Skip to content
naulon
Get started

Not checked for notices yet.

Microrna Let-7: An Emerging Next-Generation Cancer Therapeutic

Debmalya Barh, Rajesh Malhotra, B. Ravi and 1 more

Current Oncology · 2010

doi:10.3747/co.v17i1.356

Abstract

In recent years, various RNA-based technologies have been under evaluation as potential next-generation cancer therapeutics. Micrornas (miRNAS), known to regulate the cell cycle and development, are deregulated in various cancers. Thus, they might serve as good targets or candidates in an exploration of anticancer therapeutics. One attractive candidate for this purpose is let-7 ("lethal-7"). Let-7 is underexpressed in various cancers, and restoration of its normal expression is found to inhibit cancer growth by targeting various oncogenes and inhibiting key regulators of several mitogenic pathways. In vivo, let-7 administration was found effective against mouse-model lung and breast cancers, and our computational prediction supports the possible effectiveness of let-7 in estrogen receptor (ER)-positive metastatic breast cancer. Data also suggest that let-7 regulates apoptosis and cancer stem cell (CSC) differentiation and can therefore be tested as a potential therapeutic in cancer treatment. However, the exact role of let-7 in cancer is not yet fully understood. There is a need to understand the causative molecular basis of let-7 alterations in cancer and to develop proper delivery systems before proceeding to therapeutic applications. This article attempts to highlight certain critical aspects of let-7's therapeutic potential in cancer.

Shown for reading. Its publisher allows quoting it, not republishing it.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

Micrornas (mirnas) are natural non-coding rnas of approximately 22 nucleotides (nt) in size. They regulate genes post-transcriptionally by binding to a site in the 3′ untranslated region (utr) of target messenger rnas (mrnas). Identification of an mirna target involves base pairing with the target site, which is mostly imperfect in the case of animals. However, a perfect pairing in a 7-nt region at the 5′ end of mirna, called the seed region, is essential for target identification.

The mirnas are known to regulate cellular processes such as stem-cell differentiation, heart development –, insulin secretion, apoptosis,, aging,, and immunity,, among other processes. It is therefore not surprising that mirnas are differentially expressed in several pathophysiologic conditions including, for instance, Alzheimer disease,, Parkinson disease, cardiovascular diseases,,, the Cowden and Down syndromes,, and various cancers.

Let-7 was first discovered and well studied in Caenorhabditis elegans, in which it regulates developmental timing – (larval stage 4–to–adult transition,) and stage-specific neuromuscular tissue development. Let-7 has orthologs in various species. In Drosophila, let-7 plays a role in determining the timing for cell-cycle exit, metamorphosis, neuromuscular Junction development, juvenile-to-adult-stage transition, and adult behaviour,. The zebrafish ortholog of let-7 is prominently expressed in nervous tissue, indicating its certain role in neural development. In the adult newt, let-7 regulates transdifferentiation and regeneration of lens and inner ear-hair cells.

Little is known about the function of let-7 in mammalian development and normal physiology. In the mouse, let-7 is involved in neural lineage specificity of embryonic stem cells, brain development, and mammary epithelial progenitor cell maintenance by induction of loss of self-renewal. In humans, 12 genomic loci encode the let-7 family members (let-7a-1, -2, -3; let-7b; let-7c; let-7d; let-7e; let-7f-1, -2; let-7g; let-7i; mir98). Human let-7 is upregulated during embryonic cell differentiation, but the roles it plays in normal physiology are mostly unknown.

Human let-7 family members are found to be downregulated in several cancers, with a few exceptions (Table I); restoration of normal expression prevents tumorigenesis,,,. Let-7 therefore acts as a tumour suppressor and a regulator of terminal differentiation and apoptosis. This finding implies that let-7 can possibly be used as a next-generation cancer therapeutic. But, to date, the mechanism of let-7 deregulation, and its precise role in tumorigenesis, is not fully understood, creating a hurdle to effectively using this mirna in cancer therapy.

This article presents an overview of let-7 and discusses the critical issues that must be explored to develop a let-7–based therapeutic strategy against various cancers.

Biogenesis and Mechanism of Action

The biogenesis of let-7 is similar to that of other mirnas. The first step in mirna biogenesis is transcription from the mirna transcription unit by rna polymerase ii to produce a primary transcript called pri-mirna. The pri-mirna is processed by the microprocessor complex containing an rnase iii–like enzyme, Drosha, and its cofactor, a double-stranded rna binding protein, Dgcr8, to produce an approximately 60–70 nt pre-mirna (precursor mirna). The pre-mirna is then transported to cytoplasm by exportin 5 (XPO5), in a Rangtp (ras-related nuclear protein–guanosine triphosphate complex)–dependent way, where it is cleaved by Dicer (a cytoplasmic rnase iii), to generate an imperfect mirna:mirna* duplex of approximately 21–24 nt. One of the strands (the “guide strand”) from the duplex is then incorporated into Argonaute (Ago)–containing ribonucleoprotein (rnp) complex; the other strand (the “passenger strand”) is degraded. However, there are cases in which both strands of the duplex are detected in the cell. The mirna–Ago rnp complex causes posttranscriptional regulation of genes, in which mirna is used as a tether to guide the complex to the specific mrna. The exact mechanism by which the mirnp complex regulates expression of the target remains unclear. Various models try to explain this mechanism. Figure 1 shows a general model.

Regulation of Let-7

Expression of let-7 is regulated at various stages of its biogenesis and also depending on cell type. Similarly, let-7 regulates many transcription factors that play important roles in regulation of the cell cycle, cell differentiation, and apoptosis. Many of the factors controlling the expression of let-7 form regulatory circuits with the factors being regulated by such expression. These regulatory circuits—such as double-negative feedback loops and so on—are salient network motifs in development and differentiation. LIN28, POU5F1, SOX2, NANOG, TLX1, HMGA2, MYC, and IMPs are known to form such regulatory loops (Figure 2).

Regulation of Let-7 by Pluripotency-Promoting Factors in Embryonic and Cancer Stem Cells

LIN28, which maintains the undifferentiated state of embryonic cells, is a well-known target of let-7 and is downregulated by let-7 during developmental commitment,. Lin28 was recently shown to act as a posttranscriptional repressor of let-7 biogenesis, binding to the loop portion of the pri–let-7 hairpin and the stem part of pre–let-7 and thereby inhibiting its processing. Lin28 and Lin28B also inhibit processing of let-7 by mediating terminal uridylation of let-7 precursors. What is unclear is whether the regulation by Lin28 occurs at the Drosha or Dicer processing step,–. Lin28 induces pri–let-7 expression through induction of other pluripotency-promoting factors such as Pou5F1, Sox2, Nanog, and Tlx1, thus regulating let-7 expression at multiple levels.

The early embryonic oncofetal gene HMGA2 is involved in the self-renewal and maintenance of adult stem cells. It is highly expressed in hematopoietic and fetal neuronal stem cells,, and the low levels of let-7 in stem cells inversely correlate with HMGA2 expression. Thus, the undifferentiated state is maintained. In differentiated tissues, HMGA2 is downregulated because of the high expression of let-7, and during induced differentiation, ectopic expression of let-7 reduces ras and HMGA2 expression, leading to inhibition of cell proliferation and induction of apoptosis. Therefore, HMGA2 is a direct target of let-7.

Like normal stem cells, cancer stem cells (slowly dividing tumour-initiating cells) exhibit low levels of let-7 and possess unlimited self-renewal capability and pluripotency, allowing them to repopulate and metastasize,. It has been proposed that, during carcinogenesis, the let-7–targeted embryonic genes, which are otherwise not expressed in adult tissues, are re-expressed because of loss of let-7 control. This reprogramming promotes de-differentiation and cancer progression. A good example is that of HMGA2, which is undetectable in most differentiated tissues, but highly expressed in various cancers, including neuroblastoma and pancreatic, lung, and thyroid cancers –. Breast cancer stem cells are also devoid of let-7, but abundantly express HMGA2 and ras (Figure 2).

Regulatory Circuit Between Myc and Let-7

IMP1 is another oncofetal gene that is expressed only during early fetal life, and is re-expressed in several cancers. It is selectively expressed in young, but not in old, hematopoietic stem cells. IMP1 regulates stem cell functions by stabilizing insulin-like growth factor 2 and C-myc mrnas,, and the phenotype of stem cells from the IMP1 knockout mouse resembles that of cells from the HMGA2-deficient mouse,. Let-7 targets IMP1, and therefore indirectly acts as a negative regulator of MYC expression,,. It has been shown that Myc binds directly to let-7 promoter and downregulates its transcription. Thus, an indirect feedback circuit exists between let-7 and Myc (Figure 2).

Let-7 Targets Multiple Oncogenes and Components of Cell Cycle, Cell Proliferation, and Apoptosis

Apart from targeting oncogenes (ras, MYC, HMGA2, and so on) as already discussed, let-7 regulates several key components of the cell cycle and cell proliferation. Microarray analysis of hepatocellular carcinoma (HepG2) and lung cancer (A549) cell lines revealed that let-7 inhibits multiple cell-cycle- and proliferation-associated genes, including cyclin A2 (CCNA2), CDC34, Aurora A [AURKA (formerly STK6)] and B [AURKB (formerly SKT12)] kinases, E2F5, CDK8, and PLAGL2, among others. In HepG2 cells, let-7 directly represses CCNA2, CDC25A, SKP2, AURKA, CDC16, CCND1, and CDK6, among others. Let-7 also inhibits several dna replication machinery components (ORC1L; RRM1, 2; and so on) and transcription factors [E2F6, CBFB, PLAGL2, SOX9, GZF1 (formerly ZNF336), YAP1, GTF2I, ARID3A, and so on]. Surprisingly, that study also showed that let-7 represses several tumour suppressor genes (BRCA1, BRCA2, FANCD2, and PLAGL1, among others) and checkpoint regulators (CHEK1, BUB1, BUB1B, MAD2L1, and CDC23, among others). Our recent in silico analysis shows that let-7 may potentially target er signalling and angiogenic pathways by targeting key molecules of these cascades. Various targets of let-7 are listed in Table II and shown in Figure 3.

Apoptosis regulatory functions of let-7 have recently been reported in both human and mouse. Let-7 targets Casp3 in the A431 and HepG2 cell lines, and inhibits doxorubicin- and paclitaxel-induced apoptosis. In NIH3T3 mouse fibroblast cells, let-7 is involved in ultraviolet B–induced apoptosis by modulating Casp3, Bcl2, Map3k1, and Cdk5.

Emerging Role of Let-7 in Cancer Diagnosis and Therapy

The facts discussed here indicate that let-7 acts as a tumour suppressor by targeting various oncogenes and key components of the cell cycle and developmental pathways. Most reports reveal that let-7 is frequently underexpressed (Table I) and that the chromosomal region of human let-7 is frequently deleted in many cancers. Similarly, in more differentiated tumour cells, let-7 is expressed at higher levels, and its target oncogenes (HMGA2 and ras) are downregulated. Thus, loss of let-7 expression is a marker for less differentiated cancer, and expression levels are also found to be effective prognostic markers in several cancers,,. In lung cancer, reduced let-7 expression was also found to significantly correlate with shortened postoperative survival regardless of disease stage.

