Tumor necrosis factor-α promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells

Hepatocellular carcinoma (HCC) is an inflammation-related disease. Tumor necrosis factor alpha (TNF-alpha) is an important inflammatory factor and it has been confirmed to promote tumor growth and poor prognosis of HCC. Hepatic progenitor cells (HPCs) are thought to play an important role in liver injury and repair, as well as tumorigenesis. Chronic inflammation influences HPCs activation as well as differentiation. However, the mechanism is still unclear. In our study, the rat liver cancer model was constructed by DEN treatment, TNFR2-Fc fusion protein variant (TNFR2-FcV) and TNF-alpha(-/-) rats were used to detect the role of TNF-alpha in liver injury and tumorigenesis. And the effect of TNF-alpha on HPCs activation and proliferation was investigated, and the specific molecular mechanism was explored. We found that TNF-alpha inhibition and deletion could reduce tumor incidence but shorten survival time by increasing apoptosis and decreasing proliferation of hepatocytes. Further analysis indicated that TNF-alpha knochdown cloud inhibit HPCs activation and proliferation through TNFR2/STAT3 signaling pathway. And clinically TNF-alpha expression was correlated to HPCs activation and HCC recurrences. Our work suggested that TNF-alpha played a key role in liver injury and tumorigenesis.