TGF-?1 Cooperates With Hepatitis B Virus X To Promote Malignant Transformation Of Hepatic Progenitor Cells By Upregulating MiR-199a-3p

Increasing evidence has suggested that liver cancer arises partially from transformed hepatic progenitor cells(HPCs).However,the detailed mechanisms underlying HPC transformation are poorly understood.In this study,we provide evidence linking the coexistence of hepatitis B virus X protein(HBx)and transforming growth factor beta 1(TGF-?1)with miR-199a-3p in the malignant transformation of HPCs.The examination of liver cancer specimens demonstrated that HBx and TGF-?1 expression was positively correlated with epithelial cell adhesion molecule(EpCAM)and CD90.Importantly,EpCAM and CD90 expression was much higher in the specimens expressing both high HBx and high TGF-?1 than in those with high HBx or high TGF-?1 and the double low expression group.HBx and TGF-?1 double-high expression was significantly associated with poor prognosis in primary liver cancer.We also found that HBx induced the transformation of HPCs into hepatic cancer stem cells and promoted epithelial–mesenchymal transformation,which was further enhanced by TGF-?1.Moreover,activation of the c-Jun N-terminal kinase(JNK)/c-Jun pathway was involved in the malignant transformation of HPCs.miR-199a-3p was identified as a significantly upregulated microRNA in HPCs upon HBx and TGF-?1 exposure,and HBx was shown to promote miR-199a-3p expression via c-Jun-mediated activation.Finally,we found that miR-199a-3p was responsible for the malignant transformation of HPCs.In conclusion,our results provide evidence that TGF-?1 cooperates with HBx to promote the malignant transformation of HPCs through a JNK/c-Jun/miR-199a-3p-dependent pathway.This may open new avenues for therapeutic interventions targeting the malignant transformation of HPCs in treating liver cancer.