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

Authors :
Wenliang Tan
Xuan Luo
Wenda Li
Jinyi Zhong
Jun Cao
Sicong Zhu
Xianqing Chen
Rui Zhou
Changzhen Shang
Yajin Chen
Source :
EBioMedicine, Vol 40, Iss , Pp 446-456 (2019)
Publication Year :
2019
Publisher :
Elsevier, 2019.

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: Hepatocellular carcinoma, Sorafenib resistance, TNF-α, Ulinastatin, Combination treatment

Subjects

Subjects :
Medicine
Medicine (General)
R5-920

Details

Language :
English
ISSN :
23523964
Volume :
40
Issue :
446-456
Database :
Directory of Open Access Journals
Journal :
EBioMedicine
Publication Type :
Academic Journal
Accession number :
edsdoj.67142e380ea44779a7b647c3c847dce8
Document Type :
article
Full Text :
https://doi.org/10.1016/j.ebiom.2018.12.047