A Polycistronic MicroRNA Cluster, miR-17-92, Is Overexpressed in Human Lung Cancers and Enhances Cell Proliferation

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13or f 25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf 25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf 25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf 25 gene may well be serving as a vehicle in this regard. (Cancer Res 2005; 65(21): 9628-32)

Expression of miR‐18a and miR‐34c in circulating monocytes associated with vulnerability to type 2 diabetes mellitus and insulin resistance

“…MiR‐18 is expressed widely throughout the body, while expression of miR‐124a is restricted to the brain. In small cell lung cancer, reduced GR levels have been associated with GC resistance, which might be caused by miR‐18 up‐regulation 18, 19. We found that expression levels of miR‐18a in PBMCs were positively correlated with cortisol, CRH and IL‐6.…”

Analysis of the miRNA–mRNA–lncRNA networks in ER+ and ER− breast cancer cell lines

“…Overexpression of the miR‐17‐92 cluster is observed in a variety of cancers, including small‐cell lung cancer, colon cancer, neuroblastomas, medulloblastoma and gastric cancer 35, 36, 37, 38. Calvano et al .…”

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

“…The miR-17-92 cluster is frequently amplified in several lymphomas and in lung cancer, 16,42 and aberrant overexpression of the miR-17-92 polycistron is detected in many cancers. 43 Retinoblastoma-like 2 protein (p130, Rbl2), Cdk inhibitor p21CIP1, transforming growth factor β1 (TGFβ1), proapoptotic Bcl-2 protein Bim, the tumor-suppressor PTEN and transcription factor E2F1 are some of the cluster's targets.…”

“…13,14 Also known as oncomir-1, the cluster enhances cell proliferation or inhibits apoptosis by suppressing targets such as Bim, E2F1 and PTEN and is markedly overexpressed in human cancers. [15][16][17][18][19][20][21] Reduced levels of PHLPP2 in chemoresistant miR-17-92 overexpressing mantle cell lymphomas had suggested that the phosphatase could be a target of oncomir-1. 12 Known major activators of the miR-17-92 cluster are transcription factor c-MYC and members of the E2F family, whereas p53 acts as a repressor under hypoxic conditions.…”