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.

STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis

“…On the other hand, STIM2 levels were higher in ESCC cell lines (127) (127). Most importantly, exploiting in vivo mice xenograft model, the authors showed that both in vivo pharmacological blockade of SOCE and Orai1 silencing could reduce tumor volume and increase tumor free survival (127). Evaluation of clinico-pathological data also corroborated that higher Orai1 expression was associated with higher reoccurrence of esophageal carcinomas and lower patient survival (127).…”

“…Esophageal squamous cell carcinoma is highly prevalent with poor prognosis and high mortality rate (74,127). A recent study on esophageal squamous cell carcinoma (ESCC) attributes tumorigenesis to higher Orai1-mediated intracellular Ca 2ϩ oscillations (127).…”

“…A recent study on esophageal squamous cell carcinoma (ESCC) attributes tumorigenesis to higher Orai1-mediated intracellular Ca 2ϩ oscillations (127). Expression analysis of clinical tumor samples from ESCC patients and established ESCC cells showed elevated expression and activity of Orai1 compared with normal esophageal epithelial tissues (127).…”

“…However, no significant change was observed in STIM1 protein levels in both cell lines as well as human tumor biopsies. On the other hand, STIM2 levels were higher in ESCC cell lines (127) (127). Most importantly, exploiting in vivo mice xenograft model, the authors showed that both in vivo pharmacological blockade of SOCE and Orai1 silencing could reduce tumor volume and increase tumor free survival (127).…”

Orai1 mediates tumor-promoting store-operated Ca2+ entry in human gastrointestinal stromal tumors via c-KIT and the extracellular signal–regulated kinase pathway

“…[23][24][25] Orai1-mediated SOCE is implicated in cancer cell growth. [26][27][28][29][30][31][32][33] However, the role of Orai1-mediated SOCE in ICC and GISTs remains unclear.…”