MiRNAs and CLL: genomics, pathways, and clinical correlations
| Human miRNA (location)/cancer function . | Cancer-associated genomic region . | Deregulation in tumors, including CLL . | Putative functions and targets . | Diagnostic and prognostic markers . |
|---|---|---|---|---|
| Let-7 family (various)/antitumorigenic | Urothelial, bladder, esophageal, ovarian, cervical, and breast cancers and lung adenocarcinoma; FRA9D and FRA11B | (1) Down-regulation in CLL; lung, breast, gastric, ovarian, prostate, and colon cancers; and leiomyomas; (2) point mutation in the let-7e precursor sequence, which affects maturation | Molecular mechanism: MYCN positively regulates let-7b transcription, and LIN-28 regulates the maturation of let-7a, represses cell proliferation/growth, and promotes angiogenesis. Targets: CCND1, CDC25a, CDK6, CRD-BP, HOXA9, IMP-1, MYC, and RAS | Poor prognosis: low let-7a-2 expression (lung and ovarian cancer); drug resistance: let-7i affects chemotherapy potency; therapy: intranasal delivery of let-7a adenovirus reduces growth of Ras-induced lung tumors in mice |
| MiR-16-1/miR-15a cluster (13q14.3, intron 4 ncRNA DLEU2)/antitumorigenic | B-CLL, adult lymphoblastic leukemia, head and neck squamous cell carcinoma, oral cancers, and lipoma | (1) Down-regulation in CLL, DLBCLs, multiple myeloma, pituitary adenoma, and prostate and pancreatic cancers; (2) germline mutations in patients with B-CLL and the NZB mouse strain | Molecular mechanism: induce apoptosis in leukemia cells, miR-16 regulates the cell cycle via down-regulation of expression of G0/G1 proteins. Targets: BCL2, CARD10, CCND1, CDK6, CDC27, DMTF1, MCL1, NGN2, and VEGF | Poor prognosis: higher miR-15a and miR-16 expression in de novo aggressive CLL; drug resistance: miR-16 affects chemotherapy potency and modulates sensitivity to vincristine in gastric cancer cell lines |
| miR-21 (17q23.1, 3′ UTR TMEM49)/oncogenic | Neuroblastoma and breast cancer; FRA17B | Overexpression in CLL; glioblastomas; breast, lung, prostate, colon, stomach, esophageal, and cervical carcinomas; uterine leiomyosarcoma; and DLBCL | Molecular mechanism: STAT3 regulates miR-21 at the transcriptional level; miR-21 knockdown induces apoptosis in glioblastoma cells; miR-21 induces invasion and metastasis in colorectal cancers. Targets BCL2, MASPIN, PDCD4, PTEN, TPM1, MCL1, TCL1 | Poor prognosis: high miR-21 expression (in colon cancer); good prognosis: high miR-21 expression in de novo DLBCL; drug resistance: miR-21 affects chemotherapy potency in NCI60 cells |
| miR-29 family (various)/antitumorigenic | Prostate cancer aggressiveness locus; FRA7H | Down-regulation in CLL and acute myelogenous leukemia; colon, breast, and lung cancer; and cholangiocarcinoma tumor models (KMCH) | Molecular mechanism: miR-29 family reverses aberrant methylation in lung cancer and acute myelogenous leukemia. Targets: DNMT3A, DNMT3B | Poor prognosis: low miR-29c expression correlates with short intervals from diagnosis of to therapy for CLL |
| miR-34 family (1p36.23 and 11q23.1, intergenic)/antitumorigenic | CLL, lung and breast cancer; t(3;11) (B-cell leukemia line) | (1) Down-regulation in CLL and pancreatic cancer cell lines; (2) hypermethylation of miR-34b/miR-34c in colon cancer | Molecular mechanism: P53 transactivates miR-34a and the miR-34b/miR-34c cluster; miR-34a induces up-regulation of the P53 pathway and down-regulation of the E2F pathway in colon cancer cell lines. Targets: BCL2, CCND1, CCNE2, CDK4/6, DLL1, E23, Notch1, MYCN, MET | Therapy: low levels of miR-34a expression are associated with impaired DNA damage response and fludarabine-refractory CLL |
| miR-143/145 cluster (intergenic, 5q32)/antitumorigenic | Prostate cancer aggressiveness, myelodysplastic syndrome | Down-regulation in colon adenomas and carcinomas, breast and lung cancer, and B-cell malignancies | Molecular mechanism: miR-143 and miR-145 precursors are abnormally processed in colon cancer. Targets: ERK5, HOXA9, PARP8 | |
| miR-155 (21q21.3)/oncogenic | Colon cancer | Molecular mechanism: pre-B-cell proliferation and lymphoblastic leukemia/high-grade lymphoma in miR-155 transgenic mice. Targets: uc.346A and uc.160 | Poor prognosis: high miR-155 expression (in lung cancer, DLBCL, and aggressive CLL) | |
| miR-181 family (various)/oncogenic and antitumorigenic | FRA1K, FRA9E, and FRA19B | Overexpression in breast, pancreatic, and prostate cancer | Molecular mechanism: MYCN regulates the transcription of the miR-181 cluster. Targets: HOXA11, TCL1 | Poor prognosis: low miR-181 expression in aggressive CLL with 11q−; high miR-181a expression correlates with short intervals from diagnosis of to therapy for CLL |
| Human miRNA (location)/cancer function . | Cancer-associated genomic region . | Deregulation in tumors, including CLL . | Putative functions and targets . | Diagnostic and prognostic markers . |
