stem Cells. 2001;19:378-387.
Not in our library10.1634/stemcells.19-5-378
145.
Starr R., Willson T.A., Viney E.M., Murray L.J., Rayner J.R., Jenkins B.J., Gonda T.J., Alexander W.S., Metcalf D., Nicola N.A., et al. A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387:917-921.
Not in our library10.1038/43206
146.
Nicholson S.E., Willson T.A., Farley A., Starr R., Zhang J.G., Baca M., Alexander W.S., Metcalf D., Hilton D.J., Nicola N.A. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J. 1999;18:375-385.
Not in our library10.1093/emboj/18.2.375
147.
Croker B.A., Krebs D.L., Zhang J.G., Wormald S., Willson T.A., Stanley E.G., Robb L., Greenhalgh C.J., Forster I., Clausen B.E., et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat. Immunol. 2003;4:540-545.
Not in our library10.1038/ni931
148.
Alexander W.S., Starr R., Fenner J.E., Scott C.L., Handman E., Sprigg N.S., Corbin J.E., Cornish A.L., Darwiche R., Owczarek C.M., et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell. 1999;98:597-608.
Not in our library10.1016/s0092-8674(00)80047-1
149.
The molecular basis of JAK/STAT inhibition by SOCS1 · 2018
No notice
150.
Babon J.J., Kershaw N.J., Murphy J.M., Varghese L.N., Laktyushin A., Young S.N., Lucet I.S., Norton R.S., Nicola N.A. Suppression of cytokine signaling by SOCS3: Characterization of the mode of inhibition and the basis of its specificity. Immunity. 2012;36:239-250.
Not in our library10.1016/j.immuni.2011.12.015
151.
Inagaki-Ohara K., Kondo T., Ito M., Yoshimura A. SOCS, inflammation, and cancer. JAKSTAT. 2013;2:e24053.
Not in our library10.4161/jkst.24053
152.
Yasukawa H., Misawa H., Sakamoto H., Masuhara M., Sasaki A., Wakioka T., Ohtsuka S., Imaizumi T., Matsuda T., Ihle J.N., et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 1999;18:1309-1320.
Not in our library10.1093/emboj/18.5.1309
153.
Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130 · 2000
Not checked
154.
Giordanetto F., Kroemer R.T. A three-dimensional model of Suppressor Of Cytokine Signalling 1 (SOCS-1). Protein Eng. 2003;16:115-124.
Not in our library10.1093/proeng/gzg015
155.
Zhang J.G., Farley A., Nicholson S.E., Willson T.A., Zugaro L.M., Simpson R.J., Moritz R.L., Cary D., Richardson R., Hausmann G., et al. The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc. Natl. Acad. Sci. USA. 2015;112:E2979.
Not in our library10.1073/pnas.96.5.2071
156.
Kubo M., Hanada T., Yoshimura A. Suppressors of cytokine signaling and immunity. Nat. Immunol. 2003;4:1169-1176.
Not in our library10.1038/ni1012
157.
Haan S., Ferguson P., Sommer U., Hiremath M., McVicar D.W., Heinrich P.C., Johnston J.A., Cacalano N.A. Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation. J. Biol. Chem. 2003;278:31972-31979.
Not in our library10.1074/jbc.m303170200
158.
Starr R., Metcalf D., Elefanty A.G., Brysha M., Willson T.A., Nicola N.A., Hilton D.J., Alexander W.S. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc. Natl. Acad. Sci. USA. 1998;95:14395-14399.
Not in our library10.1073/pnas.95.24.14395
159.
Marine J.C., McKay C., Wang D., Topham D.J., Parganas E., Nakajima H., Pendeville H., Yasukawa H., Sasaki A., Yoshimura A., et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell. 1999;98:617-627.
Not in our library10.1016/s0092-8674(00)80049-5
160.
Roberts A.W., Robb L., Rakar S., Hartley L., Cluse L., Nicola N.A., Metcalf D., Hilton D.J., Alexander W.S. Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc. Natl. Acad. Sci. USA. 2001;98:9324-9329.
Not in our library10.1073/pnas.161271798
161.
Ogata H., Chinen T., Yoshida T., Kinjyo I., Takaesu G., Shiraishi H., Iida M., Kobayashi T., Yoshimura A. Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. Oncogene. 2006;25:2520-2530.
