- Open Access
Dysregulation of MicroRNAs in cancer
© Chen et al.; licensee BioMed Central Ltd. 2012
- Received: 28 September 2012
- Accepted: 16 October 2012
- Published: 17 October 2012
MicroRNAs (miRNAs) are involved in multiple biological activities as well as disease progression including cancer. Interestingly, miRNAs could act as either tumor suppressors or oncogenes depending on the functions of their targets. Using high-throughput profiling, dysregulation of miRNAs has been widely observed in different stages of cancer, and there is mounting evidence demonstrating several misguided mechanisms that cause miRNA dysregulation. In this review, we summarize the key functions of miRNAs in cancer, especially those affecting tumor metastasis and drug resistance. Moreover, the mechanisms leading to dysregulation of miRNAs, including genomic abnormalities, DNA/histone modifications, transcriptional regulation, abnormal biogenesis, and interaction between miRNAs, are also discussed.
- Cancer progression
- miRNA biogenesis
- miRNA dysregulation
MicroRNAs (miRNAs) are small noncoding RNAs which enhance the cleavage or translational repression of specific mRNA with recognition site(s) in the 3’-untranslated region (3′UTR). The biogenesis of miRNA is controlled by two RNase-dependent processing steps that converts a long primary transcript into a mature ~20 nt miRNA. The mature miRNA are released and then loaded onto the miRNA-induced silencing complex (miRISC), which acts as a guiding strand to recognize specific mRNA targets. Since the discovery of miRNAs, several large-scale studies have compared the profiles of miRNA expression patterns between corresponding non-tumor and tumor tissues [1, 2]. Dysregulation of miRNAs has been documented in different types of human cancers [1, 2]. As miRNA expression is tissue-specific, the expression profile of miRNAs has been proposed as a marker to identify tumor origin . Several studies have also suggested that the expression of miRNAs may even be a more reliable and better prognostic indicator than proteins or mRNAs under certain conditions [1, 3, 4]. For example, a five-miRNA signature profile could predict the cancer relapse and survival in NSCLC patients . In addition, the expression of 25 miRNAs could classify tissues as normal pancreas, chronic pancreatitis, or pancreatic adenocarcinoma . Currently, numerous cancer-specific miRNAs have been functionally identified, and the mechanisms underlying miRNA regulation are becoming more complete.
Emerging roles of miRNAs in cancer
Let-7 is the most studied miRNA both in development and cancer. The human let-7 family comprises 12 closely related members of miRNA (let-7-a-1, a-2, a-3, b, c, d, e, f-1, f-2, g, i and miR-98). Johnson et al. reported that let-7 is downregulated in lung cancer and is associated with elevated RAS expression . They further showed that let-7 is complementary to multiple sites in the 3′UTR of the human RAS genes, allowing let-7 to suppress the expression of K-RAS and N-RAS. The tumor suppressive roles of let-7 are further strengthened by its antagonistic roles toward the expression of multiple oncogenes including RAS, MYC, and other cell cycle regulators in a variety of human cancer tissues [6–8]. For example, let-7 directly targets other proto-oncogenes such as CDK6, cyclin D, CCND2, and CDC25A and represses cell proliferation by promoting the G1 to S transition . In addition, high mobility group A2 (HMGA2), an oncogene frequently mutated in multiple types of cancers, is also hindered by let-7 . There are seven let-7 binding sites in the 3′UTR of HMGA2 mRNA. Disrupting the interaction between let-7 and these binding sites reduces let-7-mediated HMGA2 downregulation and consequently enhances anchorage-independent growth of cancer cells [9, 10]. Recent studies also suggest that let-7 regulates metastasis-associated genes such as MYH9 and C-C chemokine receptor type 7 (CCR7) to facilitate invasion ability of cancer cells [11, 12].
MiRNAs derived from miR-17-92 cluster, which contains seven homologous miRNAs, including miR-17-3p, miR-17-5p, miR-18a, miR-20a, miR-19a, miR-19b-1, and miR-92a-1, have been identified as oncogenic miRNAs. These miRNAs target multiple genes involved in proapoptotic pathways, reflecting their oncogenic activities [13, 14]. The oncogenic roles of miR-17-92 cluster were reported by He et al. in which expression of this cluster accelerated c-Myc-induced lymphoma development and resulted in an advanced tumor in Eu-Myc transgenic mouse model of human B cell lymphoma . The direct targets of miR-17-92 cluster have been identified to include Bim, PTEN, and p21 [13, 15]. However, several controversial studies indicated that miR-17-92 possesses tumor suppressor activities. For instance, miR-17-92 cluster inhibits E2F1 to abolish Myc-induced cell proliferation, and miR-17-5p represses proliferation of breast cancer cells through targeting AIB1 [16, 17].
