SREBF2-STARD4 axis confers sorafenib resistance in hepatocellular carcinoma by regulating mitochondrial cholesterol homeostasis.
SREBF2-STARD4 axis confers sorafenib resistance in hepatocellular carcinoma by regulating mitochondrial cholesterol homeostasis.
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SREBF 2-STARD 4轴通过调节线粒体胆固醇稳态赋予肝细胞癌索拉非尼耐药
DOI：
10.1111/cas.15449
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发表时间：
2023-02
期刊：
影响因子：
5.7
通讯作者：
Ma, Chunhong
中科院分区：
文献类型：
--
作者：
Yue, Xuetian;Kong, Youzi;Zhang, Yankun;Sun, Min;Liu, Shuyue;Wu, Zhuanchang;Gao, Lifen;Liang, Xiaohong;Ma, Chunhong
索拉非尼耐药性限制了其治疗肝细胞癌 (HCC) 的生存获益。 HCC 中胆固醇代谢失调，其在 HCC 索拉非尼耐药中的作用尚未完全阐明。为了阐明这一点，建立了体外和体内索拉非尼耐药模型。甾醇调节元件结合转录因子 2 (SREBF2) 是胆固醇代谢的关键调节因子，在索拉非尼耐药的 HepG2 和 Huh7 细胞中被激活。 SREBF2 的敲除使索拉非尼耐药细胞和异种移植肿瘤对索拉非尼重新敏感。进一步的研究表明，在我们的索拉非尼耐药模型和公开数据集中，SREBF2 与 StAR 相关脂质转移结构域 4 (STARD4) 呈正相关。 STARD4介导胆固醇运输，不仅促进HepG2和Huh7细胞的增殖和迁移，而且还增加肝癌中索拉非尼的耐药性。从机械角度来看，SREBF2 通过直接结合 STARD4 的启动子区域来促进 STARD4 的表达，从而导致线粒体胆固醇水平增加并抑制线粒体细胞色素 c 的释放。重要的是，SREBF2 或 STARD4 的敲除分别降低了线粒体胆固醇水平并增加了线粒体细胞色素 c 的释放。此外，STARD4的过度表达逆转了SREBF2敲低对线粒体细胞色素c释放和索拉非尼耐药的影响。总之，SREBF2 促进 STARD4 转录，进而促进线粒体胆固醇转运和 HCC 中的索拉非尼耐药。因此，针对 SREBF2-STARD4 轴将有益于索拉非尼耐药的 HCC 患者亚群。 SREBF2 促进 STARD4 转录，进而促进线粒体胆固醇转运和 HCC 中的索拉非尼耐药。
Sorafenib resistance limits its survival benefit for treatment of hepatocellular carcinoma (HCC). Cholesterol metabolism is dysregulated in HCC, and its role in sorafenib resistance of HCC has not been fully elucidated. Aiming to elucidate this, in vitro and in vivo sorafenib resistant models were established. Sterol regulatory element binding transcription factor 2 (SREBF2), the key regulator of cholesterol metabolism, was activated in sorafenib resistant HepG2 and Huh7 cells. Knockdown of SREBF2 resensitized sorafenib resistant cells and xenografts tumors to sorafenib. Further study showed that SREBF2 positively correlated with StAR related lipid transfer domain containing 4 (STARD4) in our sorafenib resistant models and publicly available datasets. STARD4, mediating cholesterol trafficking, not only promoted proliferation and migration of HepG2 and Huh7 cells, but also increased sorafenib resistance in liver cancer. Mechanically, SREBF2 promoted expression of STARD4 by directly binding to its promoter region, leading to increased mitochondrial cholesterol levels and inhibition of mitochondrial cytochrome c release. Importantly, knockdown of SREBF2 or STARD4 decreased mitochondrial cholesterol levels and increased mitochondrial cytochrome c release, respectively. Moreover, overexpression of STARD4 reversed the effect of SREBF2 knockdown on mitochondrial cytochrome c release and sorafenib resistance. In conclusion, SREBF2 promotes STARD4 transcription, which in turn contributes to mitochondrial cholesterol transport and sorafenib resistance in HCC. Therefore, targeting the SREBF2–STARD4 axis would be beneficial to a subset of HCC patients with sorafenib resistance. SREBF2 promotes STARD4 transcription, which in turn contributes to mitochondrial cholesterol transport and sorafenib resistance in HCC.
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影响因子：
6.5
作者：
Röhrl C;Eigner K;Winter K;Korbelius M;Obrowsky S;Kratky D;Kovacs WJ;Stangl H
通讯作者：
Stangl H
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
6.5
作者：
Rodriguez-Agudo, Daniel;Ren, Shunlin;Pandak, William M.
通讯作者：
Pandak, William M.
DOI：
10.1073/pnas.052143799
发表时间：
2002-05-14
影响因子：
11.1
作者：
Soccio, RE;Adams, RM;Breslow, JL
通讯作者：
Breslow, JL
影响因子：
64.5
作者：
Moon, Sung-Hwan;Huang, Chun-Hao;Prives, Carol
通讯作者：
Prives, Carol