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Objective: Largely due to the fact that most of patients suffering from ESCC are diagnosed at advanced states, the 5-year survival rate is merely 19%, which is the fourth worst among all cancers.Thus, there is an urgent need to identify effective biomarkers for early detection, prognostic stratification as well as novel therapeutic interventions for ESCC.Orail, a Ca2+-permeable channel for store-operated Ca2+ entry (SOCE), plays a critical role in a diversity of cellular processes, including cell proliferation and migration.The study aims to directly address the role of Orail and intracellular Ca2+ oscillations in the development of to Esophageal Squamous Cell Carcinoma.Methods: qRT-PCR was performed to test the mRNA level; IHC and Western blot analysis was used to evaluate the protein expression.The proliferation of cells was evaluated by the MTT assay.Flow cytometry analyses of cell cycle distribution.Fura-2 was used to measure intracellular Ca2+ and SOCE activity.In vitro wound-healing cell migration assay and Boyden chamber cell migration assay were performed to test the ability of cell migration.Xenograff assay in nude mice was conducted to test the growth of tumor Results: The expression level of Orail is elevated in ESCC tumor tissues, and its expression level is reversely correlated with survival in patients with ESCC.The ESCC cells present a salient property of intracellular Ca2+ oscillations, which was depended on the Orai1-mediated SOCE.Orai1-SOCE-intracellular Ca2+ oscillations stimulate downstream signaling pathways and thus regulate cell proliferation.Orail-SOCE-intracellular Ca2+ oscillations regulate the ability of cell migration and invasion.Orai1-SOCE-intracellular Ca2+ oscillations regulate cell proliferation in vivo.Conclusions: Elevated expression of plasma membrane Ca2+ channel Orai1 and intracellular Ca2+ Oscillations contribute significantly to esophageal squamous Cell carcinoma.