From the therapeutic viewpoint, let-7 is attractive molecule for preventing tumorigenesis and angiogenesis; it is a potential therapeutic in several cancers that underexpress let-7. Let-7 replacement was found to inhibit anchorage-independent growth and cell-cycle progression in melanoma cells by repressing regulators of the cell cycle and cell proliferation such as cyclins A, D1, and D3 and CDK4. Together with TP53, ras and MYC have been implicated as key oncogenes in lung cancer. The reduced expression of let-7 in lung cancer directly correlates with upregulation of oncogene ras; introduction of let-7 represses ras and MYC translation by targeting the related mrnas,. In both lung and hepatocellular carcinomas, replacement or restoration of normal expression levels of let-7 inhibits cancer growth by repressing multiple cell-cycle and proliferation pathways, together with ras and MYC,,, (Table II). Intranasal let-7 administration was found effective in reducing tumour growth in a K-ras mutant mouse model of lung cancer. Similarly, restoration of let-7 restrains the growth and proliferation of colon and hepatic cancers,. Transfection of let-7 in a Burkitt lymphoma cell line downregulates MYC and reverts MYC-induced cell growth. Ectopic expression of let-7 inhibits cell proliferation by directly repressing the HMGA2 oncogene in lung cancers, and uterine leiomyoma.

Induced expression of let-7 in breast cancer cells targets HMGA2 and H-ras, and in a mouse model of breast cancer, exogenous let-7 delivery suppresses cell proliferation, mammosphere formation, and the population of undifferentiated cells by downregulating both of the foregoing oncogenes,. In our in silico analysis, we recently showed that, apart from repressing MYC, ras, and HMGA2, let-7 may also target CYP19A1, ESR1, and ESR2, thereby potentially blocking estrogen signalling in er-positive breast cancers. Similarly, by repressing angiogenin, fibroblast growth factor, transforming growth factor, interleukin 6, and matrix metallopeptidase 2, let-7 may prevent growth, angiogenesis, and metastasis in breast cancer (Table II).

Limitations Because of Limited Knowledge of Let-7 Biology

Although restoration of normal let-7 expression proves beneficial, limited knowledge concerning its transcriptional and processing control during biogenesis and its exact role in tumorigenesis make it difficult to directly apply let-7 as a therapeutic. It is necessary to know whether downregulation of let-7 in tumours is a primary or secondary phenomenon during tumorigenesis. Supporting the csc hypothesis, we agree with the opinion that epigenetic downregulation of let-7 in cscs leads to upregulation of oncofetal genes (HMGA2 and LIN28, among others) and, thereby, to loss of differentiation and tumorigenesis. In that scenario, downregulation of let-7 is the primary event, a view that can be supported by observation of where in ovarian cancer let-7 is hypermethylated.

Because mirnas act on the 3′ utr of target mrnas, it is important to determine how efficiently let-7 will work as a therapeutic, because 3′ utr truncated oncogenes may be prevalent in neoplasia. Grimm et al. reported that delivery of adeno-associated virus (aav)–mediated recombinant pre-mirnas causes death in mice from severe liver cytotoxicity. Details of the immunogenic and cytotoxic effects of let-7 therefore need to be explored so that such side effects can be minimized in an effective treatment strategy. Similarly, we proposed that let-7 may be involved in an as-yet-unknown regulatory network of mirnas that resembles the gene regulatory network involving transcription factors. Therefore, anti-mirna oligo-based knockdown of let-7 inhibitory mirnas is not currently possible.

Limitations in Delivery Methods and Systems

Lack of an appropriate, safe, and effective delivery method for let-7 is another drawback of possible therapy. Biological vectors such as aav and lentivirus may be used for targeted delivery, but standardization of the method is required to prevent non-targeted site introduction. Also, brain-specific mirna delivery is not yet successful, and effective neuron-specific delivery methods have to be developed to tackle brain and neuronal tumours. As discussed earlier, aav- and lentivirus-mediated delivery of let-7 in a mouse model of lung cancer, was found to be inefficient in pre-existing tumours because of the resistance to let-7 developed by the tumour over time. A strategy for let-7–mediated therapy for pre-existing tumours therefore also has to be developed.

Strategies to Overcome the Limitations

The optimal or normal level of let-7 may be restored in cancer cells either by administering exogenous let-7 in situ with a vector overexpressing let-7, or by repressing let-7 repressors. Recent mirna technologies are, in general, designed to use complementary or chemically modified single-stranded rna analogs (or both) to repress the specific mirnas responsible for a given disease or cancer. These analogs, including asos (antisense oligonucleotides), amos (anti-mirna asos called “antagomirs”), locked nucleic acids, and antisense-technology-based small interfering rnas, are widely and effectively used in regulation of mirna expression,–. But direct information is not available on the mirnas that regulate let-7 expression; this aspect limits the scope for such a strategy. Instead, technologies are required that can effectively upregulate let-7 expression. Hence, either vector-mediated overexpression of let-7 or transient transfection of double-stranded let-7 will be the choice.

