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

EBioMedicine. 2019 Feb:40:446-456. doi: 10.1016/j.ebiom.2018.12.047. Epub 2018 Dec 26.

Abstract

Background: The role of tumor necrosis factor alpha (TNF-α) in targeted therapy for hepatocellular carcinoma (HCC) remains largely unknown. The current study aimed to clarify the mechanistic effects of targeting TNF-α to overcome sorafenib resistance in HCC.

Methods: A correlation of TNF-α expression with the prognosis was analyzed in 62 HCC patients who underwent surgical resection and subsequent received adjuvant sorafenib treatment. The relation of TNF-α expression and sorafenib sensitivity was determined in different HCC cell lines. The combined therapeutic effects of sorafenib and ulinastatin, which could inhibit TNF-α expression, on HCC were examined in vitro and in vivo.

Findings: High TNF-α expression was correlated with poor outcomes in HCC patients who received adjuvant sorafenib after surgery. In vitro experiments showed that TNF-α 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-α, and sorafenib had limited effectiveness on reversing EMT in HCC cells with high TNF-α expression. Inhibiting the expression of TNF-α with ulinastatin significantly enhanced the anti-tumor effect of sorafenib on HCC cells with high expression of TNF-α in vitro and in vivo.

Interpretation: Our findings indicate that TNF-α 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-α. FUND: This work was supported by grants from the National Natural Science Foundation of China (no.81572398; no.81672419), the Science and Technology Planning Project of Guangdong Province (no. 2017A010105003; no.2015A050502023; no.2016A020216010), and the Natural Science Foundation of Guangdong Province (no.2014A030313061; no. 2013B021800101).

Keywords: Combination treatment; Hepatocellular carcinoma; Sorafenib resistance; TNF-α; Ulinastatin.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm*
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycoproteins / pharmacology
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Mice
  • Models, Biological
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Sorafenib / pharmacology*
  • Sorafenib / therapeutic use
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Glycoproteins
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Sorafenib
  • urinastatin