Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma
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Hua Zhu1,2,*, Hui Zhang4,*, Feng Jin1, Mingzhu Fang5, Mark Huang6, Chung S. Yang7, Tong Chen3, Liwu Fu4, Zui Pan1, 3
1 Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH;
2 Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH;
3 Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH;
4 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China;
5 Environmental and Occupational Health Sciences Institute;
6 Robert Wood Johnson Medical School;
7 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ;
* contribute equally to this work.
Zui Pan, email:
Liwu Fu, email:
Keywords: store-operated calcium entry, STIM1, oncogenic, knockdown, xenograft
Received: January 31, 2014 Accepted: April 16, 2014 Published: April 17, 2014
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.
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