Introduction of double-stranded let-7 duplex may produce mature let-7, equivalent to the endogenous version, during Dicer processing, potentially rescuing a downregulated let-7 level. This strategy has already been successfully used. Vectors containing pre–let-7–like synthetic short hairpin rnas, driven by highly inducible Pol iii promoters such as H1 and U6, may provide high expression of let-7 from predefined transcription start and termination sites. But instead of designing artificial hairpins, direct cloning of the entire natural pri–let-7 hairpin with flanking sequences into the expression vector may be a better approach— assuming that natural pre–let-7 will be a better substrate for generating mature let-7 during Dicer processing –. A pri-mir–Pol ii transgene system has been successfully used to overexpress mir155, mir30, and mir122. This system was also found useful in expressing multiple mirnas from a single transcript and can therefore be adopted for let-7 expression too.

High-density lipoprotein conjugated sirna has been reported to increase delivery efficacy in certain specific organs such as liver, gut, kidney, and steroid secreting organs. A similar approach may therefore have the possibility to be effective in let-7 delivery as well. But the synthesis and purification of therapeutic-grade let-7 is difficult. A nanoparticle-based delivery system may prove beneficial.

Other delivery methods that have been found promising in both in vitro and in vivo conditions include lentivirus-mediated pre–let-7 oligonucleotides, adenovirus-mediated delivery of hairpin sequences of mature let-7, cationic liposome–mediated delivery of pre–let-7, and electroporation of synthetic let-7. Although such methods are at the bench level, they might be translated into therapeutic approaches in the near future.

Current Industry Status of Let-7 Therapy

Because of its potential as a cancer therapeutic, let-7 has been filed for patent protection (Australia: 2007/333109 A1; United States: 20090163430). While diagnostic companies are developing let-7–based tests for various diseases, including several cancers, pharma giants are working toward development of effective delivery systems. But let-7 restoration methods are not yet satisfactory. Asuragen (www.asuragen.com), the rna-based therapeutic and diagnostics major with a core focus on mirna through its subsidiary Mirna Therapeutics (www.mirnatherapeutics.com), is developing mirna-based diagnostics and therapeutics for non-small-cell lung cancer, metastatic prostate cancer, and acute myeloid leukemia—all currently in preclinical trials. For lung cancer and acute myeloid leukemia, their main focus is let-7. Similarly, Regulus Therapeutics LLC (www.regulusrx.com) is using more than 60 mirnas, including let-7, to develop mirna therapeutics to treat several diseases (including cancers). Their main focus is on delivery systems and enhancement of treatment efficacy.

SUMMARY

Let-7 exerts its tumour suppressor and antiproliferative activities by repressing several oncogenes and by regulating key regulators of the cell cycle, cell differentiation, and apoptotic pathways. Downregulation of let-7 is a common phenomenon in several cancers, and restoration of normal let-7 expression has been found to prevent cancer growth. As a result, let-7 is a molecular marker in certain cancers and a potential therapeutic in cancer therapy. However, efficient delivery strategies have to be developed if this molecule is to be used as a therapeutic in vivo. Use of viral vectors, artificial virus-like particles, and nano materials may be a promising way to realize this goal, but optimization is needed. Also, a better understanding of let-7 biology and its regulatory networks is required to exploit the curative benefits of let-7 and to reduce off-target side effects.

References 110

  1. 1.

    Filipowicz W Bhattacharyya SN Sonenberg N Mechanisms of post-transcriptional regulation by micrornas: are the answers in sight?Nat Rev Genet2008 910214

    Not in our library10.1038/nrg2290

  2. 2.

    Ivey KN Muth A Arnold J Microrna regulation of cell lineages in mouse and human embryonic stem cellsCell Stem Cell2008 221929

    Not in our library10.1016/j.stem.2008.01.016

  3. 3.

    Chen JF Mandel EM Thomson JM The role of microrna-1 and microrna-133 in skeletal muscle proliferation and differentiationNat Genet2006 3822833

    Not in our library10.1038/ng1725

  4. 4.

    Zhao Y Ransom JF Li A Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking mirna-1–2Cell2007 12930317

    Not in our library10.1016/j.cell.2007.03.030

  5. 5.

    Plaisance V Abderrahmani A Perret–Menoud V Jacquemin P Lemaigre F Regazzi R Microrna-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cellsJ Biol Chem2006 2812693242

    Not in our library10.1074/jbc.m601225200

  6. 6.

    Lukiw WJ Pogue AI Induction of specific micro rna (mirna) species by ros-generating metal sulfates in primary human brain cellsJ Inorg Biochem2007 10112659

    Not in our library10.1016/j.jinorgbio.2007.06.004

  7. 7.

    Tarasov V Jung P Verdoodt B Differential regulation of micrornas by p53 revealed by massively parallel sequencing: mir-34a is a p53 target that induces apoptosis and G1-arrestCell Cycle2007 6158693

    Not in our library10.4161/cc.6.13.4436

  8. 8.

    Kumamoto K Spillare EA Fujita K Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescenceCancer Res2008 683193203

    Not in our library10.1158/0008-5472.can-07-2780

  9. 9.

    Maes OC An J Sarojini H Wang E Murine micrornas implicated in liver functions and aging processMech Ageing Dev2008 12953441

    Not in our library10.1016/j.mad.2008.05.004

  10. 10.

    Chen CZ Li L Lodish HF Bartel DP Micrornas modulate hematopoietic lineage differentiationScience2004 303836

    Not in our library10.1126/science.1091903

  11. 11.

    Rodriguez A Vigorito E Clare S Requirement of Bic/microrna-155 for normal immune functionScience2007 31660811

    Not in our library10.1126/science.1139253

  12. 12.

    Hébert SS Horré K Nicolaï L Loss of microrna cluster mir-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/β-secretase expressionProc Natl Acad Sci U S A2008 105641520

    Not in our library10.1073/pnas.0710263105

  13. 13.

