Role of the miR‐106b‐25 microRNA cluster in hepatocellular carcinoma

Abstract

MicroRNAs are tiny RNA molecules which serve as important posttranscriptional regulators of gene expression. Dysregulated expression of microRNAs has been observed in human cancers, indicating that microRNAs may function as oncogenes or as tumor suppressors. To date, the microRNAs encoded by the oncogenic miR-17-92 cluster, and its paralog the miR-106b-25 cluster, are among those which are differentially expressed in human cancers. In this study, we examined and confirmed the over-expression of these clusters in hepatocellular carcinoma and in hepatoma-derived cells. At least 50% of the tumor samples showed a greater than two-fold increase in the expression for miR-18 and for the miR-106b-25 cluster when compared with the corresponding paired non-tumor samples. Knock-down studies for the miR-106b-25 cluster, which includes miR-106b, miR-93 and miR-25, showed that the expression of the cluster is necessary for cell proliferation and for anchorageindependent growth. In tumors with high expression of this cluster, reduced expression of the BH3-only protein Bim, a miR-25 target, was observed. We further identified the transcription factor E2F1 as a target gene for miR-106b and miR-93 and it is likely that one of the roles of the miR-106b-25 cluster is to prevent excessively high E2F1 expression, which may then cause apoptosis. We conclude that there is aberrant expression of microRNAs encoded by the oncogenic miR-17-92 cluster and the miR-106b-25 cluster in hepatocellular carcinoma. The consistent overexpression of the miR-106b-25 cluster and its role in cell proliferation and anchorage-independent growth points to the oncogenic potential of this cluster. (Cancer Sci 2009; 100: 1234-1242) M icroRNAs (miRNAs) are small, endogenous RNA molecules which are transcribed as long primary transcripts, processed to the precursor miRNAs (pre-miRNA), and further processed to yield approximately 22-nucleotide duplexes of which one arm gives rise to the mature miRNA.(1) Depending on the degree of complementarity, binding of miRNA to its target mRNA can result in either cleavage of the target or in translation repression.(2-4) Despite a comprehensive registry of known miRNAs and the genes which encode them (http://microrna.sanger.ac.uk/sequences/), knowledge of exactly which mRNA and processes each miRNA regulates is incomplete. Studies have shown that miRNAs can influence diverse pathways and affect many physiological processes including metabolism, development, differentiation, and apoptosis.(5-8) Altered expression of miRNAs has been demonstrated in various human cancers including chronic lymphocytic leukemia, (9) lung cancer, (10)(11)(12) colorectal neoplasia, (13,14) breast cancer, (15) and several types of lymphoma. (16)(17)(18)(19) This suggests that miRNAs might function as oncogenes or as tumor suppressors. (20) MicroRNA genes can occur in clusters and these are transcribed as polycistronic transcripts. To date, the miR-17-92 cluster is the best characterized. The miRNAs encoded by this cluster are overexpressed in many ...

Regulation of miR106b cluster through the RB pathway

“…The mir106b cluster is embedded within the MCM7 gene, which is a direct RB/E2F target gene. 16,[26][27][28][29][30] The mir106b cluster targets the expression of several genes that are directly disease-relevant and that provide a mechanism for cross-talk from the canonical RB pathway to PTEN and p21…”

MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

“…For example, the BH3-only proteins, BMF and BID, are targeted by miR-221 and miR-25, respectively. 29,30,43 These mechanisms have the potential to allow miR-221 to protect cells from 'anoikis', a form of apoptosis induced by the detachment of anchorage-dependent cells from the surrounding extracellular matrix. MiR-25 may also impair the TGF-b tumor suppressor pathway.…”

“…CDKN1A/p21 is downregulated by oncogenic members of the miR-17-92 family. [29][30][31][32][33] Among the three clusters of the miR-17-92 family of the human genome, those on chromosomes 13 and 7 are upregulated in HCC. 34 Disruption of apoptosis in HCC has been extensively reviewed.…”

MiR-25 regulates apoptosis by targeting Bim in human ovarian cancer

“…Thus, there are urgent needs to develop novel therapeutic approaches by targeting the molecules that are altered in this malignancy. Recent studies showed that miR-25, a member of miR-106b clusters was frequent deregulated in a variety of cancer types (7)(8)(9). So far, there are few reports on miR-25 in ovarian cancer.…”