MiR-21 has been shown to be overexpressed in a wide variety of cancers, including malignant human glioblastoma tumor tissues . Knockdown of miR-21 induced activation of caspases and resulted in apoptosis in glioblastoma cells . In addition, Papagiannakopoulos et al. indicated that knockdown of miR-21 activates the p53 pathway, mediates the induction of TGF-β signaling, and eventually suppresses cell growth, increases apoptosis, and induces cell cycle arrest in glioblastoma cells . Downregulation of miR-21 also repressed cell growth in breast cancer cells by directly regulating PDCD4 tumor suppressor . Moreover, Yao et al. reported a proliferation-promoting function of miR-21 in which knockdown of miR-21 suppressed proliferation of HeLa cells . These studies suggest that miR-21 enables cells to gain their growth advantages.
The roles of miRNAs in tumor metastasis
Functions of miRNAs in drug resistance
In addition to the studies showing that miRNAs are associated with tumorigenesis and metastasis, several miRNAs have also been found to affect the drug resistance of cancer cells (Figure 1). MiR-519c was first found to increase drug sensitivity of colon cancer cells by regulating ABCG2  and was later shown to suppress the expression of HIF-1α which consequently attenuates tumor angiogenesis . Paradoxically, Su et al. showed that E1A downregulates the expression of miR-520h, induces protein phosphatase PP2A/C upregulation, suppresses IKK/NF-κB pathway, and eventually, mitigates Twist expression in breast cancer . Recently, Yu et al. further demonstrated an oncogenic effect of miR-520h via repression of PP2A/C. Interestingly, the expression of miR-520h is inhibited by resveratrol, leading to NF-κB-mediated reduction of Forkhead box protein C2 (FOXC2) . These studies indicate that miR-520 family could act as tumor suppressor or oncogenes depending on their downstream signaling. MiR-15a and miR-16-1 have been documented as tumor suppressor in chronic lymphocytic leukemia (CLL) . They are clustered on human chromosome 13q14, which is frequently deleted or downregulated in CLL and some solid tumors. Because the 3′UTR region of antiapoptotic BCL2 mRNA contains a potential binding site for these miRNAs, a deficiency in miR-15a and miR-16-1 enhances the expression of BCL2, blocking the cleavage of pro-caspase 9 and poly-ADP-ribose polymerase (PARP) required to activate the intrinsic apoptosis pathway. Further studies revealed that expression of miR-15b and miR-16 negatively regulate the Bcl-2 protein level, leading to sensitization of gastric cancer cells to anticancer drugs . Another miRNA, miR-451, has been found to be downregulated in the doxorubicin-resistant breast cancer cells. While expression of miR-451 sensitized breast cancer cells to doxorubicin treatment through regulating Mdr1/P-glycoprotein , Zhu et al. identified a controversial role of miR-451 in protecting cancer cells from anticancer drugs . Functional inhibition of miR-21 has been shown to dramatically reduce the topotecan-resistance of breast cancer cells . The tumor suppressor function of miR-29 has also been identified in human cholangiocarcinoma . Mott et al. observed an inverse correlation between Mcl-1 protein and miR-29b expression. They further demonstrated the ability of miR-29 to inhibit expression of Mcl-1 protein and sensitize cancer cells to TRAIL cytotoxicity through targeting a putative target site in the 3′UTR of Mcl-1 mRNA. Later, Garzon et al. found that ectopic expression of miR-29b downregulates the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B in AML cell, resulting in increased global DNA hypomethylation and restoring the expression of tumor suppressor genes such as the CDK inhibitor p15INK4b and oestrogen receptor, ESR1 . In nasopharyngeal carcinoma, miR-29c also suppresses the metastasis by downregulating collagen and laminin 1 .
