High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo.
High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo.
复制标题
高迁移率族盒 1 促进 HepG2 细胞和体内索拉非尼耐药
DOI：
10.1186/s12885-017-3868-2
复制
发表时间：
2017-12-15
期刊：
影响因子：
3.8
通讯作者：
Fan XG
中科院分区：
文献类型：
--
作者：
Xiao Y;Sun L;Fu Y;Huang Y;Zhou R;Hu X;Zhou P;Quan J;Li N;Fan XG
背景原发性肝癌是一种致命的恶性肿瘤，在全世界范围内死亡率很高。目前，索拉非尼是治疗肝细胞癌（HCC）最有效的分子靶向药物。但索拉非尼耐药率较高。这种耐药性的分子机制尚未完全阐明。高迁移率族蛋白 1 (HMGB1) 是一种多面蛋白，在 HCC 细胞的增殖、凋亡、转移和血管生成中发挥关键作用。此外，HMGB1 还被认为有助于肿瘤的化疗耐药性，包括肺癌、骨肉瘤、神经母细胞瘤、白血病和结直肠癌。本研究调查了 HCC 中 HMGB1 与索拉非尼耐药之间的关联。方法产生了 HMGB1 敲低或过表达的 HepG2 细胞。使用流式细胞术和细胞计数测定法测试了索拉非尼在这些细胞中的功效。通过蛋白质印迹和共聚焦显微镜测量索拉非尼治疗后 HepG2 细胞中 HMGB1 的亚细胞定位。建立小鼠皮下HCC模型来检查HMGB1与索拉非尼治疗敏感性之间的关联。结果在索拉非尼治疗后，HMGB1敲低细胞比正常HMGB1表达细胞表现出显着更高的凋亡水平和更低的细胞活力。此外，在索拉非尼干预后，在 HMGB1 过表达细胞中观察到的细胞活力高于在对照细胞中观察到的细胞活力。索拉非尼在体内HMGB1敲低组中具有更好的抑瘤效果。暴露于索拉非尼后，线粒体 HMGB1 的量减少，而胞质 HMGB1 的量增加。总而言之，在 HepG2 细胞暴露于索拉非尼后，HMGB1 从线粒体转移到线粒体外的细胞质。结论观察到 HMGB1 在调节 HCC 索拉非尼治疗耐药中的新潜在作用。 HMGB1 的敲低可恢复对索拉非尼的敏感性并增强 HepG2 细胞死亡，而 HMGB1 的过度表达会减弱这些作用。索拉非尼治疗后 HMGB1 从线粒体易位到细胞质，为 HCC 索拉非尼耐药性提供了新的见解。
BackgroundPrimary liver cancer is a lethal malignancy with a high mortality worldwide. Currently, sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). However, the sorafenib resistance rate is high. The molecular mechanism of this resistance has not been fully elucidated. High mobility group box 1 (HMGB1) is a multifaceted protein that plays a key role in the proliferation, apoptosis, metastasis and angiogenesis of HCC cells. In addition, HMGB1 has been suggested to contribute to chemotherapy resistance in tumours, including lung cancer, osteosarcoma, neuroblastoma, leukaemia, and colorectal cancer. This study investigated the association between HMGB1 and sorafenib resistance in HCC.MethodsHepG2 cells with HMGB1 knockdown or overexpression were generated. The efficacy of sorafenib in these cells was tested using flow cytometry and a cell counting assay. The subcellular localization of HMGB1 in HepG2 cells following sorafenib treatment was measured by western blotting and confocal microscopy. A murine subcutaneous HCC model was generated to examine the association between HMGB1 and the sensitivity of sorafenib treatment.ResultsThe HMGB1 knockdown cells exhibited a significantly higher apoptotic level and lower cell viability than the normal HMGB1 expressing cells following the sorafenib treatment. In addition, the cell viability observed in the HMGB1 overexpressing cells was higher than that observed in the control cells following the sorafenib intervention. Sorafenib had a better tumour inhibition effect in the HMGB1 knockdown group in vivo. The amount of mitochondrial HMGB1 decreased, while the amount of cytosolic HMGB1 increased following the exposure to sorafenib. Altogether, HMGB1 translocated from the mitochondria to the cytoplasm outside the mitochondria following the exposure of HepG2 cells to sorafenib.ConclusionsA novel potential role of HMGB1 in the regulation of sorafenib therapy resistance in HCC was observed. The knockdown of HMGB1 restores sensitivity to sorafenib and enhances HepG2 cell death, while HMGB1 overexpression blunts these effects. The translocation of HMGB1 from the mitochondria to the cytosol following sorafenib treatment provides new insight into sorafenib resistance in HCC.
登录
查看更多内容
影响因子：
10.6
作者：
Kang, Rui;Chen, Ruochan;Zhang, Qiuhong;Hou, Wen;Wu, Sha;Cao, Lizhi;Huang, Jin;Yu, Yan;Fan, Xue-gong;Yan, Zhengwen;Sun, Xiaofang;Wang, Haichao;Wang, Qingde;Tsung, Allan;Billiar, Timothy R.;Zeh, Herbert J., III;Lotze, Michael T.;Tang, Daolin
通讯作者：
Tang, Daolin
影响因子：
7.4
作者：
Liu F;Zhang Y;Peng Z;Gao H;Xu L;Chen M
通讯作者：
Chen M
影响因子：
5.7
作者：
Huang J;Liu K;Song D;Ding M;Wang J;Jin Q;Ni J
通讯作者：
Ni J
影响因子：
8
作者：
Kang, R.;Tang, D.;Zeh, H. J.
通讯作者：
Zeh, H. J.
影响因子：
11.5
作者：
Amaravadi, Ravi K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.