Esophageal cancer is the 6th leading cause of cancer death worldwide with more than 90% of all cases being esophageal squamous cell carcinoma (ESCC). The overall 5-year survival rate for this disease is only 13% in US, which is the fourth worst among all cancers. There is an urgent need to identify effective biomarkers for early detection, prognostic stratification as well as novel therapeutic interventions for esophageal cancer. Dysregulation in Ca2+ signaling has been linked to many human diseases including cancers. Understanding the pathophysiological roles of Ca2+ permeable channels has recently emerged as an exciting area of cancer research. We have obtained exciting preliminary data suggesting that Orai1, a plasma membrane Ca2+ channel, acts as an oncogene that contributes to the progression of esophageal cancer through regulation of intracellular Ca2+ oscillations. In tumors removed from patients with ESCC, we detected elevated expression of Orai1 which was associated with poor survival rate. In cultured human ESCC cells, we identified a striking hyperactivity in intracellular Ca2+ oscillations, in sharp contrast to the quiescent nature in non-tumor cells. Inhibition of Orai1 by either pharmacological or molecular means could harness hyper Ca2+ oscillations, which in turn suppress cell proliferation and migration in ESCC cells. Moreover, our preliminary data showed that inhibition of Orai1 prevents tumor growth in xenograft nude mice. In this project, we hypothesize that hyperactivity of Orai1-mediated Ca2+ oscillations contributes to carcinogenesis in esophageal epithelia, and targeting Orai1 function represents a potential means for treatment of esophageal cancer. First, we will identify the molecular mechanisms underlying the hyperactivity of Ca2+ oscillations resulting from elevated Orai1-SOCE. Next, we will define the oncogenic role of Orai1 during esophageal carcinogenesis in vivo. Lastly, we will target Orai1-SOCE for ESCC therapy. A multidisciplinary approach will be used including live cell imaging, ultrastructure analysis, intracellular Ca2+ measurement, robust xenograft and carcinogen-induced esophageal cancer animal models. The innovative aspects of this project include the first study on abnormal Orai1 expression and hyperactivity of intracellular Ca2+ oscillations in ESCC, identification of the first molecule mediating endoplasmic reticulum and plasma membranes junctional structures in epithelial cells, a novel transgenic mouse model in which the expression of Orai1 is controlled in an inducible and reversible manner specifically in esophageal epithelial cells. The outcome of this project will reveal the cellular mechanistic understanding of the role of Orai1-SOCE-Ca2+ oscillations in esophageal carcinogenesis. These studies will provide proof-of-principle data on therapeutic approach for ESCC by targeting Orai1 channel activity.

Public Health Relevance

Esophageal cancer is the 6th leading cause of cancer death worldwide and accounts for more than fifteen thousand death each year in the United States. The long term survival rate for esophageal cancer is very poor. Therefore, biomarkers for early detection and prognosis as well as novel therapeutic options for treatment are urgently needed. Our research team has identified a protein, named Orai1 (after 'the Keeper of Heaven's gate in Greek mythology) that is strongly associated with esophageal tumor progression in both animal study and patients. We will study how it contributes to tumor initiation and progression. We will evaluate it as a potential biomarker for esophageal cancer detection and prognosis. This research project will also aid searching for more effective therapeutic interventions for patients suffering from this deadly disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Yassin, Rihab R,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Cui, Chaochu; Chang, Yan; Zhang, Xiaoli et al. (2018) Targeting Orai1-mediated store-operated calcium entry by RP4010 for anti-tumor activity in esophagus squamous cell carcinoma. Cancer Lett 432:169-179
Pan, Zui; Choi, Sangyong; Luo, Yanhong (2018) Mn2+ Quenching Assay for Store-Operated Calcium Entry. Methods Mol Biol 1843:55-62
Choi, Sangyong; Cui, Chaochu; Luo, Yanhong et al. (2018) Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1. FASEB J 32:404-416
Fan, Zhen; Chang, Yan; Cui, Chaochu et al. (2018) Near infrared fluorescent peptide nanoparticles for enhancing esophageal cancer therapeutic efficacy. Nat Commun 9:2605
Cui, Chaochu; Merritt, Robert; Fu, Liwu et al. (2017) Targeting calcium signaling in cancer therapy. Acta Pharm Sin B 7:3-17
Shi, Ni; Chen, Fang; Zhang, Xiaoli et al. (2017) Suppression of Oxidative Stress and NF?B/MAPK Signaling by Lyophilized Black Raspberries for Esophageal Cancer Prevention in Rats. Nutrients 9:
Zimering, Mark B; Pan, Zui (2017) Increased Neuronal Depolarization Evoked by Autoantibodies in Diabetic Obstructive Sleep Apnea: Role for Inflammatory Protease(s) in Generation of Neurotoxic Immunoglobulin Fragment. J Endocrinol Diabetes 4:
Pan, Zui; Choi, Sangyong; Ouadid-Ahidouch, Halima et al. (2017) Zinc transporters and dysregulated channels in cancers. Front Biosci (Landmark Ed) 22:623-643
Niu, Wenwen; Zhang, Min; Chen, Hui et al. (2016) Peroxiredoxin 1 promotes invasion and migration by regulating epithelial-to-mesenchymal transition during oral carcinogenesis. Oncotarget 7:47042-47051
Shi, Ni; Riedl, Kenneth M; Schwartz, Steven J et al. (2016) Efficacy comparison of lyophilised black raspberries and combination of celecoxib and PBIT in prevention of carcinogen-induced oesophageal cancer in rats. J Funct Foods 27:84-94