    Wang WX Rajeev BW Stromberg AJ The expression of microrna mir-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1J Neurosci2008 28121323

    Not in our library10.1523/jneurosci.5065-07.2008

  14. 14.

    Wang G van der Walt JM Mayhew G Variation in the mirna-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synucleinAm J Hum Genet2008 822839

    Not in our library10.1016/j.ajhg.2007.09.021

  15. 15.

    Sayed D Hong C Chen IY Lypowy J Abdellatif M Micrornas play an essential role in the development of cardiac hypertrophyCirc Res2007 10041624

    Not in our library10.1161/01.res.0000257913.42552.23

  16. 16.

    Zhao Y Samal E Srivastava D Serum response factor regulates a muscle-specific microrna that targets Hand2 during cardiogenesisNature2005 43621420

    Not in our library10.1038/nature03817

  17. 17.

    Pezzolesi MG Platzer P Waite KA Eng C Differential expression of PTEN-targeting micrornas mir-19a and mir-21 in Cowden syndromeAm J Hum Genet2008 8211419

    Not in our library10.1016/j.ajhg.2008.04.005

  18. 18.

    Kuhn DE Nuovo GJ Martin MM Human chromosome 21–derived mirnas are overexpressed in Down syndrome brains and heartsBiochem Biophys Res Commun2008 3704737

    Not in our library10.1016/j.bbrc.2008.03.120

  19. 19.

    Blenkiron C Miska EA mirnas in cancer: approaches, aetiology, diagnostics and therapyHuman Mol Genet2007 16R10613

    Not in our library10.1093/hmg/ddm056

  20. 20.

    Reinhart BJ Slack FJ Basson M The 21-nucleotide let-7 rna regulates developmental timing in Caenorhabditis elegansNature2000 4039016

    Not in our library10.1038/35002607

  21. 21.

    Grishok A Pasquinelli AE Conte D Genes and mechanisms related to rna interference regulate expression of the small temporal rnas that control C. elegans developmental timingCell2001 62334

    Not in our library10.1016/s0092-8674(01)00431-7

  22. 22.

    Abbott AL Alvarez–Saavedra E Miska EA The let-7 microrna family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegansDev Cell2005 940314

    Not in our library10.1016/j.devcel.2005.07.009

  23. 23.

    Li M Jones–Rhoades MW Lau NC Bartel DP Rougvie AE Regulatory mutations of mir-48, a C. elegans let-7 family microrna, cause developmental timing defectsDev Cell2005 941522

    Not in our library10.1016/j.devcel.2005.08.002

  24. 24.

    Grosshans H Johnson T Reinert KL Gerstein M Slack FJ The temporal patterning microrna let-7 regulates several transcription factors at the larval to adult transition in C. elegansDev Cell2005 832130

    Not in our library10.1016/j.devcel.2004.12.019

  25. 25.

    Frasch M A matter of timing: microrna-controlled temporal identities in worms and fliesGenes Dev2008 2215726

    Not in our library10.1101/gad.1690608

  26. 26.

    Caygill EE Johnston LA Temporal regulation of metamorphic processes in Drosophila by the let-7 and mir-125 heterochronic micrornasCurr Biol2008 1894350

    Not in our library10.1016/j.cub.2008.06.020

  27. 27.

    Sokol NS Xu P Jan YN Ambros V Drosophila let-7 microrna is required for remodeling of the neuromusculature during metamorphosisGenes Dev2008 2215916

    Not in our library10.1101/gad.1671708

  28. 28.

    Wienholds E Kloosterman WP Miska E Microrna expression in zebrafish embryonic developmentScience2005 30931011

    Not in our library10.1126/science.1114519

  29. 29.

    Tsonis PA Call MK Grogg MW Micrornas and regeneration: let-7 members as potential regulators of dedifferentiation in lens and inner ear hair cell regeneration of the adult newtBiochem Biophys Res Commun2007 3629405

    Not in our library10.1016/j.bbrc.2007.08.077

  30. 30.

    Wulczyn FG Smirnova L Rybak A Post-transcriptional regulation of the let-7 microrna during neural cell specificationFASEB J2006 2141526

    Not in our library10.1096/fj.06-6130com

  31. 31.

    Ibarra I Erlich Y Muthuswamy SK Sachidanandam R Hannon GJ A role for micrornas in maintenance of mouse mammary epithelial progenitor cellsGenes Dev2007 21323843

    Not in our library10.1101/gad.1616307

  32. 32.

    Bar M Wyman SK Fritz BR Microrna discovery and profiling in human embryonic stem cells by deep sequencing of small rna librariesStem Cells2008 262496505

    Not in our library10.1634/stemcells.2008-0356

  33. 33.

    Mi S Lu J Sun M Microrna expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemiaProc Natl Acad Sci U S A2007 104199716

    Not in our library10.1073/pnas.0709313104

  34. 34.

    Nam S Kim B Shin S Lee S mirGator: an integrated system for functional annotation of micrornasNucleic Acids Res2008 36D15964

    Not in our library10.1093/nar/gkm829

  35. 35.

    Sempere LF Christensen M Silahtaroglu A Altered microrna expression confined to specific epithelial cell sub-populations in breast cancerCancer Res2007 671161220

    Not in our library10.1158/0008-5472.can-07-5019

  36. 36.

    Yu F Yao H Zhu P Let-7 regulates self renewal and tumorigenicity of breast cancer cellsCell2007 131110923

    Not in our library10.1016/j.cell.2007.10.054

  37. 37.

