MicroRNA‐206 prevents the pathogenesis of hepatocellular carcinoma by modulating expression of met proto‐oncogene and cyclin‐dependent kinase 6 in mice

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell cycle progression and cMet signaling pathway. MicroRNA-206 was under-expressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto-oncogene), CCND1, and CDK6 as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1 and CDK6, microRNA-206 delayed cell cycle progression, induced apoptosis and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and AKT/Ras HCC mice, while 100% of control mice died from lethal tumor burdens. Conversely, re-introduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. In summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC, and suggests its use as a potential therapeutic strategy for this malignancy.

MiR‐205 suppresses tumor growth, invasion, and epithelial‐mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma

“…Emerging evidence has demonstrated that dysregulation of miRNAs has a crucial role in the carcinogenesis and progression of HCC (25)(26)(27). A previous study (28) showed that miR-205 expression levels decrease in HCC tissues as compared with those in matched healthy tissues, and down-regulation of miR-205 promotes stemness of HCC by targeting PLCb1 and increasing CD24 expression.…”

MicroRNAs in Animal Models of HCC

“…In line, we demonstrated p27 as a miR-494 direct target gene in HCC cell lines and xenograft mice playing a role in cell cycle fastening and cell proliferation in miR-494 overexpressing Huh-7 cells, suggesting that both animal models might be suitable for identification of miR-494 downstream molecular mechanisms [15]. Similarly, miR-206 was commonly downregulated among c-Myc and AKT/Ras-oncogene induced HCC mouse models, HCC cell lines, and human HCCs contributing to tumor development and progression through cell cycle regulator cyclin D1 (CCND1), c-MET, and cyclin-dependent kinase 6 (CDK6) direct targeting, as demonstrated by in vitro and in vivo experiments [21]. Notably, oncogene overexpression might be obtained not only through the establishment of TG mice but, more easily, through hydrodynamic tail-vein injection, which is an efficient procedure to deliver nucleic acids, primarily to the liver, taking advantage of its peculiar fenestrated sinusoids.…”

“…The second strategy considered miRNA mimics modified at 2'O-methyl and labeled with four cholesterol groups, to increase the stability and transfection efficiency. Both strategies showed a marked anticancer effect in c-Myc mice, decreasing tumor growth and target genes expression, but failed to repress tumor growth of AKT/Ras mice, perhaps due to their more rapid growth, underlining the importance to test miRNA-based therapeutics in different animal models and suggesting again the need for patient stratification based on genomic and transcriptomic backgrounds [21]. In the following paragraphs, we describe miRNA-based antitumor approaches in xenograft and orthotopic HCC mouse models, focusing on their representativeness of human pathology and translation into the clinics (Figure 1).…”

miR‐1‐3p and miR‐206 sensitizes HGF‐induced gefitinib‐resistant human lung cancer cells through inhibition of c‐Met signalling and EMT

“…Therefore, they have many predicted and validated common targets, such as ARPC3, c-Met, VEGFA. [26][27][28] Figure 3A Figure S3). However, the combination of miR-1-3p or miR-206 mimics and gefitinib, significantly inhibited HGF-induced pc-Met expression.…”