Not in our library10.1038/sj.onc.1209281
162.
Yoshikawa H., Matsubara K., Qian G.S., Jackson P., Groopman J.D., Manning J.E., Harris C.C., Herman J.G. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat. Genet. 2001;28:29-35.
Not in our library10.1038/ng0501-29
163.
Wunderlich C.M., Hovelmeyer N., Wunderlich F.T. Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. JAKSTAT. 2013;2:e23878.
Not in our library10.4161/jkst.23878
164.
Siegel R.L., Miller K.D., Jemal A. Cancer Statistics, 2017. CA Cancer J. Clin. 2017;67:7-30.
Not in our library10.3322/caac.21387
165.
Cunningham D., Atkin W., Lenz H.J., Lynch H.T., Minsky B., Nordlinger B., Starling N. Colorectal cancer. Lancet. 2010;375:1030-1047.
Not in our library10.1016/s0140-6736(10)60353-4
166.
Rubin D.C., Shaker A., Levin M.S. Chronic intestinal inflammation: Inflammatory bowel disease and colitis-associated colon cancer. Front. Immunol. 2012;3:107.
Not in our library10.3389/fimmu.2012.00107
167.
Dignam J.J., Polite B.N., Yothers G., Raich P., Colangelo L., O’Connell M.J., Wolmark N. Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J. Natl. Cancer Inst. 2006;98:1647-1654.
Not in our library10.1093/jnci/djj442
168.
Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674.
Not in our library10.1016/j.cell.2011.02.013
169.
Baltgalvis K.A., Berger F.G., Pena M.M., Davis J.M., Carson J.A. The interaction of a high-fat diet and regular moderate intensity exercise on intestinal polyp development in Apc Min/+ mice. Cancer Prev. Res. 2009;2:641-649.
Not in our library10.1158/1940-6207.capr-09-0017
170.
Yang K., Edelmann W., Fan K., Lau K., Leung D., Newmark H., Kucherlapati R., Lipkin M. Dietary modulation of carcinoma development in a mouse model for human familial adenomatous polyposis. Cancer Res. 1998;58:5713-5717.
Not in our library
171.
Schulz M.D., Atay C., Heringer J., Romrig F.K., Schwitalla S., Aydin B., Ziegler P.K., Varga J., Reindl W., Pommerenke C., et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature. 2014;514:508-512.
Not in our library10.1038/nature13398
172.
Newmark H.L., Yang K., Kurihara N., Fan K., Augenlicht L.H., Lipkin M. Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: A preclinical model for human sporadic colon cancer. Carcinogenesis. 2009;30:88-92.
Not in our library10.1093/carcin/bgn229
173.
Yang K., Kurihara N., Fan K., Newmark H., Rigas B., Bancroft L., Corner G., Livote E., Lesser M., Edelmann W., et al. Dietary induction of colonic tumors in a mouse model of sporadic colon cancer. Cancer Res. 2008;68:7803-7810.
Not in our library10.1158/0008-5472.can-08-1209
174.
Liu Z., Brooks R.S., Ciappio E.D., Kim S.J., Crott J.W., Bennett G., Greenberg A.S., Mason J.B. Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: A mechanism for obesity-associated colorectal cancer. J. Nutr. Biochem. 2012;23:1207-1213.
Not in our library10.1016/j.jnutbio.2011.07.002
175.
High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22 · 2016
No notice
176.
Ahmad R., Rah B., Bastola D., Dhawan P., Singh A.B. Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching. Sci. Rep. 2017;7:5125.
Not in our library10.1038/s41598-017-04989-8
177.
Peterson L.W., Artis D. Intestinal epithelial cells: Regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 2014;14:141-153.
Not in our library10.1038/nri3608
178.
Moreno-Navarrete J.M., Manco M., Ibanez J., Garcia-Fuentes E., Ortega F., Gorostiaga E., Vendrell J., Izquierdo M., Martinez C., Nolfe G., et al. Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance. Int. J. Obes. 2010;34:240-249.
Not in our library10.1038/ijo.2009.242
179.
Reinecker H.C., Steffen M., Witthoeft T., Pflueger I., Schreiber S., MacDermott R.P., Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin. Exp. Immunol. 1993;94:174-181.
Not in our library10.1111/j.1365-2249.1993.tb05997.x
180.