    Inamura K Togashi Y Nomura K Let-7 microrna expression is reduced in bronchioloalveolar carcinoma, a non-invasive carcinoma, and is not correlated with prognosisLung Cancer2007 583926

    Not in our library10.1016/j.lungcan.2007.07.013

  38. 38.

    Sampson VB Rong NH Han J Microrna let-7a downregulates MYC and reverts MYC-induced growth in Burkitt lymphoma cellsCancer Res2007 67976270

    Not in our library10.1158/0008-5472.can-07-2462

  39. 39.

    Michael MZ O’Connor SM van Holst Pellekaan NG Young GP James RJ Reduced accumulation of specific micrornas in colorectal neoplasiaMol Cancer Res2003 188291

    Not in our library

  40. 40.

    Akao Y Nakagawa Y Naoe T Let-7 microrna functions as a potential growth suppressor in human colon cancer cellsBiol Pharm Bull2006 299036

    Not in our library10.1248/bpb.29.903

  41. 41.

    Fang WJ Lin CZ Zhang HH Qian J Zhong L Xu N Detection of let-7a microrna by real-time pcr in colorectal cancer: a single-centre experience from ChinaJ Int Med Res2007 3571623

    Not in our library10.1177/147323000703500518

  42. 42.

    Zhang HH Wang XJ Li GX Yang E Yang NM Detection of let-7a microrna by real-time pcr in gastric carcinomaWorld J Gastroenterol2007 1328838

    Not in our library10.3748/wjg.v13.i20.2883

  43. 43.

    Motoyama K Inoue H Nakamura Y Uetake H Sugihara K Mori M Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microrna familyClin Cancer Res2008 14233440

    Not in our library10.1158/1078-0432.ccr-07-4667

  44. 44.

    Johnson CD Esquela–Kerscher A Stefani G The let-7 microrna represses cell proliferation pathways in human cellsCancer Res2007 67771322

    Not in our library10.1158/0008-5472.can-07-1083

  45. 45.

    Takamizawa J Konishi H Yanagisawa K Reduced expression of the let-7 micrornas in human lung cancers in association with shortened postoperative survivalCancer Res2004 6437536

    Not in our library10.1158/0008-5472.can-04-0637

  46. 46.

    Johnson SM Grosshans H Shingara J Ras is regulated by the let-7 microrna familyCell2005 12063547

    Not in our library10.1016/j.cell.2005.01.014

  47. 47.

    Schultz J Lorenz P Gross G Ibrahim S Kunz M Microrna let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growthCell Res2008 1854957

    Not in our library10.1038/cr.2008.45

  48. 48.

    Lu L Katsaros D de la Longrais IA Sochirca O Yu H Hyper-methylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-ii expression and favorable prognosisCancer Res2007 671011722

    Not in our library10.1158/0008-5472.can-07-2544

  49. 49.

    Jérôme T Laurie P Louis B Pierre C Enjoy the silence: the story of let-7 microrna and cancerCurr Genomics2007 822933

    Not in our library10.2174/138920207781386933

  50. 50.

    Jiang J Lee EJ Gusev Y Schmittgen TD Real-time expression profiling of microrna precursors in human cancer cell linesNucleic Acids Res2005 335394403

    Not in our library10.1093/nar/gki863

  51. 51.

    Garzon R Garofalo M Martelli MP Distinctive microrna signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosminProc Natl Acad Sci U S A2008 105394550

    Not in our library10.1073/pnas.0800135105

  52. 52.

    Kumar MS Erkeland SJ Pester RE Suppression of non-small cell lung tumor development by the let-7 microrna familyProc Natl Acad Sci U S A2008 10539038

    Not in our library10.1073/pnas.0712321105

  53. 53.

    Okamura K Phillips MD Tyler DM Duan H Chou YT Lai EC The regulatory activity of microrna* species has substantial influence on microrna and 3′ utr evolutionNat Struct Mol Biol2008 1535463

    Not in our library10.1038/nsmb.1409

  54. 54.

    Richards M Tan SP Tan JH Chan WK Bongso A The transcriptome profile of human embryonic stem cells as defined by SAGEStem Cells2004 225164

    Not in our library10.1634/stemcells.22-1-51

  55. 55.

    Viswanathan SR Daley GQ Gregory RI Selective blockade of microrna processing by Lin-28Science2008 32097100

    Not in our library10.1126/science.1154040

  56. 56.

    Heo I Joo C Cho J Ha M Han J Kim VN Lin28 mediates the terminal uridylation of let-7 precursor micrornaMol Cell2008 3227684

    Not in our library10.1016/j.molcel.2008.09.014

  57. 57.

    Newman MA Thomson JM Hammond SM Lin-28 interaction with the let-7 precursor loop mediates regulated microrna processingRNA2008 14153949

    Not in our library10.1261/rna.1155108

  58. 58.

    Piskounova E Viswanathan SR Janas M Determinants of microrna processing inhibition by the developmentally regulated rna-binding protein Lin28J Biol Chem2008 2832131014

    Not in our library10.1074/jbc.c800108200

  59. 59.

    Rybak A Fuchs H Smirnova L A feedback loop comprising lin-28 and let-7 controls pre–let-7 maturation during neural stem-cell commitmentNat Cell Biol2008 1098793

    Not in our library10.1038/ncb1759

  60. 60.

    Peter ME Let-7 and mir-200 micrornas: guardians against pluripotency and cancer progressionCell Cycle2009 884352

    Not in our library10.4161/cc.8.6.7907

  61. 61.

    Nishino J Kim I Chada K Morrison SJ Hmga2 promotes neural stem cell self-renewal in young, but not old, mice by reducing p16Ink4a and p19Arf expressionCell2008 13522739

    Not in our library10.1016/j.cell.2008.09.01

  62. 62.

