MicroRNA‐494 within an oncogenic microRNA megacluster regulates G ₁ /S transition in liver tumorigenesis through suppression of mutated in colorectal cancer

Abstract

Hepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver’s unique affinity for small nucleic acids, miRNA based therapy has been proposed in the treatment of liver disease. There is thus an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCC. We identified an upregulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is upregulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed. Conclusion We found that miR-494 is overexpressed in human HCC, and aids in transformation by regulating the G1/S cell cycle transition through targeting of the Mutated in Colorectal Cancer (MCC) tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size. Our findings identify a new therapeutic target, miR-494, for the treatment of HCC.

RETRACTED: MicroRNA‐379 suppresses osteosarcoma progression by targeting PDK1

“…Several studies have demonstrated abnormal expression of miRNAs in different types of cancer, including gastric cancer, hepatocellular carcinoma, glioblastoma, ovarian carcinoma, breast cancer and laryngeal cancer 17, 18, 19, 20, 21, 22. Moreover, increasing evidence showed that miRNAs play important roles in many biological processes, including cell proliferation, apoptosis, metabolism, differentiation and invasion 23, 24, 25, 26.…”

MiR-29a and miR-652 Attenuate Liver Fibrosis by Inhibiting the Differentiation of CD4+ T Cells

“…The analysis of miRNA on liver diseases have been documented several years before, the down-regulations of miR-150 and miR-194 were demonstrated to lead to severe liver fibrosis (Venugopal et al, 2010), while the over-expression of miR-494 acted as an oncogenicmiRNA that regulated liver tumorgensis (Lim et al, 2014). These findings indicated the decisive role of miRNAs on liver function.…”

miR-494 is an independent prognostic factor and promotes cell migration and invasion in colorectal cancer by directly targeting PTEN

“…Previous reports showed that mir-494 was downregulated and functioned as a tumor suppressor in human cholangiocarcinoma (21), gastric cancer (23) and lung cancer (28). However, other studies demonstrated that upregulation of mir-494 was associated with several types of human malignant solid tumors, including hepatocellular carcinoma (29), non-small cell lung cancer (30), and carcinoma induced by anti-BPDe (27). in these types of cancer, mir-494 seemed to be an oncogene, and promoted tumor cell proliferation, cell cycle, cell migration and invasion via regulation of the target genes Pten, BiM and Mcc.…”