Abstract
Aberrant expression of microRNA-34a (miR-34a) has been reported to be involved in the tumorigenesis and progression of various classes of malignancies. However, its role in hepatocellular carcinoma (HCC) has not been completely clarified. In the current study, we have investigated the clinical significance and the in vitro contribution of miR-34a on biological functions of human HCCs. miR-34a expression in eighty-three cases of HCC formalin-fixed paraffin-embedded (FFPE) tissues decreased significantly compared to that in the adjacent liver tissues (P<0.01), as detected by real-time quantitative RT-PCR (RT-qPCR). miR-34a expression in the groups of TNM stage I and II, without metastasis and without portal vein tumor embolus, was significantly higher than that of their corresponding groups (P<0.05). In functional experiments, miR-34a mimic suppressed cell growth, migration and invasion, meanwhile it increased cellular apoptosis and caspase activity in HCC cells. miR-34a mimic also reduced phospho-ERK1/2 and phospho-stat5 signaling. In addition, miR-34a mimic enhanced the effect of cell proliferation inhibition and caspase activity induction of agents targeting c-MET (siRNAs and small molecular inhibitor su11274). In conclusion, miR-34a may act as a tumor suppressor miRNA of HCC. The strategies to increase miR-34a level might be a critical targeted therapy for HCC in future.
Highlights
Studies have shown that aberrant microRNAs expression is correlated with the development and progression of cancer, miRNAs could be used as biomarkers for diagnosis and prognosis of cancer
We investigated the expression of miRNA-34a in Hepatocellular carcinoma (HCC) and their matched adjacent noncancerous liver tissues in 83 cases of formalin-fixed paraffin-embedded (FFPE) surgically resected samples, using real time quantitative RT-PCR (RT-qPCR)
Discussion miR-34a was reported to be down-regulated in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet, which is relevant to the hepatocarcinogenesis in humans associated with viral hepatitis C and B infections, alcohol exposure and metabolic liver diseases [18]
Summary
Studies have shown that aberrant microRNAs (miRNAs) expression is correlated with the development and progression of cancer, miRNAs could be used as biomarkers for diagnosis and prognosis of cancer. Among all the HCC-related miRNAs, contradictory relationship between miR-34a levels and HCC was reported [13,14]. C-MET is a proved target gene of miR-34a [14,15] and c-MET inhibitor demonstrated a manageable safety profile and preliminary antitumor activity in patients with HCC and Child-Pugh A or B cirrhosis [16], we have for the first time investigated the combinatorial effect of miR-34a mimic and c-MET targeting agents (c-MET siRNAs or c-MET kinase inhibitor su11274) in HCC cells We performed in vitro experiments to study the effect of miR-34a on the cell growth, apoptosis, caspase-3/7 activity, migration and invasion in HCC cell lines. c-MET is a proved target gene of miR-34a [14,15] and c-MET inhibitor demonstrated a manageable safety profile and preliminary antitumor activity in patients with HCC and Child-Pugh A or B cirrhosis [16], we have for the first time investigated the combinatorial effect of miR-34a mimic and c-MET targeting agents (c-MET siRNAs or c-MET kinase inhibitor su11274) in HCC cells
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