title: Orai1 mediates tumor-promoting store-operated Ca2+entry in human gastrointestinal stromal tumors via c-KIT and the extracellular signal-regulated kinase pathway.
abstract: Gastrointestinal stromal tumors originate from interstitial cells of Cajal, the pacemaker cells of the gut. Ca2+regulates the pacemaker activity of interstitial cells of Cajal. Store-operated Ca2+entry mediates the majority of Ca2+entry in most cancer cells and may be a factor in regulating intracellular Ca2+in interstitial cells of Cajal and gastrointestinal stromal tumors. Therefore, a blockade of this mechanism may affect the progression of gastrointestinal stromal tumors. Orai1 is the pore subunit of store-operated Ca2+channels. Here, we reported that Orai1 was overexpressed in gastrointestinal stromal tumor tissues and was positively correlated with a high-risk grade in gastrointestinal stromal tumor patients. Furthermore, upon Orai1 silencing, the functional store-operated Ca2+entry in gastrointestinal stromal tumor cells was decreased, indicating that the function of store-operated Ca2+entry was mediated by Orai1. Inhibition of Orai1-mediated store-operated Ca2+entry by Orai1 silencing or store-operated Ca2+entry blockers (SKF-96365 and 2-aminoethyl diphenylborate) induced obvious cell proliferation suppression, cell-cycle distribution, and apoptosis stimulation in GIST-T1 cells. Conversely, Orai1 overexpression increased store-operated Ca2+entry and cell proliferation in GIST882 cells. In addition, we found that activation of c-KIT and the extracellular signal-regulated kinase pathway participated in the oncogenic functions of Orai1-mediated store-operated Ca2+entry in gastrointestinal stromal tumor cells. These results revealed that Orai1-mediated store-operated Ca2+entry is critical for gastrointestinal stromal tumor cell proliferation via c-KIT and ERK signaling pathway activation. Orai1-mediated store-operated Ca2+entry plays an oncogenic role and may be a novel prognostic factor and therapeutic target for patients with gastrointestinal stromal tumors.
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yijian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Lv
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
mesh_terms: D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000071740:ORAI1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D012307:Risk Factors; D014162:Transfection
chemical_list: D001896:Boron Compounds; D002121:Calcium Channel Blockers; D007093:Imidazoles; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C109986:2-aminoethoxydiphenyl borate; D019009:Proto-Oncogene Proteins c-kit; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium
keywords: ERK pathway; Gastrointestinal stromal tumors; Orai1; c-KIT; store-operated Ca2+ entry; tumor progression