Harper J.W., Zisman T.L. Interaction of obesity and inflammatory bowel disease. World J. Gastroenterol. 2016;22:7868-7881.
Not in our library10.3748/wjg.v22.i35.7868
181.
Izano M., Wei E.K., Tai C., Swede H., Gregorich S., Harris T.B., Klepin H., Satterfield S., Murphy R., Newman A.B., et al. Chronic inflammation and risk of colorectal and other obesity-related cancers: The health, aging and body composition study. Int. J. Cancer. 2016;138:1118-1128.
Not in our library10.1002/ijc.29868
182.
Popivanova B.K., Kitamura K., Wu Y., Kondo T., Kagaya T., Kaneko S., Oshima M., Fujii C., Mukaida N. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Investig. 2008;118:560-570.
Not in our library10.1172/jci32453
183.
Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment · 2018
No notice
184.
Sakai H., Yamada Y., Shimizu M., Saito K., Moriwaki H., Hara A. Genetic ablation of Tnfalpha demonstrates no detectable suppressive effect on inflammation-related mouse colon tumorigenesis. Chem. Biol. Interact. 2010;184:423-430.
Not in our library10.1016/j.cbi.2010.01.014
185.
Naito Y., Takagi T., Handa O., Ishikawa T., Nakagawa S., Yamaguchi T., Yoshida N., Minami M., Kita M., Imanishi J., et al. Enhanced intestinal inflammation induced by dextran sulfate sodium in tumor necrosis factor-alpha deficient mice. J. Gastroenterol. Hepatol. 2003;18:560-569.
Not in our library10.1046/j.1440-1746.2003.03034.x
186.
Kojouharoff G., Hans W., Obermeier F., Männel D.N., Andus T., Schölmerich J., Gross V., Falk W. Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin. Exp. Immunol. 1997;107:353-358.
Not in our library10.1111/j.1365-2249.1997.291-ce1184.x
187.
Pendyala S., Neff L.M., Suarez-Farinas M., Holt P.R. Diet-induced weight loss reduces colorectal inflammation: Implications for colorectal carcinogenesis. Am. J. Clin. Nutr. 2011;93:234-242.
Not in our library10.3945/ajcn.110.002683
188.
Olivo-Marston S.E., Hursting S.D., Perkins S.N., Schetter A., Khan M., Croce C., Harris C.C., Lavigne J. Effects of calorie restriction and diet-induced obesity on murine colon carcinogenesis, growth and inflammatory factors, and microRNA expression. PLoS ONE. 2014;9:e94765.
Not in our library10.1371/journal.pone.0094765
189.
Aboura I., Nani A., Belarbi M., Murtaza B., Fluckiger A., Dumont A., Benammar C., Tounsi M.S., Ghiringhelli F., Rialland M., et al. Protective effects of polyphenol-rich infusions from carob (Ceratonia siliqua) leaves and cladodes of Opuntia ficus-indica against inflammation associated with diet-induced obesity and DSS-induced colitis in Swiss mice. Biomed. Pharmacother. 2017;96:1022-1035.
Not in our library10.1016/j.biopha.2017.11.125
190.
Saadatdoust Z., Pandurangan A.K., Ananda Sadagopan S.K., Mohd Esa N., Ismail A., Mustafa M.R. Dietary cocoa inhibits colitis associated cancer: A crucial involvement of the IL-6/STAT3 pathway. J. Nutr. Biochem. 2015;26:1547-1558.
Not in our library10.1016/j.jnutbio.2015.07.024
191.
Yook J.S., Kim K.A., Kim M., Cha Y.S. Black Adzuki Bean (Vigna angularis) Attenuates High-Fat Diet-Induced Colon Inflammation in Mice. J. Med. Food. 2017;20:367-375.
Not in our library10.1089/jmf.2016.3821
192.
Bibi S., de Sousa Moraes L.F., Lebow N., Zhu M.J. Dietary Green Pea Protects against DSS-Induced Colitis in Mice Challenged with High-Fat Diet. Nutrients. 2017;9.
Not in our library10.3390/nu9050509
193.
Setayesh T., Nersesyan A., Misik M., Noorizadeh R., Haslinger E., Javaheri T., Lang E., Grusch M., Huber W., Haslberger A., et al. Gallic acid, a common dietary phenolic protects against high fat diet induced DNA damage. Eur. J. Nutr. 2018.
Not in our library10.1007/s00394-018-1782-2
194.
Guan F., Tabrizian T., Novaj A., Nakanishi M., Rosenberg D.W., Huffman D.M. Dietary Walnuts Protect Against Obesity-Driven Intestinal Stem Cell Decline and Tumorigenesis. Front. Nutr. 2018;5:37.
Not in our library10.3389/fnut.2018.00037
195.
Wang H., Guan L., Li J., Lai M., Wen X. The Effects of Berberine on the Gut Microbiota in Apc (min/+) Mice Fed with a High Fat Diet. Molecules. 2018;23.
Not in our library10.3390/molecules23092298
196.
Greten F.R., Eckmann L., Greten T.F., Park J.M., Li Z.W., Egan L.J., Kagnoff M.F., Karin M. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285-296.
Not in our library10.1016/j.cell.2004.07.013
197.
Bibi S., Kang Y., Du M., Zhu M.J. Maternal high-fat diet consumption enhances offspring susceptibility to DSS-induced colitis in mice. Obesity. 2017;25:901-908.
Not in our library10.1002/oby.21816
198.
Wang S.W., Sun Y.M. The IL-6/JAK/STAT3 pathway: Potential therapeutic strategies in treating colorectal cancer (Review). Int. J. Oncol. 2014;44:1032-1040.
Not in our library10.3892/ijo.2014.2259
199.
Kantola T., Klintrup K., Vayrynen J.P., Vornanen J., Bloigu R., Karhu T., Herzig K.H., Napankangas J., Makela J., Karttunen T.J., et al. Stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma. Br. J. Cancer. 2012;107:1729-1736.
Not in our library10.1038/bjc.2012.456
200.
Knupfer H., Preiss R. Serum interleukin-6 levels in colorectal cancer patients--a summary of published results. Int. J. Color. Dis. 2010;25:135-140.
Not in our library10.1007/s00384-009-0818-8
201.
Lee W.S., Baek J.H., You D.H., Nam M.J. Prognostic value of circulating cytokines for stage III colon cancer. J. Surg. Res. 2013;182:49-54.
Not in our library10.1016/j.jss.2012.08.051
202.
Sasaki Y., Takeda H., Sato T., Orii T., Nishise S., Nagino K., Iwano D., Yaoita T., Yoshizawa K., Saito H., et al. Serum Interleukin-6, insulin, and HOMA-IR in male individuals with colorectal adenoma. Clin. Cancer Res. 2012;18:392-399.
Not in our library10.1158/1078-0432.ccr-11-0896
203.
Bollrath J., Phesse T.J., von Burstin V.A., Putoczki T., Bennecke M., Bateman T., Nebelsiek T., Lundgren-May T., Canli O., Schwitalla S., et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009;15:91-102.
Not in our library10.1016/j.ccr.2009.01.002
204.
Becker C., Fantini M.C., Neurath M.F. TGF-beta as a T cell regulator in colitis and colon cancer. Cytokine Growth Factor Rev. 2006;17:97-106.
Not in our library10.1016/j.cytogfr.2005.09.004
205.
Becker C., Fantini M.C., Wirtz S., Nikolaev A., Lehr H.A., Galle P.R., Rose-John S., Neurath M.F. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle. 2005;4:217-220.
Not in our library10.4161/cc.4.2.1413
206.
Hu B., Elinav E., Huber S., Strowig T., Hao L., Hafemann A., Jin C., Wunderlich C., Wunderlich T., Eisenbarth S.C., et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc. Natl. Acad. Sci. USA. 2013;110:9862-9867.
Not in our library10.1073/pnas.1307575110
207.
Li Y., de Haar C., Chen M., Deuring J., Gerrits M.M., Smits R., Xia B., Kuipers E.J., van der Woude C.J. Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut. 2010;59:227-235.
Not in our library10.1136/gut.2009.184176
208.
Aden K., Breuer A., Rehman A., Geese H., Tran F., Sommer J., Waetzig G.H., Reinheimer T.M., Schreiber S., Rose-John S., et al. Classic IL-6R signalling is dispensable for intestinal epithelial proliferation and repair. Oncogenesis. 2016;5:e270.
Not in our library10.1038/oncsis.2016.71

Cited by papers we hold 3

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.