TNF-alpha is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma

Background: The role of tumor necrosis factor alpha (TNF-alpha) in targeted therapy for hepatocellular carcinoma (HCC) remains largely unknown. The current study aimed to clarify the mechanistic effects of targeting TNF-alpha to overcome sorafenib resistance in HCC. Methods: A correlation of TNF-alpha expression with the prognosis was analyzed in 62 HCC patients who underwent surgical resection and subsequent received adjuvant sorafenib treatment. The relation of TNF-alpha expression and sorafenib sensitivity was determined in different HCC cell lines. The combined therapeutic effects of sorafenib and ulinastatin, which could inhibit TNF-alpha expression, on HCC were examined in vitro and in vivo. Findings: High TNF-alpha expression was correlated with poor outcomes in HCC patients who received adjuvant sorafenib after surgery. In vitro experiments showed that TNF-alpha promotes HCC cell resistant to sorafenib through inducing epithelial-mesenchymal transition (EMT). Notably, the current study revealed that sorafenib has no significant influence on the expression and secretion of TNF-alpha, and sorafenib had limited effectiveness on reversing EMT in HCC cells with high TNF-alpha expression. Inhibiting the expression of TNF-alpha with ulinastatin significantly enhanced the anti-tumor effect of sorafenib on HCC cells with high expression of TNF-alpha in vitro and in vivo. Interpretation: Our findings indicate that TNF-alpha may serve as a novel predictor of sorafenib sensitivity in HCC patients. Sorafenib combined with ulinastatin may improve the effectiveness of treatment of HCC in patients with high expression of TNF-alpha. (C) 2018 The Authors. Published by Elsevier B.V.