MiRNAs and Cancer
2009; Elsevier BV; Volume: 174; Issue: 4 Linguagem: Inglês
10.2353/ajpath.2009.080794
ISSN1525-2191
Autores Tópico(s)Circular RNAs in diseases
ResumoCancer is the result of a complex multistep process that involves the accumulation of sequential alterations of several genes, including those encoding microRNAs (miRNAs). miRNAs are a class of 17- to 27-nucleotide single-stranded RNA molecules that regulate gene expression posttranscriptionally. A large body of evidence implicates aberrant miRNA expression patterns in most, if not all, human malignancies. This article reviews our current knowledge about miRNAs, focusing on their involvement in cancer and their potential as diagnostic, prognostic, and therapeutic tools. Cancer is the result of a complex multistep process that involves the accumulation of sequential alterations of several genes, including those encoding microRNAs (miRNAs). miRNAs are a class of 17- to 27-nucleotide single-stranded RNA molecules that regulate gene expression posttranscriptionally. A large body of evidence implicates aberrant miRNA expression patterns in most, if not all, human malignancies. This article reviews our current knowledge about miRNAs, focusing on their involvement in cancer and their potential as diagnostic, prognostic, and therapeutic tools. Cancer, which develops because of a multistep process resulting in the accumulation of several genomic alterations, is characterized by unrestricted proliferation, invasion, and metastasis. In cancer, many molecular pathways are affected, involving canonical protein-coding genes as well as recently discovered noncoding genes. Noncoding RNAs include a class of small RNAs (17 to 27 nucleotides in length), microRNAs (miRNAs), that control gene expression by regulating mRNA translation. The biogenesis of miRNAs starts with the transcription of genomic regions located within or between protein-coding genes, resulting in the synthesis of miRNA precursor molecules (pri-miRNAs). Pri-miRNAs are currently thought to be transcribed primarily by RNA polymerase II and, less frequently by RNA polymerase III. Drosha, a specific ribonuclease of the RNase III endonuclease family, then enzymatically cuts the transcribed pri-miRNA in a smaller fragment (∼70 nucleotides). This hairpin pre-miRNA is then exported to the cytoplasm by Exportin-5 in a Ran-GTP-dependent manner and cleaved into an imperfect double-strand RNA (dsRNA), duplex-designated miRNA, which is termed miRNA/miRNA*. This process is performed by Dicer, an RNase III endonuclease composed of a helicase domain and a dsRNA-binding domain. One strand of the miRNA/miRNA* duplex is then selected to function as a mature miRNA and preferentially loaded into a miRNA ribonucleoprotein (miRNP) complex, whereas the other strand is likely degraded.1Filipowicz W Bhattacharyya SN Sonenberg N Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?.Nat Rev Genet. 2008; 9: 102-114Crossref PubMed Scopus (4127) Google Scholar As a part of the miRNP complex, single or multiple miRNA copies bind to mRNA 3′untranslated regions (3′UTR). Those that bind with perfect complimentarity lead to mRNA degradation; whereas imperfect binding leads to inhibition of translation (Figure 1). The numerous biochemical mechanisms that govern miRNA function, however, are likely dependent on the availability of local regulatory factors.2Eulalio A Huntzinger E Izaurralde E Getting to the root of miRNA-mediated gene silencing.Cell. 2008; 132: 9-14Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar An estimated one-third of protein-coding human mRNAs are susceptible to this complex miRNA regulatory network. Every cellular process is regulated by miRNAs, and an aberrant miRNA expression signature is a hallmark of several diseases, including cancer. These data suggest that miRNA genes could function as potential oncogenes and tumor repressors genes in the human body. Thus, an accurate evaluation of changes in miRNA expression could provide new insight into basic mechanisms of cancer. The first evidence of aberrant miRNA expression in human cancers was described in B-cell chronic lymphocytic leukemia, wherein hemizygous and/or homozygous chromosomal deletion at the 13q14 locus resulted in the loss or reduction of miR-15 and miR-16 expression.3Calin 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 USA. 2002; 99: 15524-15529Crossref PubMed Scopus (4196) Google Scholar This discovery of new genes linked to cancer prompted investigation of miRNA expression in human tumors. Consequently, several techniques have been developed to support this research. Two widely performed high-throughput techniques are used for miRNA profiling. The solid-phase array-based platform, developed first by Liu and colleagues,4Liu CG Calin GA Meloon B Gamliel N Sevignani C Ferracin M Dumitru CD Shimizu M Zupo S Dono M Alder H Bullrich F Negrini M Croce CM An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues.Proc Natl Acad Sci USA. 2004; 101: 9740-9744Crossref PubMed Scopus (817) Google Scholar is semiquantitative, requires transcript amplification/labeling, and carries an inherent limitation of cross-hybridization among miRNAs of the same family. Conversely, flow-based, liquid-phase profiling has the advantage of increased specificity in discriminating the expression of closely related miRNAs as well as higher sensitivity in detecting modest decreases in down-regulated miRNAs. However, flow-based, liquid-phase profiling is technically demanding with respect to quality consistency in the production of miRNA probes.5Lu 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: 834-838Crossref PubMed Scopus (8165) Google Scholar Data obtained by either of these two methods needs to be validated independently by a second technique, such as Northern blot or quantitative real-time polymerase chain reaction, to confirm the miRNA expression profile. The use of these techniques revealed aberrant miRNA expression in numerous tumors when they were compared with their normal counterparts, thereby suggesting that a link does exist between miRNAs and cancer (Table 1).6Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 7Calin GA Liu CG Sevignani C Ferracin M Felli N Dumitru CD Shimizu M Cimmino A Zupo S Dono M Dell'Aquila ML Alder H Rassenti L Kipps TJ Bullrich F Negrini M Croce CM MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.Proc Natl Acad Sci USA. 2004; 101: 11755-11760Crossref PubMed Scopus (1149) Google Scholar, 8Iorio MV Visone R Di Leva G Donati V Petrocca F Casalini P Taccioli C Volinia S Liu CG Alder H Calin GA Menard S Croce CM MicroRNA signatures in human ovarian cancer.Cancer Res. 2007; 67: 8699-8707Crossref PubMed Scopus (1293) Google Scholar, 9Iorio MV Ferracin M Liu CG Veronese A Spizzo R Sabbioni S Magri E Pedriali M Fabbri M Campiglio M Menard S Palazzo JP Rosenberg A Musiani P Volinia S Nenci I Calin GA Querzoli P Negrini M Croce CM MicroRNA gene expression deregulation in human breast cancer.Cancer Res. 2005; 65: 7065-7070Crossref PubMed Scopus (3455) Google Scholar, 10Bottoni A Piccin D Tagliati F Luchin A Zatelli MC degli Uberti EC miR-15a and miR-16–1 down-regulation in pituitary adenomas.J Cell Physiol. 2005; 204: 280-285Crossref PubMed Scopus (310) Google Scholar, 11Ambs S Prueitt RL Yi M Hudson RS Howe TM Petrocca F Wallace TA Liu CG Volinia S Calin GA Yfantis HG Stephens RM Croce CM Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer.Cancer Res. 2008; 68: 6162-6170Crossref PubMed Scopus (605) Google Scholar, 12Pallante P Visone R Ferracin M Ferraro A Berlingieri MT Troncone G Chiappetta G Liu CG Santoro M Negrini M Croce CM Fusco A MicroRNA deregulation in human thyroid papillary carcinomas.Endocr Relat Cancer. 2006; 13: 497-508Crossref PubMed Scopus (456) Google Scholar, 13He H Jazdzewski K Li W Liyanarachchi S Nagy R Volinia S Calin GA Liu CG Franssila K Suster S Kloos RT Croce CM de la Chapelle A The role of microRNA genes in papillary thyroid carcinoma.Proc Natl Acad Sci USA. 2005; 102: 19075-19080Crossref PubMed Scopus (1069) Google Scholar, 14Visone R Pallante P Vecchione A Cirombella R Ferracin M Ferraro A Volinia S Coluzzi S Leone V Borbone E Liu CG Petrocca F Troncone G Calin GA Scarpa A Colato C Tallini G Santoro M Croce CM Fusco A Specific microRNAs are downregulated in human thyroid anaplastic carcinomas.Oncogene. 2007; 26: 7590-7595Crossref PubMed Scopus (340) Google ScholarTable 1Selected miRNAs Aberrantly Expressed in TumorsSelected miRNAsOrganDisease typeUp-regulatedDown-regulatedReferencesLiverHCA and FNH*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.224122a, 422b, 203, 200c6Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarHCC*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.†miRNA comparative analysis: tumor tissue versus adjacent nontumor tissue.21, 224, 10b, 221, 222, 20, 18199a, 199b, 200b, 223, 122, 214,145, 1506Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarCholangiocarcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.21, 23a, 141, 200b, 27a6Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarPancreasPET*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.23a, 342, 26a, 30d, 26b, 103, 107155, 326, 339, 3266Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarInsulinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.203, 204, 211,6Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarPACC*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.23a, 342, 26a, 30d, 26b, 103, 105155, 326, 339,3266Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarDuctal adenocarcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.†miRNA comparative analysis: tumor tissue versus adjacent nontumor tissue.21, 221, 181a, 155, 222, 181b, 107148a, 3756Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarEsophagusESCC*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.25, 424, 151100, 99, 29c, 140, 205,203, 2026Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarStomachAdenocarcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.†miRNA comparative analysis: tumor tissue versus adjacent nontumor tissue.21, 223, 25, 17-5p, 125b, 181b, 106a, 107, 92, 103, 221, 93, 100, 106b136, 218, 212, 96, 3396Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarColonAdenomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.216Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarAdenocarcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.†miRNA comparative analysis: tumor tissue versus adjacent nontumor tissue.21, 92, 20a, 106a, 92, 223, 2036Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarAdenocarcinomas stage II*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.1456Visone R Petrocca F Croce CM Micro-RNAs in gastrointestinal and liver disease.Gastroenterology. 2008; 135: 1866-1869Abstract Full Text Full Text PDF PubMed Scopus (55) Google ScholarHematopoietic tissueCLL*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.190, 33, 19a, 140, 123, 10b, 92, 188, 154, 217, 101, 196, 134, 141, 132, 192, 16, 15181b, 2207Calin GA Liu CG Sevignani C Ferracin M Felli N Dumitru CD Shimizu M Cimmino A Zupo S Dono M Dell'Aquila ML Alder H Rassenti L Kipps TJ Bullrich F Negrini M Croce CM MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.Proc Natl Acad Sci USA. 2004; 101: 11755-11760Crossref PubMed Scopus (1149) Google ScholarOvaryCarcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue. (serous, clear cell, endometrioid)200a, 200clet-7d, 100, 101, 105, 125a, 125b, 126, 133a, 137, 140, 143, 147, 199a, 199b, 224, 9, 9*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue., 99a8Iorio MV Visone R Di Leva G Donati V Petrocca F Casalini P Taccioli C Volinia S Liu CG Alder H Calin GA Menard S Croce CM MicroRNA signatures in human ovarian cancer.Cancer Res. 2007; 67: 8699-8707Crossref PubMed Scopus (1293) Google ScholarBreastCarcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.155, 21125b, 145, 10b9Iorio MV Ferracin M Liu CG Veronese A Spizzo R Sabbioni S Magri E Pedriali M Fabbri M Campiglio M Menard S Palazzo JP Rosenberg A Musiani P Volinia S Nenci I Calin GA Querzoli P Negrini M Croce CM MicroRNA gene expression deregulation in human breast cancer.Cancer Res. 2005; 65: 7065-7070Crossref PubMed Scopus (3455) Google ScholarLungNSCLC†miRNA comparative analysis: tumor tissue versus adjacent nontumor tissue.21, 191, 155, 210126*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue., 224Pituitary glandAdenoma*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.15, 1610Bottoni A Piccin D Tagliati F Luchin A Zatelli MC degli Uberti EC miR-15a and miR-16–1 down-regulation in pituitary adenomas.J Cell Physiol. 2005; 204: 280-285Crossref PubMed Scopus (310) Google ScholarProstateCarcinomas†miRNA comparative analysis: tumor tissue versus adjacent nontumor tissue.32, 182, 31, 26a, 200c520h, 494, 490, 133a, 1, 218, 220, 128a11Ambs S Prueitt RL Yi M Hudson RS Howe TM Petrocca F Wallace TA Liu CG Volinia S Calin GA Yfantis HG Stephens RM Croce CM Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer.Cancer Res. 2008; 68: 6162-6170Crossref PubMed Scopus (605) Google ScholarThyroidPapillary carcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.221, 221, 146a, 181b12Pallante P Visone R Ferracin M Ferraro A Berlingieri MT Troncone G Chiappetta G Liu CG Santoro M Negrini M Croce CM Fusco A MicroRNA deregulation in human thyroid papillary carcinomas.Endocr Relat Cancer. 