title: STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1.
abstract: Hypoxia and intracellular Ca(2+) transients are fundamental traits of cancer, whereas the route and regulation of Ca(2+) mobilization in hypoxic tumorigenesis are unknown. Here, we show that stromal-interaction molecule 1 (STIM1), an ER Ca(2+) sensor, correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1α) in hypoxic hepatocarcinoma cells (HCCs) and is upregulated during hepatocarcinoma growth. HIF-1 directly controls STIM1 transcription and contributes to store-operated Ca(2+) entry (SOCE). STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCCs via activation of Ca(2+)/calmodulin-dependent 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-1α 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 Ca(2+) mobilization and hypoxic tumor growth and highlight a potential target for early hypoxia-related intervention.
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Department of Anesthesia, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: yli@tmmu.edu.cn.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Guo
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Duyun
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Dongxin
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. Electronic address: b.davis.zhu@gmail.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D063646:Carcinogenesis; D015687:Cell Hypoxia / Q000502:physiology; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium