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

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).

• Authors: Wenliang Tan, Xuan Luo, Wenda Li, Jinyi Zhong, Jun Cao, Sicong Zhu, Xianqing Chen, Rui Zhou, Changzhen Shang, Yajin Chen
• Journal: EBioMedicine (EBioMedicine) Vol. 40 Pg. 446-456 (Feb 2019) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30594557 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

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

Topics

• Animals
• Carcinoma, Hepatocellular (drug therapy, metabolism, mortality, 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, metabolism, mortality, pathology)
• Mice
• Models, Biological
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Sorafenib (pharmacology, therapeutic use)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays