MiR-3677-3p promotes development and sorafenib resistance of hepatitis B-related hepatocellular carcinoma by inhibiting FOXM1 ubiquitination.

Being encoded by hepatitis B, hepatitis B X (HBx) protein plays crucial roles in hepatitis B-related hepatocellular carcinoma (HCC) occurrence, development, and metastasis. miRNAs also function in the progression of hepatitis B-related HCC. Hence, the objective of this study was to explore the impacts of miR-3677-3p on tumor progression and sorafenib resistance in hepatitis B-related HCC and the related underlying mechanisms. Our research revealed that miR-3677-3p and FOXM1 was up-regulated and FBXO31 was down-regulated in HBV HCC cells and tumor tissues from nude mice. After miR-3677-3p overexpression, cell proliferative, invasive, and migrating potentials and stemness-related protein (CD133, EpCAM, and OCT4) levels were enhanced, and cell apoptosis was reduced in Huh7 + HBx/SR cells and HepG2.2.15/SR cells. Besides, miR-3677-3p promoted the drug resistance of Huh7 + HBx/SR cells and HepG2.2.15/SR cells to sorafenib and lifted IC50. In vivo experiments, miR-3677-3p down-regulation suppressed the tumor growth in the hepatitis B HCC nude mouse models. Mechanistically, miR-3677-3p targeted and negatively-regulated FBXO31 and FBXO31 could enrich FOXM1 protein. miR-3677-3p down-regulation or FBXO31 overexpression promoted the ubiquitylation of FOXM1. In a word, miR-3677-3p bound to FBXO31 and inhibited FBXO31 expression, thus curtailing the ubiquitylation degradation of FOXM1, contributing to HCC development and sorafenib resistance.