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TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinomaResearch in context
- 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 :
- Medicine
Medicine (General)
R5-920
Subjects
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