Purpose: Recent studies have identified microRNA-944 (miR-944) as a cancer-related miRNA, but its expression and precise functions in hepatocellular carcinoma (HCC) remain unknown.
Patients and methods: miR-944 expression in HCC tissues and cell lines were detected by RT-qPCR. A series of functional assays were utilized to examine the influence of miR-944 on the malignant phenotypes of HCC cells in vitro and in vivo. More importantly, the associated mechanisms underlying the activity of miR-944 in HCC cells were investigated using bioinformatics, luciferase reporter assays, RT-qPCR, and western blot analysis.
Results: In this study, we report for the first time, a significant downregulation of miR-944 in HCC tissues and cell lines and the correlation between its downregulation and malignant clinical parameters, including Edmondson-Steiner grade, TNM stage, and venous infiltration. Low miR-944 expression predicted poorer overall survival rate and disease-free survival rate in patients with HCC. Functionally, exogenous miR-944 expression attenuated cell proliferation, clone formation, metastasis, and epithelial-mesenchymal transition and increased apoptosis in HCC, whereas miR-944 knockdown produced the opposite results. In addition, ectopic miR-944 expression hindered HCC tumor growth in vivo. Mechanistically, insulin-like growth factor 1 receptor (IGF-1R) was demonstrated to be the direct target gene of miR-944 in HCC cells. Furthermore, the expression level of miR-944 was inversely correlated with IGF-1R expression in HCC tissues. Rescue experiments showed that IGF-1R was at least partially responsible for the effects of miR-944 on the malignant phenotypes of HCC cells. In addition, the PI3K/Akt pathway was notably deactivated, both in vitro and in vivo, upon miR-944 upregulation.
Conclusion: This study provides the first evidence that miR-944 directly targets IGF-1R and inhibits the aggressiveness of HCC, in vitro and in vivo, by decreasing PI3K/Akt signaling. Hence, targeting miR-944 may open a new avenue for the treatment of patients with HCC.
Keywords: hepatocellular carcinoma, microRNA-944, insulin-like growth factor 1 receptor, PI3K/Akt pathway, epithelial-mesenchymal transition