Mechanisms of dysregulation of miRNAs in cancer
CpG methylation and histone modification
Transcriptional silencing of tumor suppressor genes by CpG island promoter hypermethylation is a common hallmark of cancer. Similar phenomenon has been identified in miRNA regulation in which Saito et al. showed that a subset of miRNAs is upregulated by treatment of inhibitors specific for DNA methylation (5-aza-2′-deoxycytidine) or histone deacetylase (4-phenylbutyric acid) in cancer cells . One of these miRNAs, miR-127, is downregulated in human cancers. MiR-127 is embedded in a CpG island and dramatically upregulated through its own promoter, suggesting that DNA methylation or histone modification at this promoter region hinders the expression of miR-127 in cancer cells. The downstream target of miR-127, Bcl-6, is also consistently repressed after the treatments. Lujambio et al. later identified another miRNA that is transcriptionally repressed in cancer cells by CpG island hypermethylation . They investigated the profile of miRNA expression in cells lacking DNA methyltransferases and found that miRNA-124a is downregulated by CpG island hypermethylation. This epigenetic silencing subsequently activates CDK6 and induces Rb phosphorylation . One of the let-7 genes, Let-7a-3, is also located within the CpG islands. Lu et al. found that let-7a-3 gene is hypermethylated in ovarian cancer and hypermethylated let-7a-3 is associated with downregulation of IGFII expression and poor prognosis in ovarian cancer patients, suggesting that let-7 expression may target IGF-II . Recently, Mazar et al. identified several miRNAs regulated epigenetically in melanoma. MiR-375 is one of these miRNAs with hypomethylation in melanocytes, keratinocytes, and normal skin. In contrast, tissues of melanoma exhibits hypermethylated miR-375 . Overexpression of miR-375 alters the cell morphology and attenuates proliferation and invasion of melanoma cells, indicating a tumor suppressive function of miR-375 . These studies explain the mechanisms of DNA/histone methylation-regulated miRNAs in human cancers.
Abnormal maturation pathways
After generation of primary miRNAs, a two-step RNase-dependent maturation pathway is required to produce mature miRNAs (Figure 2). First, primary miRNAs (pri-miRNA) are processed by Drosha-containing complex to stem-loop pre-miRNAs, which are then further processed by the second RNase, Dicer, to short, double-strand duplexes. Eventually, one of the functional strands in the resulting duplexes is preserved, forming a functional complex with the RISC proteins, and acts as guiding strands for specific recognition. Currently, several RNA-binding proteins have been found to affect this canonical pathway with some that are involved in the regulation of cancer progression.
Lin-28 is the most studied RNA-binding protein being capable of regulating let-7 biogenesis. Overexpression of Lin-28 has been shown as an unfavorable prognostic marker in human cancers . Lin-28 modulates the structural alternation of pre-let-7g to inhibit Dicer-dependent processing . Another mechanism underlying let-7-mediated Dicer processing step also has been uncovered in which the terminal uridylyltransferase 4 (TUT4) is recruited by Lin-28 to promote uridylation of pre-let-7, and thus destabilizing pre-let-7 and blocking Dicer-dependent maturation . Lin-28B, a homolog of Lin-28 (also called Lin-28A), also modulates let-7 maturation in a TUT4-independent pathway . Both mechanisms result in the downregulation of mature let-7, leading to cancer progression.
The KH-type splicing regulatory protein (KSRP) was identified to enhance both Drosha- and Dicer-mediated miRNA processing through interaction with specific sequences in the loop region of a subset of pri-miRNAs . Knockdown of KSRP represses the expression of specific mature miRNAs, such as let-7a and miR-206, and consequently affects cell proliferation and differentiation. Regulation at the pri-miRNA to pre-miRNA processing step is also affected by hnRNP A1, a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein. HnRNP A1 facilitates pri-miR-18a for conversion into pre-miR-18a  and recognizes the highly-conserved loop region of miR-18a, resulting in a structural rearrangement of this hairpin to generate a more favorable cleavage site for Drosha . Furthermore, upon binding to hnRNP A1, pri-let-7a-1 is unable to be processed by KSRP because the conserved binding site of hnRNP A1 for pri-let-7a overlaps with that of KSRP .
