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c-Jun的过表达导致人肝癌细胞系对索拉非尼耐药。

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.

作者信息

Haga Yuki, Kanda Tatsuo, Nakamura Masato, Nakamoto Shingo, Sasaki Reina, Takahashi Koji, Wu Shuang, Yokosuka Osamu

机构信息

Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.

Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan.

出版信息

PLoS One. 2017 Mar 21;12(3):e0174153. doi: 10.1371/journal.pone.0174153. eCollection 2017.

DOI:10.1371/journal.pone.0174153
PMID:28323861
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5360329/
Abstract

BACKGROUND

Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC). Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.

METHODS

The expression of molecules involved in the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun) was measured.

RESULTS

The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.

CONCLUSIONS

The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

摘要

背景

尽管治疗策略最近取得了进展，但肝细胞癌（HCC）患者的治愈仍然困难。索拉非尼是唯一被批准用于晚期HCC患者全身化疗的多激酶抑制剂。大多数晚期HCC患者对索拉非尼耐药。索拉非尼耐药的机制仍然未知。

方法

在有或没有索拉非尼的情况下，检测人肝癌细胞系中丝裂原活化蛋白激酶（MAPK）信号通路相关分子的表达。研究用索拉非尼处理的人肝癌细胞的凋亡情况，并检测原癌基因Jun（c-Jun）的表达。

结果

用索拉非尼处理后人肝癌细胞系中c-Jun的表达和磷酸化增强。抑制c-Jun可增强索拉非尼诱导的凋亡。c-Jun的过表达损害索拉非尼诱导的凋亡。在人肝癌细胞系中用索拉非尼处理后，已确定的AP-1靶基因之一骨桥蛋白的表达增强。

结论

蛋白c-Jun在人肝癌细胞系的索拉非尼耐药中起作用。c-Jun的调节和磷酸化可能是增强对索拉非尼反应性的一种新的治疗选择。调节c-Jun可能对某些对索拉非尼耐药的HCC患者有用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/453c6295f784/pone.0174153.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/5f73857b3b57/pone.0174153.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/c5b448226b90/pone.0174153.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/e41b72d95f8d/pone.0174153.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/e43f7f0b761a/pone.0174153.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/8c86bd722034/pone.0174153.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/1e78a8b5eff4/pone.0174153.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/453c6295f784/pone.0174153.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/5f73857b3b57/pone.0174153.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/c5b448226b90/pone.0174153.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/e41b72d95f8d/pone.0174153.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/e43f7f0b761a/pone.0174153.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/8c86bd722034/pone.0174153.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/1e78a8b5eff4/pone.0174153.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7e1/5360329/453c6295f784/pone.0174153.g007.jpg

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