2006; 13: 497-508Crossref PubMed Scopus (456) Google Scholar, 13He H Jazdzewski K Li W Liyanarachchi S Nagy R Volinia S Calin GA Liu CG Franssila K Suster S Kloos RT Croce CM de la Chapelle A The role of microRNA genes in papillary thyroid carcinoma.Proc Natl Acad Sci USA. 2005; 102: 19075-19080Crossref PubMed Scopus (1069) Google ScholarAnaplastic carcinomas*miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.30 days, 125b, 26a, 30a-5p14Visone R Pallante P Vecchione A Cirombella R Ferracin M Ferraro A Volinia S Coluzzi S Leone V Borbone E Liu CG Petrocca F Troncone G Calin GA Scarpa A Colato C Tallini G Santoro M Croce CM Fusco A Specific microRNAs are downregulated in human thyroid anaplastic carcinomas.Oncogene. 2007; 26: 7590-7595Crossref PubMed Scopus (340) Google ScholarHCA, hepatocellular carcinomas; FNH, focal nodular hyperplasia; PET, pancreatic endocrine tumors; PACC, pancreatic acinar cell carcinomas; ESCC, esophageal squamous cell carcinomas; CLL, chronic lymphocytic leukemia; NSCLC, non-small cell lung cancer.* miRNA comparative analysis: nontumor or tumor tissue versus normal tissue.† miRNA comparative analysis: tumor tissue versus adjacent nontumor tissue. Open table in a new tab HCA, hepatocellular carcinomas; FNH, focal nodular hyperplasia; PET, pancreatic endocrine tumors; PACC, pancreatic acinar cell carcinomas; ESCC, esophageal squamous cell carcinomas; CLL, chronic lymphocytic leukemia; NSCLC, non-small cell lung cancer. MiRNA expression can be altered by several mechanisms in human cancer including chromosomal abnormalities, epigenetic changes, mutations and polymorphisms (SNPs), and defects in the miRNA biogenesis machinery. MiRNAs often reside in particular genomic regions that are prone to alterations in cancer. These regions could include either a minimal region of loss of heterozygosity, which can harbor a tumor suppressor gene; a minimal region of amplification, which might contain oncogenes; or fragile sites. Fragile sites are preferential sites of sister chromatid exchange, translocation, deletion, amplification or integration of plasmid DNA, and insertion of tumor-associated viruses such as human papilloma virus.15Calin GA Croce CM MicroRNAs and chromosomal abnormalities in cancer cells.Oncogene. 2006; 25: 6202-6210Crossref PubMed Scopus (219) Google Scholar The high frequency of genomic alterations in miRNA loci was recently confirmed by an extensive study of high-resolution array-based genomic hybridization on 227 human ovarian cancer, breast cancer, and melanomas samples.16Zhang 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 USA. 2006; 103: 9136-9141Crossref PubMed Scopus (912) Google Scholar The findings of this study proved that miRNA expression correlated with miRNA copy number, and these data tightly overlap with the miRNA expression data analyzed on a set of breast cancer samples in an independent study.9Iorio MV Ferracin M Liu CG Veronese A Spizzo R Sabbioni S Magri E Pedriali M Fabbri M Campiglio M Menard S Palazzo JP Rosenberg A Musiani P Volinia S Nenci I Calin GA Querzoli P Negrini M Croce CM MicroRNA gene expression deregulation in human breast cancer.Cancer Res. 2005; 65: 7065-7070Crossref PubMed Scopus (3455) Google Scholar Specific examples of miRNAs located in instable genomic regions include the miR-15a/16 cluster, embedded into 13q14, and both miR-143 and miR-145, located at 5q33. In fact, B-cell chronic lymphocytic leukemias and pituitary adenomas, which often harbor 13q14 deletions, showed a decreased expression of miR-15a and miR-16,3Calin 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 USA. 2002; 99: 15524-15529Crossref PubMed Scopus (4196) Google Scholar, 7Calin GA Liu CG Sevignani C Ferracin M Felli N Dumitru CD Shimizu M Cimmino A Zupo S Dono M Dell'Aquila ML Alder H Rassenti L Kipps TJ Bullrich F Negrini M Croce CM MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.Proc Natl Acad Sci USA. 2004; 101: 11755-11760Crossref PubMed Scopus (1149) Google Scholar, 10Bottoni A Piccin D Tagliati F Luchin A Zatelli MC degli Uberti EC miR-15a and miR-16–1 down-regulation in pituitary adenomas.J Cell Physiol. 2005; 204: 280-285Crossref PubMed Scopus (310) Google Scholar whereas deletion of the 5q33 region observed in lung cancer seems to contribute to the decreased levels of miR-143 and miR-145 in this tumor.15Calin GA Croce CM MicroRNAs and chromosomal abnormalities in cancer cells.Oncogene. 2006; 25: 6202-6210Crossref PubMed Scopus (219) Google Scholar Conversely, cluster miR-17-92, located at chromosome 13q31, a region amplified in B-cell lymphomas17Ota A Tagawa H Karnan S Tsuzuki S Karpas A Kira S Yoshida Y Seto M Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma.Cancer Res. 2004; 64: 3087-3095Crossref PubMed Scopus (626) Google Scholar and lung cancers,18Hayashita Y Osada H Tatematsu Y Yamada H Yanagisawa K Tomida S Yatabe Y Kawahara K Sekido Y Takahashi T A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation.Cancer Res. 2005; 65: 9628-9632Crossref PubMed Scopus (1371) Google Scholar has been found to be overexpressed in these malignancies. Overall, these findings suggest that the location of miRNAs in a genomic region amenable to alterations is not a random event, thereby indicating that the loss or the gain of genomic regions including miRNAs in a specific type of cancer could participate to the cause of this malignancy. Recent findings indicate that epigenetic aberrations affect miRNA expression. An extensive analysis of genomic sequences of miRNA genes showed that approximately half of these genes are associated with CpG islands, suggesting that miRNAs can represent candidate targets of the DNA methylation machinery. Analysis of several miRNA-associated CpG islands in five cell lines also indicated that miRNA gene methylation is detectable at high frequencies, both in normal and malignant cells. Methylation status could possibly explain the deregulated expression of miRNAs in cancer.19Weber B Stresemann C Brueckner B Lyko F Methylation of human microRNA genes in normal and neoplastic cells.Cell Cycle. 2007; 6: 1001-1005Crossref PubMed Scopus (241) Google Scholar Some examples have been reported by Iorio and colleagues.8Iorio MV Visone R Di Leva G Donati V Petrocca F Casalini P Taccioli C Volinia S Liu CG Alder H Calin GA Menard S Croce CM MicroRNA signatures in human ovarian cancer.Cancer Res. 2007; 67: 8699-8707Crossref PubMed Scopus (1293) Google Scholar They found that the treatment of a human ovarian cancer cell line (OVCAR3) with the demethylating agent 5-aza-2′deoxycytide (5-AZA-CdR) increased the expression levels of nine miRNAs. Interestingly, three of nine miRNAs, miR-21, miR-203, and miR-205, have been found to be also overexpressed in ovarian carcinomas when compared with their normal counterparts, suggesting that hypomethylation could be the mechanism responsible for their overexpression in vivo.8Iorio MV Visone R Di Leva G Donati V Petrocca F Casalini P Taccioli C Volinia S Liu CG Alder H Calin GA Menard S Croce CM MicroRNA signatures in human ovarian cancer.Cancer Res. 2007; 67: 8699-8707Crossref PubMed Scopus (1293) Google Scholar Moreover, miR-21 and miR-203 are embedded in a region associated with CpG islands, whereby the DNA methylation machinery could directly affect the expression of these miRNAs.8Iorio MV Visone R Di Leva G Donati V Petrocca F Casalini P Taccioli C Volinia S Liu CG Alder H Calin GA Menard S Croce CM MicroRNA signatures in human ovarian cancer.Cancer Res. 2007; 67: 8699-8707Crossref PubMed Scopus (1293) Google Scholar Conversely, decreased miR-124a expression was attributed to DNA hypermethylation in colon, breast, and lung carcinomas.20Lujambio A Esteller M CpG island hypermethylation of tumor suppressor microRNAs in human cancer.Cell Cycle. 2007; 6: 1455-1459Crossref PubMed Scopus (5) Google Scholar Mutations and polymorphisms located in mature miRNA, pre-miRNA, or more likely in adjacent genomics regions can also change miRNA expression by affecting their processing. These events in miRNAs are rarer than in mRNA protein coding genes, because the size of miRNAs and their precursors is small. A few cases have been already reported in the literature, however. Inherited mutations in the primary transcripts of miR-15a and miR-16–1 have been reported to be responsible for low expression levels in vitro and in vivo. Decreased expression of these miRNAs in familial chronic lymphocytic leukemia and familial breast cancer was also associated with deletion of the normal allele encompassing miR-15a and miR-16–1.21Calin 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: 1793-1801Crossref PubMed Scopus (2078) Google Scholar The importance of this mutation was further supported in a spontaneous mouse model of chronic lymphocytic leukemia.22Raveche ES Salerno E Scaglione BJ Manohar V Abbasi F Lin YC Fredrickson T Landgraf P Ramachandra S Huppi K Toro JR Zenger VE Metcalf RA Marti GE Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice.Blood. 