A small molecule modulator of the tumor suppressor miRNA-34a inhibits the growth of hepatocellular carcinoma
Menée in vitro et in vivo, cette étude met en évidence l'activité antitumorale d'une petite molécule appelée Rubone, un modulateur de l'expression du micro-ARN suppresseur de tumeurs miR-34a, pour le traitement d'un carcinome hépatocellulaire
Small molecules that restore the expression of growth inhibitory microRNAs downregulated in tumors may have potential as anticancer agents. miR-34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR-34a luciferase reporter system to screen for miR-34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR-34a in HCC cells. Rubone activated miR-34a expression in HCC cells with wild type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth inhibitory effects on non-tumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of Cyclin D1, Bcl-2 and other miR-34a target genes and that it enhanced the occupancy of p53 on the miR-34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR-34a tumor suppressor function.