|---|---|---|---|---|
| Let-7 family (various)/antitumorigenic | Urothelial, bladder, esophageal, ovarian, cervical, and breast cancers and lung adenocarcinoma; FRA9D and FRA11B | (1) Down-regulation in CLL; lung, breast, gastric, ovarian, prostate, and colon cancers; and leiomyomas; (2) point mutation in the let-7e precursor sequence, which affects maturation | Molecular mechanism: MYCN positively regulates let-7b transcription, and LIN-28 regulates the maturation of let-7a, represses cell proliferation/growth, and promotes angiogenesis. Targets: CCND1, CDC25a, CDK6, CRD-BP, HOXA9, IMP-1, MYC, and RAS | Poor prognosis: low let-7a-2 expression (lung and ovarian cancer); drug resistance: let-7i affects chemotherapy potency; therapy: intranasal delivery of let-7a adenovirus reduces growth of Ras-induced lung tumors in mice |
| MiR-16-1/miR-15a cluster (13q14.3, intron 4 ncRNA DLEU2)/antitumorigenic | B-CLL, adult lymphoblastic leukemia, head and neck squamous cell carcinoma, oral cancers, and lipoma | (1) Down-regulation in CLL, DLBCLs, multiple myeloma, pituitary adenoma, and prostate and pancreatic cancers; (2) germline mutations in patients with B-CLL and the NZB mouse strain | Molecular mechanism: induce apoptosis in leukemia cells, miR-16 regulates the cell cycle via down-regulation of expression of G0/G1 proteins. Targets: BCL2, CARD10, CCND1, CDK6, CDC27, DMTF1, MCL1, NGN2, and VEGF | Poor prognosis: higher miR-15a and miR-16 expression in de novo aggressive CLL; drug resistance: miR-16 affects chemotherapy potency and modulates sensitivity to vincristine in gastric cancer cell lines |
| miR-21 (17q23.1, 3′ UTR TMEM49)/oncogenic | Neuroblastoma and breast cancer; FRA17B | Overexpression in CLL; glioblastomas; breast, lung, prostate, colon, stomach, esophageal, and cervical carcinomas; uterine leiomyosarcoma; and DLBCL | Molecular mechanism: STAT3 regulates miR-21 at the transcriptional level; miR-21 knockdown induces apoptosis in glioblastoma cells; miR-21 induces invasion and metastasis in colorectal cancers. Targets BCL2, MASPIN, PDCD4, PTEN, TPM1, MCL1, TCL1 | Poor prognosis: high miR-21 expression (in colon cancer); good prognosis: high miR-21 expression in de novo DLBCL; drug resistance: miR-21 affects chemotherapy potency in NCI60 cells |
| miR-29 family (various)/antitumorigenic | Prostate cancer aggressiveness locus; FRA7H | Down-regulation in CLL and acute myelogenous leukemia; colon, breast, and lung cancer; and cholangiocarcinoma tumor models (KMCH) | Molecular mechanism: miR-29 family reverses aberrant methylation in lung cancer and acute myelogenous leukemia. Targets: DNMT3A, DNMT3B | Poor prognosis: low miR-29c expression correlates with short intervals from diagnosis of to therapy for CLL |
| miR-34 family (1p36.23 and 11q23.1, intergenic)/antitumorigenic | CLL, lung and breast cancer; t(3;11) (B-cell leukemia line) | (1) Down-regulation in CLL and pancreatic cancer cell lines; (2) hypermethylation of miR-34b/miR-34c in colon cancer | Molecular mechanism: P53 transactivates miR-34a and the miR-34b/miR-34c cluster; miR-34a induces up-regulation of the P53 pathway and down-regulation of the E2F pathway in colon cancer cell lines. Targets: BCL2, CCND1, CCNE2, CDK4/6, DLL1, E23, Notch1, MYCN, MET | Therapy: low levels of miR-34a expression are associated with impaired DNA damage response and fludarabine-refractory CLL |
| miR-143/145 cluster (intergenic, 5q32)/antitumorigenic | Prostate cancer aggressiveness, myelodysplastic syndrome | Down-regulation in colon adenomas and carcinomas, breast and lung cancer, and B-cell malignancies | Molecular mechanism: miR-143 and miR-145 precursors are abnormally processed in colon cancer. Targets: ERK5, HOXA9, PARP8 | |
| miR-155 (21q21.3)/oncogenic | Colon cancer | Molecular mechanism: pre-B-cell proliferation and lymphoblastic leukemia/high-grade lymphoma in miR-155 transgenic mice. Targets: uc.346A and uc.160 | Poor prognosis: high miR-155 expression (in lung cancer, DLBCL, and aggressive CLL) | |
| miR-181 family (various)/oncogenic and antitumorigenic | FRA1K, FRA9E, and FRA19B | Overexpression in breast, pancreatic, and prostate cancer | Molecular mechanism: MYCN regulates the transcription of the miR-181 cluster. Targets: HOXA11, TCL1 | Poor prognosis: low miR-181 expression in aggressive CLL with 11q−; high miR-181a expression correlates with short intervals from diagnosis of to therapy for CLL |
For more details, see Spizzo et al.16 Gene symbols appear as indicated in the National Center for Biotechnology Information PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez).17
DLBCL indicates diffuse large-B cell lymphoma; and STAT3, signal transducer and activator of transcription 3.