STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1
STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1
复制标题
STIM1 通过与 HIF-1 相互作用介导缺氧驱动的肝癌发生
DOI：
10.1016/j.celrep.2015.06.033
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发表时间：
2015-07-21
期刊：
影响因子：
8.8
通讯作者：
Zhu, Bo
中科院分区：
文献类型：
--
作者：
Li, Yongsheng;Guo, Bo;Zhu, Bo
缺氧和细胞内Ca 2+瞬变是癌症的基本特征，而缺氧肿瘤发生中Ca 2+动员的途径和调节尚不清楚。在这里，我们表明，基质相互作用分子1（STIM 1），ER Ca 2+传感器，与缺氧肝癌细胞（HCC）中升高的缺氧诱导因子-1 α（HIF-1 α）相关，并在肝癌生长过程中上调。HIF-1直接控制STIM 1的转录，并促进钙库操纵的钙离子进入（SOCE）。STIM 1介导的SOCE也是缺氧HCC中HIF-1通过激活Ca 2 +/钙调素非依赖性蛋白激酶II和p300积累所必需的。给予YC-1（一种HIF-1抑制剂）或敲低HIF 1A可显著减少缺氧增强的STIM 1并抑制肿瘤发生。此外，STIM 1或HIF-1 α的异位表达部分逆转了YC-1治疗的肿瘤生长受损。这些结果表明，STIM 1和HIF-1在控制Ca 2+动员和缺氧肿瘤生长方面相互依赖和调节，并突出了早期缺氧相关干预的潜在靶点。
Hypoxia and intracellular Ca2+ transients are fundamental traits of cancer, whereas the route and regulation of Ca2+ mobilization in hypoxic tumorigenesis are unknown. Here, we show that stromal-interaction molecule 1 (STIM1), an ER Ca2+ sensor, correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1 alpha) in hypoxic hepatocarcinoma cells (HCCs) and is upregulated during hepatocarcinoma growth. HIF-1 directly controls STIM1 transcription and contributes to store-operated Ca2+ entry (SOCE). STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCCs via activation of Ca2+/calmodulindependent protein kinase II and p300. Administration of YC-1, a HIF-1 inhibitor, or knockdown of HIF1A significantly diminishes hypoxia-enhanced STIM1 and suppresses tumorigenesis. Moreover, ectopic expression of STIM1 or HIF-1 alpha partially reverses impaired growth of tumors treated with YC-1. These results suggest a mutual dependency and regulation of STIM1 and HIF-1 in controlling Ca2+ mobilization and hypoxic tumor growth and highlight a potential target for early hypoxia-related intervention.