The two DEAD-box RNA helicases, p68 (DDX5) and p72 (DDX17), are components of the Drosha microprocessor complex . Recently, protein factors associating with the Drosha-p68 or Drosha-p72 have been identified as key regulators controlling miRNA biogenesis. The transforming growth factor-β (TGF-β) family and its signal transducers, Smads, play important roles during cancer progression. TGF-β and one of its family members, the bone morphogenetic protein 4 (BMP4), was found to induce the expression of mature miR-21 through an R-smad-dependent pathway . This effect was further identified to be posttranscriptional, as they upregulate pre- and mature miR-21 without affecting pri-miR-21 . R-smad interacts and stabilizes Drosha-p68 complex on the pri-miR-21 hairpin, thus promoting the maturation of miR-21. In addition to its function as a transcription factor, p53 was also identified to modulate miRNA biogenesis directly by binding to Drosha-p68 complex . A subset of miRNAs, such as miR-143 and miR-16, are induced posttranscriptionally under DNA damage condition, whereas this effect could not be observed in p53-null HCT116 cells . Another report indicated that estrogen receptor-α (ERα) also interacts with Drosha-p72 complex, leading to a reduced affinity of Drosha complex to a subset of miRNA in the presence of estradiol . Recently, Kawai et al. demonstrated that breast cancer 1 (BRCA1), a human tumor suppressor gene, regulates miRNA biogenesis by recognizing pri-miRNA and binding to the Drosha microprocessor and Smads/p53, which enhances processing of a subset of miRNAs . As the above-mentioned protein factors are critical determinants during cancer progression, it would be interesting to investigate the detailed mechanisms mediating miRNA biogenesis in the context of cancer.
After processing, mature miRNAs are produced as functional strands, loaded onto miRISC, and targeted to specific 3′UTRs, thereafter. In addition to the binding between miRNA and 3′UTR of its target mRNA, Chen et al. recently identified a direct interaction between two individual miRNAs, miR-107 and let-7 (Figure 2). This study provides the first evidence that two different miRNAs could interact directly with each other through sequence match . Using a mutation system, Chen et al. further identified the essential role of an internal loop within the miR-107::let-7 duplex, which provides important clues for further investigation on the underlying mechanism . MiR-107 mitigates the tumor suppressive effects of let-7, and thus facilitating cancer progression. As endogenous let-7 is capable of suppressing the expression of multiple oncogenes including Ras and Hmga2, inhibition of let-7 allows cancer cells becoming aggressive. During the progression of cancer, overexpressed miR-107 targets and destabilizes let-7, enabling oncoproteins to escape from let-7-mediated suppression. Another study simultaneously published by Tang et al. also provides functional evidence of miRNA-miRNA interaction between miR-709 and pri-miR-15a/16-1 . This newly discovered regulation sheds light on our current knowledge in the posttranscriptional control of miRNA. Considering the interaction and the multi-faceted roles of a given miRNA may have, the regulation network of miRNA becomes more complex than we originally thought.
MiRNAs have been known to function in most physiological processes in humans. As dysregulated expression of specific miRNAs is a common phenomenon observed in human cancers, unraveling the underlying mechanisms misguided at each step of miRNA biogenesis is crucial to our knowledge on how these miRNAs are altered. Accumulating evidence in both transcriptional and posttranscriptional regulation have enabled us to understand the novel functions of classical transcription factors, and more interestingly, RNA binding proteins, in controlling cancer-specific miRNAs. Because miRNAs play key roles in human cancer, identifying the underlying pathways will provide a more complete understanding of their functions and regulations during cancer progression and may have clinical applications in the future.
This work was supported by grants from the U.S. National Institutes of Health (RO1 CA109311 and PO1 CA099031), National Science Council, Taiwan (NSC 99-2314-B-039-002-MY3); National Health Research Institutes grants from Taiwan (NHRI-EX101-10033BI and NHRI-EX100-9712BC); grants from China Medical University (CMU99-TC-22 and CMU100-S-22); and The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (DMR-101-115). We apologize to the many investigators whose important studies could not be cited directly here owing to space limitation.
- Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR: MicroRNA expression profiles classify human cancers. Nature. 2005, 435 (7043): 834-838. 10.1038/nature03702.View ArticlePubMedGoogle Scholar
- Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 2006, 6 (11): 857-866. 10.1038/nrc1997.View ArticlePubMedGoogle Scholar
- Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, Cheng CL, Yu CJ, Lee YC, Chen HS, Su TJ, Chiang CC, Li HN, Hong QS, Su HY, Chen CC, Chen WJ, Liu CC, Chan WK, Li KC, Chen JJ, Yang PC: MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell. 2008, 13 (1): 48-57. 10.1016/j.ccr.2007.12.008.View ArticlePubMedGoogle Scholar
- Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005, 353 (17): 1793-1801. 10.1056/NEJMoa050995.View ArticlePubMedGoogle Scholar
- Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu CG, Bhatt D, Taccioli C, Croce CM: MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. Jama. 2007, 297 (17): 1901-1908. 10.1001/jama.297.17.1901.View ArticlePubMedGoogle Scholar
- Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ: RAS is regulated by the let-7 microRNA family. Cell. 2005, 120 (5): 635-647. 10.1016/j.cell.2005.01.014.View ArticlePubMedGoogle Scholar
- Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, Jacks T: Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci U S A. 2008, 105 (10): 3903-3908. 10.1073/pnas.0712321105.PubMed CentralView ArticlePubMedGoogle Scholar
- Nadiminty N, Tummala R, Lou W, Zhu Y, Shi XB, Zou JX, Chen H, Zhang J, Chen X, Luo J, Devere White RW, Kung HJ, Evans CP, Gao AC: MicroRNA let-7c Is Downregulated in Prostate Cancer and Suppresses Prostate Cancer Growth. PLoS One. 2012, 7 (3): e32832-10.1371/journal.pone.0032832.PubMed CentralView ArticlePubMedGoogle Scholar
- Mayr C, Hemann MT, Bartel DP: Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science. 2007, 315 (5818): 1576-1579. 10.1126/science.1137999.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee YS, Dutta A: The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev. 2007, 21 (9): 1025-1030. 10.1101/gad.1540407.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim SJ, Shin JY, Lee KD, Bae YK, Sung KW, Nam SJ, Chun KH: MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7. Breast Cancer Res. 2012, 14 (1): R14-10.1186/bcr3098.PubMed CentralView ArticlePubMedGoogle Scholar
- Liang S, He L, Zhao X, Miao Y, Gu Y, Guo C, Xue Z, Dou W, Hu F, Wu K, Nie Y, Fan D: MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer. PLoS One. 2011, 6 (4): e18409-10.1371/journal.pone.0018409.PubMed CentralView ArticlePubMedGoogle Scholar
- Olive V, Bennett MJ, Walker JC, Ma C, Jiang I, Cordon-Cardo C, Li QJ, Lowe SW, Hannon GJ, He L: miR-19 is a key oncogenic component of mir-17-92. Genes Dev. 2009, 23 (24): 2839-2849. 10.1101/gad.1861409.PubMed CentralView ArticlePubMedGoogle Scholar
- He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM: A microRNA polycistron as a potential human oncogene. Nature. 2005, 435 (7043): 828-833. 10.1038/nature03552.PubMed CentralView ArticlePubMedGoogle Scholar
- Hong L, Lai M, Chen M, Xie C, Liao R, Kang YJ, Xiao C, Hu WY, Han J, Sun P: The miR-17-92 cluster of microRNAs confers tumorigenicity by inhibiting oncogene-induced senescence. Cancer Res. 2010, 70 (21): 8547-8557. 10.1158/0008-5472.CAN-10-1938.PubMed CentralView ArticlePubMedGoogle Scholar
- Coller HA, Forman JJ, Legesse-Miller A: "Myc'ed messages": myc induces transcription of E2F1 while inhibiting its translation via a microRNA polycistron. PLoS Genet. 2007, 3 (8): e146-10.1371/journal.pgen.0030146.PubMed CentralView ArticlePubMedGoogle Scholar
- Hossain A, Kuo MT, Saunders GF: Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol Cell Biol. 2006, 26 (21): 8191-8201. 10.1128/MCB.00242-06.PubMed CentralView ArticlePubMedGoogle Scholar
- Chan JA, Krichevsky AM, Kosik KS: MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005, 65 (14): 6029-6033. 10.1158/0008-5472.CAN-05-0137.View ArticlePubMedGoogle Scholar
- Corsten MF, Miranda R, Kasmieh R, Krichevsky AM, Weissleder R, Shah K: MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res. 2007, 67 (19): 8994-9000. 10.1158/0008-5472.CAN-07-1045.View ArticlePubMedGoogle Scholar
