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.
Highlights
Esophageal cancer is the 6th leading cause of human cancer death worldwide[1]
Quantitative real-time RT-PCR analysis revealed that stim1 and orai1 were expressed abundantly in esophageal tumor tissues, but that their homologues were less abundant in these tissues
In cultured epithelial cells derived from esophageal squamous cell carcinoma (ESCC) patients, strikingly hyperactive intracellular Ca2+ oscillations were observed (Fig. 3); reduction of Orail1 function using either pharmacologic or molecular approaches suppressed these oscillations (Fig. 4) indicating that they were mediated by Orai1 channel activity
Summary
Esophageal cancer is the 6th leading cause of human cancer death worldwide[1]. Whereas esophageal adenocarcinoma is the main form of esophageal cancer in the United States and other western countries, esophageal squamous cell carcinoma (ESCC) accounts for more than 90% of esophageal cancer cases in such countries as Japan, China, Mongolia and Iran. Confined Ca2+ signaling is highly regulated in the form of waves, spikes or oscillations [4]. The latter is a remarkable process since its frequency, amplitude and duration can serve as a “calcium code” to activate transcription factors associated with cellular responses to environmental changes [5]. Oscillations in [Ca2+]i are coordinated with the release of Ca2+ through the InsP3 receptor present on internal Ca2+ storage sites such as the endoplasmic reticulum (ER), with the accumulation of Ca2+ by the ER, and with Ca2+ influx from extracellular Ca2+ reservoirs The last of these processes is governed mainly by a process termed store-operated Ca2+ entry (SOCE) [6]
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