TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p

Abstract

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-β1) with miR-199a-3p in the malignant transformation of HPCs. The examination of liver cancer specimens demonstrated that HBx and TGF-β1 expression was positively correlated with epithelial cell adhesion molecule (EpCAM) and cluster of differentiation 90 (CD90). Importantly, EpCAM and CD90 expression was much higher in the specimens expressing both high HBx and high TGF-β1 than in those with high HBx or high TGF-β1 and the double-low-expression group. HBx and TGF-β1 double-high expression was significantly associated with poor prognosis in primary liver cancer. We also found that HBx and TGF-β1 induced the transformation of HPCs into hepatic cancer stem cells and promoted epithelial-mesenchymal transformation, which was further enhanced by concomitant HBx and TGF-β1 exposure. 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-β1 exposure, which were 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-β1 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.

Recent Advances in Liver Cancer Stem Cells: Non-coding RNAs, Oncogenes and Oncoproteins

“…TGF-β1 cooperation with HBx can activate the c-Jun N-terminal kinase (JNK)/c-Jun pathway, while miR-199a-3p, a regulator of hepatic progenitor cell (HPC) transformation, can be activated by c-Jun. In conclusion, TGF-β1/HBx co-regulated the miR-199a-3p signaling axis targeting malignant transformation of HPCs ( Dong et al, 2019 ). Furthermore, miR-155 overexpression promoted cell EMT in liver cancer cells, and overexpression of miR-155 promoted the stemness of LCSCs via down-regulation of tumor protein P53 inducible nuclear protein 1 (TP53INP1), which is a downstream target gene of miR-155.…”

Dysregulation of Liver Regeneration by Hepatitis B Virus Infection: Impact on Development of Hepatocellular Carcinoma

“…Although some studies reported the anti-HBV action of TGF-β [ 107 ], it has also been suggested that HBV infection upregulated the expression of TGF-β [ 108 , 109 , 110 , 111 ], which might be related to the inhibition of immune responses, as well as the development of fibrosis and intra hepatic cholangiocarcinoma [ 110 , 111 ]. The mechanisms whereby TGF-β regulates liver pathogenesis during chronic HBV infection includes but is not restricted to the regulation of extracellular matrix system [ 112 ], regulation of immune modulators such as Th17 and regulatory T cells (Tregs) [ 113 , 114 ], production of cytokines and chemokines [ 115 ], regulation of miRNA signaling [ 116 ], and cell proliferation [ 117 ].…”

Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

“…Of note, CD13 expression positively correlates with metastatic lung foci, suggesting that miR-125b mimics can inhibit the CSC population in HCC [ 83 ]. Interestingly, HBx and TGF-β1 overexpression led to c-Jun N-terminal kinase (JNK)/c-Jun-mediated miR-199a-3p upregulation in the rat-derived hepatic stem cell line LE/6, helping to trigger stem cell-like characteristics in vitro and increased in vivo tumorigenesis [ 84 ]. Despite its well-known role as a tumor suppressor miRNA, this study suggests a possible role for miR-199a-3p in the induction and maintenance of the CSC population in HCC.…”