- Papagiannakopoulos T, Shapiro A, Kosik KS: MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 2008, 68 (19): 8164-8172. 10.1158/0008-5472.CAN-08-1305.View ArticlePubMedGoogle Scholar
- Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH: Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 2008, 283 (2): 1026-1033. 10.1074/jbc.M707224200.View ArticlePubMedGoogle Scholar
- Yao Q, Xu H, Zhang QQ, Zhou H, Qu LH: MicroRNA-21 promotes cell proliferation and down-regulates the expression of programmed cell death 4 (PDCD4) in HeLa cervical carcinoma cells. Biochem Biophys Res Commun. 2009, 388 (3): 539-542. 10.1016/j.bbrc.2009.08.044.View ArticlePubMedGoogle Scholar
- Ma L, Weinberg RA: Micromanagers of malignancy: role of microRNAs in regulating metastasis. Trends Genet. 2008, 24 (9): 448-456. 10.1016/j.tig.2008.06.004.View ArticlePubMedGoogle Scholar
- Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA: MicroRNAs–the micro steering wheel of tumour metastases. Nat Rev Cancer. 2009, 9 (4): 293-302. 10.1038/nrc2619.View ArticlePubMedGoogle Scholar
- Ma L, Teruya-Feldstein J, Weinberg RA: Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007, 449 (7163): 682-688. 10.1038/nature06174.View ArticlePubMedGoogle Scholar
- Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J: Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008, 451 (7175): 147-152. 10.1038/nature06487.PubMed CentralView ArticlePubMedGoogle Scholar
- Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008, 133 (4): 704-715. 10.1016/j.cell.2008.03.027.PubMed CentralView ArticlePubMedGoogle Scholar
- Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH, Liu M, Chen CT, Yu D, Hung MC: p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol. 2011, 13 (3): 317-323. 10.1038/ncb2173.PubMed CentralView ArticlePubMedGoogle Scholar
- Xu Y: MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1. Oncogene. 2011, 31 (11): 1398-407.PubMed CentralView ArticlePubMedGoogle Scholar
- Lynch J: MiRNA-335 Suppresses Neuroblastoma Cell Invasiveness By Direct Targeting of Multiple Genes from the non-Canonical TGF-beta Signalling Pathway. Carcinogenesis. 2012, 33 (5): 976-85. 10.1093/carcin/bgs114.PubMed CentralView ArticlePubMedGoogle Scholar
- Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, Egan DA, Li A, Huang G, Klein-Szanto AJ, Gimotty PA, Katsaros D, Coukos G, Zhang L, Pure E, Agami R: The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol. 2008, 10 (2): 202-210. 10.1038/ncb1681.View ArticlePubMedGoogle Scholar
- Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G, Nojima H, Looijenga LH, Agami R: A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006, 124 (6): 1169-1181. 10.1016/j.cell.2006.02.037.View ArticlePubMedGoogle Scholar
- Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y, Li Q, Qiao T, Zhao Q, Nie Y, Fan D: MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 2010, 6 (3): e1000879-10.1371/journal.pgen.1000879.PubMed CentralView ArticlePubMedGoogle Scholar
- Ding Q, Chang CJ, Xie X, Xia W, Yang JY, Wang SC, Wang Y, Xia J, Chen L, Cai C, Li H, Yen CJ, Kuo HP, Lee DF, Lang J, Huo L, Cheng X, Chen YJ, Li CW, Jeng LB, Hsu JL, Li LY, Tan A, Curley SA, Ellis LM, Dubois RN, Hung MC: APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis. The Journal of clinical investigation. 2011, 121 (11): 4526-4536. 10.1172/JCI45008.PubMed CentralView ArticlePubMedGoogle Scholar
- To KK, Robey RW, Knutsen T, Zhan Z, Ried T, Bates SE: Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2. Mol Cancer Ther. 2009, 8 (10): 2959-2968. 10.1158/1535-7163.MCT-09-0292.PubMed CentralView ArticlePubMedGoogle Scholar
- Cha ST, Chen PS, Johansson G, Chu CY, Wang MY, Jeng YM, Yu SL, Chen JS, Chang KJ, Jee SH, Tan CT, Lin MT, Kuo ML: MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis. Cancer Res. 2010, 70 (7): 2675-2685. 10.1158/0008-5472.CAN-09-2448.View ArticlePubMedGoogle Scholar
- Su JL, Chen PB, Chen YH, Chen SC, Chang YW, Jan YH, Cheng X, Hsiao M, Hung MC: Downregulation of microRNA miR-520h by E1A contributes to anticancer activity. Cancer Res. 2010, 70 (12): 5096-5108. 10.1158/0008-5472.CAN-09-4148.PubMed CentralView ArticlePubMedGoogle Scholar
- Yu YH: MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol. Oncogene. 2012, 10.1038/onc.2012.74. [Epub ahead of print]Google Scholar
- Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005, 102 (39): 13944-13949. 10.1073/pnas.0506654102.PubMed CentralView ArticlePubMedGoogle Scholar
- Xia L, Zhang D, Du R, Pan Y, Zhao L, Sun S, Hong L, Liu J, Fan D: miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 2008, 123 (2): 372-379. 10.1002/ijc.23501.View ArticlePubMedGoogle Scholar
- Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, Chekhun VF, Pogribny IP: Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 2008, 7 (7): 2152-2159. 10.1158/1535-7163.MCT-08-0021.View ArticlePubMedGoogle Scholar
- Zhu H, Wu H, Liu X, Evans BR, Medina DJ, Liu CG, Yang JM: Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol. 2008, 76 (5): 582-588. 10.1016/j.bcp.2008.06.007.PubMed CentralView ArticlePubMedGoogle Scholar
- Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY: miR-21-mediated tumor growth. Oncogene. 2007, 26 (19): 2799-2803. 10.1038/sj.onc.1210083.View ArticlePubMedGoogle Scholar
- Mott JL, Kobayashi S, Bronk SF, Gores GJ: mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene. 2007, 26 (42): 6133-6140. 10.1038/sj.onc.1210436.PubMed CentralView ArticlePubMedGoogle Scholar
- Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E, Schwind S, Pang J, Yu J, Muthusamy N, Havelange V, Volinia S, Blum W, Rush LJ, Perrotti D, Andreeff M, Bloomfield CD, Byrd JC, Chan K, Wu LC, Croce CM, Marcucci G: MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 2009, 113 (25): 6411-6418. 10.1182/blood-2008-07-170589.PubMed CentralView ArticlePubMedGoogle Scholar
- Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, Chen CJ, Hildesheim A, Sugden B, Ahlquist P: MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci U S A. 2008, 105 (15): 5874-5878. 10.1073/pnas.0801130105.PubMed CentralView ArticlePubMedGoogle Scholar
- Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004, 101 (9): 2999-3004. 10.1073/pnas.0307323101.PubMed CentralView ArticlePubMedGoogle Scholar
- Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM: Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002, 99 (24): 15524-15529. 10.1073/pnas.242606799.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A, O'Brien-Jenkins A, Katsaros D, Hatzigeorgiou A, Gimotty PA, Weber BL, Coukos G: microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci U S A. 2006, 103 (24): 9136-9141. 10.1073/pnas.0508889103.PubMed CentralView ArticlePubMedGoogle Scholar
- Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A: High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer. 2004, 39 (2): 167-169. 10.1002/gcc.10316.View ArticlePubMedGoogle Scholar
- Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, Jones PA: Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 2006, 9 (6): 435-443. 10.1016/j.ccr.2006.04.020.View ArticlePubMedGoogle Scholar
- Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, Casado S, Suarez-Gauthier A, Sanchez-Cespedes M, Git A, Spiteri I, Das PP, Caldas C, Miska E, Esteller M: Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007, 67 (4): 1424-1429. 10.1158/0008-5472.CAN-06-4218.View ArticlePubMedGoogle Scholar
- Lu L, Katsaros D, de la Longrais IA, Sochirca O, Yu H: Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Cancer Res. 2007, 67 (21): 10117-10122. 10.1158/0008-5472.CAN-07-2544.View ArticlePubMedGoogle Scholar
- Mazar J, DeBlasio D, Govindarajan SS, Zhang S, Perera RJ: Epigenetic regulation of microRNA-375 and its role in melanoma development in humans. FEBS Lett. 2011, 585 (15): 2467-2476. 10.1016/j.febslet.2011.06.025.View ArticlePubMedGoogle Scholar
- He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ: A microRNA component of the p53 tumour suppressor network. Nature. 2007, 447 (7148): 1130-1134. 10.1038/nature05939.PubMed CentralView ArticlePubMedGoogle Scholar
- Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M: Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007, 26 (5): 731-743. 10.1016/j.molcel.2007.05.017.View ArticlePubMedGoogle Scholar
- Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, Arking DE, Beer MA, Maitra A, Mendell JT: Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007, 26 (5): 745-752. 10.1016/j.molcel.2007.05.010.PubMed CentralView ArticlePubMedGoogle Scholar
