Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1)

Hepatocellular carcinoma (HCC) is a rapidly progressing, incurable cancer that frequently spreads to portal vein and lung. New insights are needed to identify therapeutic targets to prevent or retard HCC metastatic progression. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of HCC. Here we found miR-28-5p is a liver-relevant anti-proliferative miRNA whose expression, functions, and mechanisms were analyzed in human hepatoma cells, HepG2 and Huh7. Interestingly, when evaluating the specific targets of miR-28-5p, we found that ectopic miR-28-5p expression down-regulates insulin-like growth factor 1 (IGF1) protein and that the expression of miR-28-5p correlates negatively with IGF1 protein in HCC cells. Luciferase report in HCC cells expressing miR-28-5p suggests that miR-28-5p reduces luciferase activity by targeting the 3'-UTR of IGF1 mRNA. Additionally, we show that the selective inhibition of either the PI3K/AKT pathway prior to miR-28-5p stimulation prevents the expression of previously described tumor suppressor miRNAs that are family and cluster specific. Together, our results defined miR-28-5p as a critical regulator of IGF1 mRNA translation function, down-regulated miR-28-5p in HCC was associated with tumor growth through PI3K/AKT pathway by targeting IGF1. miR-28-5p-IGF1-PI3K/AKT pathway may play an important role in the development of HCC.