2007; 109: 5079-5086Crossref PubMed Scopus (239) Google Scholar MiRNA genomic region can also include SNPs. Hu and colleagues,23Hu Z Chen J Tian T Zhou X Gu H Xu L Zeng Y Miao R Jin G Ma H Chen Y Shen H Genetic variants of miRNA sequences and non-small cell lung cancer survival.J Clin Invest. 2008; 118: 2600-2608Crossref PubMed Scopus (100) Google Scholar conducted a systematic survey of common pre-miRNA sequences and their surrounding regions and evaluated in detail the association of four selected SNPs in four miRNAs (miR-146a, miR-196a2, miR-499, and miR-149) with the survival of individuals with non-small cell lung cancer. They found that patients with non-small cell lung cancer carrying a variant homozygote of the SNP located in the 3p miRNA region of miR-196a-2 had poor survival, possibly through a mechanism of elevated expression of mature miR-196*.23Hu Z Chen J Tian T Zhou X Gu H Xu L Zeng Y Miao R Jin G Ma H Chen Y Shen H Genetic variants of miRNA sequences and non-small cell lung cancer survival.J Clin Invest. 2008; 118: 2600-2608Crossref PubMed Scopus (100) Google Scholar These findings suggest that SNPs located in miRNA regions may be prognostic biomarkers of certain malignancies. Despite normal expression levels of pri-miRNA, a number of human primary cancers displayed reduced levels of mature miRNAs. Thomson and colleagues24Thomson JM Newman M Parker JS Morin-Kensicki EM Wright T Hammond SM Extensive post-transcriptional regulation of microRNAs and its implications for cancer.Genes Dev. 2006; 20: 2202-2207Crossref PubMed Scopus (754) Google Scholar explained this difference as a processing defect because of the loss of the RNase III Drosha. Conversely, targeted Drosha activity, directed by the ALL1(MLL) fused gene, appeared to be responsible for miR-191 up-regulation in human acute lymphoblastic leukemia.25Nakamura T Canaani E Croce CM Oncogenic All1 fusion proteins target Drosha-mediated microRNA processing.Proc Natl Acad Sci USA. 2007; 104: 10980-10985Crossref PubMed Scopus (71) Google Scholar In addition, decreased Dicer endonuclease activity in a proportion of non-small cell lung cancers, correlated with reduced let-7 expression, unfavorable postoperative survival, and poor tumor differentiation status.26Karube Y Tanaka H Osada H Tomida S Tatematsu Y Yanagisawa K Yatabe Y Takamizawa J Miyoshi S Mitsudomi T Takahashi T Reduced expression of Dicer associated with poor prognosis in lung cancer patients.Cancer Sci. 2005; 96: 111-115Crossref PubMed Scopus (523) Google Scholar The loss of Dicer likely represents a somatic alteration because Dicer-deficient mice failed to thrive beyond gastrulation because of the lack of multipotent stem cell development.27Bernstein E Kim SY Carmell MA Murchison EP Alcorn H Li MZ Mills AA Elledge SJ Anderson KV Hannon GJ Dicer is essential for mouse development.Nat Genet. 2003; 35: 215-217Crossref PubMed Scopus (1561) Google Scholar Finally, changes in miRNA expression can be attributable also to either the frequent deregulation of transcription factors in cancer or viruses that often integrate within the DNA of tumoral cells.28Petrocca 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: 272-286Abstract Full Text Full Text PDF PubMed Scopus (785) Google Scholar, 29Motsch N Pfuhl T Mrazek J Barth S Grasser FA Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) induces the expression of the cellular microRNA miR-146a.RNA Biol. 2007; 4: 131-137Crossref PubMed Scopus (165) Google Scholar High-throughput analyses have reported altered miRNA expression in all tumors investigated to date, suggesting that miRNAs might be implicated in tumorigenesis, likely by regulating oncogene or tumor suppressor genes. The miR-17-92 polycistron represents the first example of miRNA acting as a mammalian oncogene. This cluster is embedded in a human genomic locus, 13q31.3, which is a region that is amplifie
Referência(s)