    Lengner CJ Camargo FD Hochedlinger K OCT4 expression is not required for mouse somatic stem cell self-renewalCell Stem Cell2007 140315

    Not in our library10.1016/j.stem.2007.07.020

  63. 63.

    Droge P Davey CA Do cells let-7 determine stemness?Cell Stem Cell2008 289

    Not in our library10.1016/j.stem.2007.12.003

  64. 64.

    Boyerinas B Park SM Shomron N Identification of let-7–regulated oncofetal genesCancer Res2008 68258791

    Not in our library10.1158/0008-5472.can-08-0264

  65. 65.

    Dalerba P Cho RW Clarke MF Cancer stem cells: models and conceptsAnnu Rev Med2007 5826784

    Not in our library10.1146/annurev.med.58.062105.204854

  66. 66.

    Lobo NA Shimono Y Qian D Clarke MF The biology of cancer stem cellsAnnu Rev Cell Dev Biol2007 2367599

    Not in our library10.1146/annurev.cellbio.22.010305.104154

  67. 67.

    Park SM Shell S Radjabi AR Let-7 prevents early cancer progression by suppressing expression of the embryonic gene HMGA2Cell Cycle2007 6258590

    Not in our library10.4161/cc.6.21.4845

  68. 68.

    Giannini G Kim CJ Di Marcotullio L Expression of the HMGI(Y) gene products in human neuroblastic tumours correlates with differentiation statusBr J Cancer2000 8315039

    Not in our library10.1054/bjoc.2000.1494

  69. 69.

    Chiappetta G Bandiera A Berlingieri MT The expression of the high mobility group HMGI (Y) proteins correlates with the malignant phenotype of human thyroid neoplasiasOncogene1995 10130714

    Not in our library

  70. 70.

    Abe N Watanabe T Suzuki Y An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissueBr J Cancer2003 8921049

    Not in our library10.1038/sj.bjc.6601391

  71. 71.

    Sarhadi VK Wikman H Salmenkivi K Increased expression of high mobility group A proteins in lung cancerJ Pathol2006 20920612

    Not in our library10.1002/path.1960

  72. 72.

    Nielsen J Christiansen J Lykke–Andersen J Johnsen AH Wewer UM Nielsen FC A family of insulin-like growth factor ii mrna-binding proteins represses translation in late developmentMol Cell Biol1999 19126270

    Not in our library10.1128/mcb.19.2.1262

  73. 73.

    Hansen TV Hammer NA Nielsen J Dwarfism and impaired gut development in insulin-like growth factor ii mrna-binding protein 1–deficient miceMol Cell Biol2004 24444864

    Not in our library10.1128/mcb.24.10.4448-4464.2004

  74. 74.

    Yisraeli JK vickz proteins: a multi-talented family of regulatory rna-binding proteinsBiol Cell2005 978796

    Not in our library10.1042/bc20040151

  75. 75.

    Kiel MJ Iwashita T Yilmaz OH Morrison SJ Spatial differences in hematopoiesis but not in stem cells indicate a lack of regional patterning in definitive hematopoietic stem cellsDev Biol2005 2832939

    Not in our library10.1016/j.ydbio.2005.03.037

  76. 76.

    Sun Y Li H Liu Y Mattson MP Rao MS Zhan M Evolutionarily conserved transcriptional co-expression guiding embryonic stem cell differentiationPLoS ONE2008 33406

    Not in our library10.1371/journal.pone.0003406

  77. 77.

    Knoepfler PS Why Myc? An unexpected ingredient in the stem cell cocktailCell Stem Cell2008 21821

    Not in our library10.1016/j.stem.2007.12.004

  78. 78.

    Zhou X Benson KF Ashar HR Chada K Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor Hmgi-CNature1995 3767714

    Not in our library10.1038/376771a0

  79. 79.

    Ioannidis P Mahaira LG Perez SA CRD-BP/IMP1 expression characterizes cord blood CD34+ stem cells and affects C-myc and igf-ii expression in MCF-7 cancer cellsJ Biol Chem2005 2802008693

    Not in our library10.1074/jbc.m410036200

  80. 80.

    Shah YM Morimura K Yang Q Tanabe T Takagi M Gonzalez FJ ppara regulates an mirna-mediated signaling cascade responsible for hepatocellular proliferationMol Cell Biol2007 27423847

    Not in our library10.1128/mcb.00317-07

  81. 81.

    Chang TC Yu D Lee YS Widespread microrna repression by Myc contributes to tumorigenesisNat Genet2008 404350

    Not in our library10.1038/ng.2007.30

  82. 82.

    Barh D Parida S Parida BP Viswanathan G Let-7, mir-125, mir-205, and mir-296 are prospective therapeutic agents in breast cancer molecular medicineGene Ther Mol Biol2008 12189206

    Not in our library

  83. 83.

    Lee YS Dutta A The tumor suppressor microrna let-7 represses the HMGA2 oncogeneGenes Dev2007 21102530

    Not in our library10.1101/gad.1540407

  84. 84.

    Peng Y Laser J Shi G Antiproliferative effects by let-7 repression of high-mobility group A2 in uterine leiomyomaMol Cancer Res2008 666373

    Not in our library10.1158/1541-7786.mcr-07-0370

  85. 85.

    Tsang WP Kwok TT Let-7a microrna suppresses therapeutics-induced cancer cell death by targeting caspase-3Apoptosis2008 13121522

    Not in our library10.1007/s10495-008-0256-z

  86. 86.

    He YJ Guo L D ZH Let-7 and mir-24 in uvb-induced apoptosis [Chinese]Zhonghua Fang She Yi Xue Yu Fang Hu Za Zhi2009 292346

    Not in our library

  87. 87.

    Calin GA Sevignani C Dumitru CD Human microrna genes are frequently located at fragile sites and genomic regions involved in cancersProc Natl Acad Sci U S A2004 10129993004

    Not in our library10.1073/pnas.0307323101

  88. 88.

    Shell S Park SM Radjabi AR Let-7 expression defines two differentiation stages of cancerProc Natl Acad Sci U S A2007 104114005

    Not in our library10.1073/pnas.0704372104

  89. 89.

    Kuehbacher A Urbich C Zeiher AM Dimmeler S Role of Dicer and Drosha for endothelial microrna expression and angiogenesisCirc Res2007 1015968

    Not in our library10.1161/circresaha.107.153916

  90. 90.

    Esquela–Kerscher A Trang P Wiggins JF The let-7 microrna reduces tumor growth in mouse models of lung cancerCell Cycle2008 775964

    Not in our library10.4161/cc.7.6.5834

  91. 91.

    Grimm D Streetz KL Jopling CL Fatality in mice due to oversaturation of cellular microrna/short hairpin rna pathwaysNature2006 44153741

    Not in our library10.1038/nature04791

  92. 92.

    Krutzfeldt J Rajewsky N Braich R Silencing of micrornas in vivo with “antagomirsNature2005 4386859

    Not in our library10.1038/nature04303

  93. 93.

    Krutzfeldt J Kuwajima S Braich R Specificity, duplex degradation and subcellular localization of antagomirsNucleic Acids Res2007 35288592

    Not in our library10.1093/nar/gkm024

  94. 94.

    Valoczi A Hornyik C Varga N Burgyan J Kauppinen S Havelda Z Sensitive and specific detection of micrornas by northern blot analysis using lna-modified oligonucleotide probesNucleic Acids Res2004 32175

    Not in our library10.1093/nar/gnh171

  95. 95.

    Davis S Lollo B Freier S Esau C Improved targeting of mirna with antisense oligonucleotidesNucleic Acids Res2006 342294304

    Not in our library10.1093/nar/gkl183

  96. 96.

    Esau C Davis S Murray SF mir-122 regulation of lipid metabolism revealed by in vivo antisense targetingCell Metab2006 38798

    Not in our library10.1016/j.cmet.2006.01.005

  97. 97.

    Orom UA Kauppinen S Lund AH lna-modified oligonucleotides mediate specific inhibition of microrna functionGene2006 37213741

    Not in our library10.1016/j.gene.2005.12.031

  98. 98.

    Weiler J Hunziker J Hall J Anti-mirna oligonucleotides (amos): ammunition to target mirnas implicated in human disease?Gene Ther2006 13496502

    Not in our library10.1038/sj.gt.3302654

  99. 99.

    Esau CC Monia BP Therapeutic potential for micrornasAdv Drug Deliv Rev2007 5910114

    Not in our library10.1016/j.addr.2007.03.007

  100. 100.

    Brummelkamp TR Bernards R Agami R A system for stable expression of short interfering rnas in mammalian cellsScience2002 2965503

    Not in our library10.1126/science.1068999

  101. 101.

    Miyagishi M Taira K U6 promoter-driven sirnas with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cellsNat Biotechnol2002 20497500

    Not in our library10.1038/nbt0502-497

  102. 102.

    Soifer HS Rossi JJ Saetrom P Micrornas in disease and potential therapeutic applicationsMol Ther2007 1520709

    Not in our library10.1038/sj.mt.6300311

  103. 103.

    Boden D Pusch O Silbermann R Lee F Tucker L Ramratnam B Enhanced gene silencing of hiv-1 specific sirna using microrna designed hairpinsNucl Acids Res2004 3211548

    Not in our library10.1093/nar/gkh278

  104. 104.

    Chung KH Hart CC Al-Bassam S Polycistronic rna polymerase ii expression vectors for rna interference based on Bic/mir-155Nucl Acids Res2006 34e53

    Not in our library10.1093/nar/gkl143

  105. 105.

    Zeng Y Cai X Cullen BR Use of rna polymerase ii to transcribe artificial micrornasMethods Enzymol2005 39237180

    Not in our library10.1016/s0076-6879(04)92022-8

  106. 106.

    Zeng Y Wagner EJ Cullen BR Both natural and designed micro rnas can inhibit the expression of cognate mrnas when expressed in human cellsMol Cell2002 9132733

    Not in our library10.1016/s1097-2765(02)00541-5

  107. 107.

    Zhou H Xia XG Xu Z An rna polymerase ii construct synthesizes short-hairpin rna with a quantitative indicator and mediates highly efficient rnaiNucl Acids Res2005 33e62

    Not in our library10.1093/nar/gni061

  108. 108.

    Stegmeier F Hu G Rickles RJ Hannon GJ Elledge SJ A lentiviral microrna-based system for single-copy polymerase ii–regulated rna interference in mammalian cellsProc Natl Acad Sci U S A2005 1021321217

    Not in our library10.1073/pnas.0506306102

  109. 109.

    Chen S Ni M Yu B Lv T Lu M Gong F Construction and identification of a human liver specific microrna eukaryotic expression vectorCell Mol Immunol2007 44737

    Not in our library

  110. 110.

    Wolfrum C Shi S Jayaprakash KN Mechanisms and optimization of in vivo delivery of lipophilic sirnasNat Biotechnol2007 25114957

    Not in our library10.1038/nbt1339

Cited by papers we hold 6

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.