- O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT: c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005, 435 (7043): 839-843. 10.1038/nature03677.View ArticlePubMedGoogle Scholar
- Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, Dang CV, Thomas-Tikhonenko A, Mendell JT: Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008, 40 (1): 43-50. 10.1038/ng.2007.30.PubMed CentralView ArticlePubMedGoogle Scholar
- Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A: E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008, 13 (3): 272-286. 10.1016/j.ccr.2008.02.013.View ArticlePubMedGoogle Scholar
- Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, O'Sullivan M, Lu J, Phillips LA, Lockhart VL, Shah SP, Tanwar PS, Mermel CH, Beroukhim R, Azam M, Teixeira J, Meyerson M, Hughes TP, Llovet JM, Radich J, Mullighan CG, Golub TR, Sorensen PH, Daley GQ: Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009, 41 (7): 843-848. 10.1038/ng.392.PubMed CentralView ArticlePubMedGoogle Scholar
- Lightfoot HL, Bugaut A, Armisen J, Lehrbach NJ, Miska EA, Balasubramanian S: A LIN28-dependent structural change in pre-let-7g directly inhibits dicer processing. Biochemistry. 2011, 50 (35): 7514-7521. 10.1021/bi200851d.PubMed CentralView ArticlePubMedGoogle Scholar
- Hagan JP, Piskounova E, Gregory RI: Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol. 2009, 16 (10): 1021-1025. 10.1038/nsmb.1676.PubMed CentralView ArticlePubMedGoogle Scholar
- Piskounova E, Polytarchou C, Thornton JE, LaPierre RJ, Pothoulakis C, Hagan JP, Iliopoulos D, Gregory RI: Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell. 2011, 147 (5): 1066-1079. 10.1016/j.cell.2011.10.039.PubMed CentralView ArticlePubMedGoogle Scholar
- Trabucchi M, Briata P, Garcia-Mayoral M, Haase AD, Filipowicz W, Ramos A, Gherzi R, Rosenfeld MG: The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature. 2009, 459 (7249): 1010-1014. 10.1038/nature08025.PubMed CentralView ArticlePubMedGoogle Scholar
- Guil S, Caceres JF: The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol. 2007, 14 (7): 591-596. 10.1038/nsmb1250.View ArticlePubMedGoogle Scholar
- Michlewski G, Guil S, Semple CA, Caceres JF: Posttranscriptional regulation of miRNAs harboring conserved terminal loops. Mol Cell. 2008, 32 (3): 383-393. 10.1016/j.molcel.2008.10.013.PubMed CentralView ArticlePubMedGoogle Scholar
- Michlewski G, Caceres JF: Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nat Struct Mol Biol. 2010, 17 (8): 1011-1018. 10.1038/nsmb.1874.PubMed CentralView ArticlePubMedGoogle Scholar
- Shiohama A, Sasaki T, Noda S, Minoshima S, Shimizu N: Nucleolar localization of DGCR8 and identification of eleven DGCR8-associated proteins. Exp Cell Res. 2007, 313 (20): 4196-4207. 10.1016/j.yexcr.2007.07.020.View ArticlePubMedGoogle Scholar
- Davis BN, Hilyard AC, Lagna G, Hata A: SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008, 454 (7200): 56-61. 10.1038/nature07086.PubMed CentralView ArticlePubMedGoogle Scholar
- Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K: Modulation of microRNA processing by p53. Nature. 2009, 460 (7254): 529-533. 10.1038/nature08199.View ArticlePubMedGoogle Scholar
- Yamagata K, Fujiyama S, Ito S, Ueda T, Murata T, Naitou M, Takeyama K, Minami Y, O'Malley BW, Kato S: Maturation of microRNA is hormonally regulated by a nuclear receptor. Mol Cell. 2009, 36 (2): 340-347. 10.1016/j.molcel.2009.08.017.View ArticlePubMedGoogle Scholar
- Kawai S, Amano A: BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex. J Cell Biol. 2012, 197 (2): 201-208. 10.1083/jcb.201110008.PubMed CentralView ArticlePubMedGoogle Scholar
- Chen PS, Su JL, Cha ST, Tarn WY, Wang MY, Hsu HC, Lin MT, Chu CY, Hua KT, Chen CN, Kuo TC, Chang KJ, Hsiao M, Chang YW, Chen JS, Yang PC, Kuo ML: miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans. J Clin Invest. 2011, 121 (9): 3442-3455. 10.1172/JCI45390.PubMed CentralView ArticlePubMedGoogle Scholar
- Tang R, Li L, Zhu D, Hou D, Cao T, Gu H, Zhang J, Chen J, Zhang CY, Zen K: Mouse miRNA-709 directly regulates miRNA-15a/16-1 biogenesis at the posttranscriptional level in the nucleus: evidence for a microRNA hierarchy system. Cell Res. 2012, 22 (3): 504-515. 10.1038/cr.2011.137.PubMed CentralView ArticlePubMedGoogle Scholar
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