title: Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma.
abstract: Effective treatment as well as prognostic biomarker for malignant esophageal squamous cell carcinoma (ESCC) is urgently needed. The present study was aimed at identifying oncogenic genes involving dysregulated intracellular Ca2+ signaling, which is known to function importantly in cellular proliferation and migration. Tumors from patients with ESCC were found to display elevated expression of Orai1, a store-operated Ca2+ entry (SOCE) channel, and the high expression of Orai1 was associated with poor overall and recurrence-free survival. In contrast to the quiescent nature of non-tumorigenic epithelial cells, human ESCC cells exhibited strikingly hyperactive in intracellular Ca2+ oscillations, which were sensitive to treatments with Orai1 channel blockers and to orai1 silencing. Moreover, pharmacologic inhibition of Orai1 activity or reduction of Orai1 expression suppressed proliferation and migration of ESCC in vitro and slowed tumor formation and growth in in vivo xenografted mice. Combined, these findings provide the first evidence to imply Orai1 as a novel biomarker for ESCC prognostic stratification and also highlight Orai1-mediated Ca2+ signaling pathway as a potential target for treatment of this deadly disease.
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Fang
authors.forename: Mark
authors.initials: M
authors.lastname: Huang
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.forename: Tong
authors.initials: T
authors.lastname: Chen
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China;
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH;
authors.forename: Zui
authors.initials: Z
authors.lastname: Pan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D000071740:ORAI1 Protein; D011379:Prognosis; D011897:Random Allocation; D000071737:Stromal Interaction Molecule 1; D015854:Up-Regulation
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007093:Imidazoles; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium