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.
Highlights
These authors contributed : Ke-shuai Dong, Yan Chen
To investigate the functional crosstalk between TGF-β1 and hepatitis B virus X protein (HBx) in hepatic progenitor cells (HPCs) transformation and hepatic cancer stem cells (HCSC) generation, we measured the expression of TGF-β1, HBx, and cancer stem cell (CSC) markers cluster of differentiation 90 (CD90) and epithelial cell adhesion molecule (EpCAM) by IHC staining in a liver tumor tissue microarray
Current evidence suggests that primary liver cancers derive from mature hepatocytes subjected to reprogramming events that result in CSC features, or from the transformation of progenitor cells [38]
Summary
Expansion is mainly caused by various pathologies, or environmental or genetic etiologies of liver cancer, such as fibrosis, cirrhosis, inflammation, and viral infection [4] These factors cause some HPC descendants to evolve into hepatic cancer stem cells (HCSC) with an unlimited self-renewal capacity and differentiation potential, resulting in the formation of a premalignant lesion [8]. Transforming growth factor beta 1 (TGF-β1) is a multifunctional cytokine predominantly produced by activated mesenchymal cells in HBV-related liver injury [14]. TGF-β1 is known to activate hepatic stellate cells and cause liver fibrosis, which contributes to hepatocarcinogenesis and tumor progression [17]. The present study, determined whether TGFβ1 synergistically functions with HBx to promote the malignant transformation of HPCs, and aimed to identify the miRNAs involved in this progression. Our findings unveil a novel TGF-β1/HBx coregulated miR199a-3p signaling axis in HPCs that may allow the development of novel therapeutic interventions for targeting the malignant transformation of HPCs
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