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TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma
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 expressio...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412090/ https://www.ncbi.nlm.nih.gov/pubmed/30594557 http://dx.doi.org/10.1016/j.ebiom.2018.12.047 |
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author | Tan, Wenliang Luo, Xuan Li, Wenda Zhong, Jinyi Cao, Jun Zhu, Sicong Chen, Xianqing Zhou, Rui Shang, Changzhen Chen, Yajin |
author_facet | Tan, Wenliang Luo, Xuan Li, Wenda Zhong, Jinyi Cao, Jun Zhu, Sicong Chen, Xianqing Zhou, Rui Shang, Changzhen Chen, Yajin |
author_sort | Tan, Wenliang |
collection | PubMed |
description | 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). |
format | Online Article Text |
id | pubmed-6412090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-64120902019-03-21 TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma Tan, Wenliang Luo, Xuan Li, Wenda Zhong, Jinyi Cao, Jun Zhu, Sicong Chen, Xianqing Zhou, Rui Shang, Changzhen Chen, Yajin EBioMedicine Research paper 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). Elsevier 2018-12-26 /pmc/articles/PMC6412090/ /pubmed/30594557 http://dx.doi.org/10.1016/j.ebiom.2018.12.047 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Tan, Wenliang Luo, Xuan Li, Wenda Zhong, Jinyi Cao, Jun Zhu, Sicong Chen, Xianqing Zhou, Rui Shang, Changzhen Chen, Yajin TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma |
title | TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma |
title_full | TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma |
title_fullStr | TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma |
title_full_unstemmed | TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma |
title_short | TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma |
title_sort | tnf-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412090/ https://www.ncbi.nlm.nih.gov/pubmed/30594557 http://dx.doi.org/10.1016/j.ebiom.2018.12.047 |
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