Abstract
Deregulation of microRNAs (miRNAs) is a typical feature of human hepatocellular carcinoma (HCC). However, the in vivo relevance of miRNAs along hepatocarcinogenesis remains largely unknown. Here, we show that liver tumors induced in mice by c-Myc overexpression or AKT/Ras co-expression exhibit distinct miRNA expression profiles. Among the downregulated miRNAs, eight (miR-101, miR-107, miR-122, miR-29, miR-365, miR-375, miR-378, and miR-802) were selected and their tumor suppressor activity was determined by overexpressing each of them together with c-Myc or AKT/Ras oncogenes in mouse livers via hydrodynamic transfection. The tumor suppressor activity of these microRNAs was extremely heterogeneous in c-Myc and AKT/Ras mice: while miR-378 had no tumor suppressor activity, miR-107, mir-122, miR-29, miR-365 and miR-802 exhibited weak to moderate tumor suppressor potential. Noticeably, miR-375 showed limited antineoplastic activity against c-Myc driven tumorigenesis, whereas it strongly inhibited AKT/Ras induced hepatocarcinogenesis. Furthermore, miR-101 significantly suppressed both c-Myc and AKT/Ras liver tumor development. Altogether, the present data demonstrate that different oncogenes induce distinct miRNA patterns, whose modulation differently affects hepatocarcinogenesis depending on the driving oncogenes. Finally, our findings support a strong tumor suppressor activity of miR-101 in liver cancer models regardless of the driver oncogenes involved, thus representing a promising therapeutic target in human HCC.
Highlights
Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is one of the leading causes of cancer-related death worldwide [1]
To characterize miRNAs regulated by different oncogene stimuli during hepatocarcinogenesis, we compared the global miRNA expression patterns of normal mouse livers with those from liver tumors induced by c-Myc or AKT/Ras oncogenes (n = 9 total; and n = 3 in each group)
We assessed whether liver tumors induced by the overexpression of different oncogenes display distinct miRNA expression profiles
Summary
Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is one of the leading causes of cancer-related death worldwide [1]. According to the American Cancer Society, there will be 30,640 newly diagnosed cases and 21,670 deaths due to HCC in the US in the year 2014 A multikinase inhibitor targeting the Raf/VEGFR/PDGFR/c-Kit axis, is the only FDA approved drug for HCC treatment [6, 7]. It has very limited efficacy in improving the length of patients’ survival [8]. One of the major challenges in drug development for HCC treatment resides in the fact that HCC is a highly heterogeneous disease at the molecular level, it is conceivable that only certain HCC subsets would benefit of the use of targeted therapies
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