Identification and characterization of ORAI calcium release-activated calcium modulator 2 in gastric cancer : role in tumor survival, progression and metastasis

Abstract

Gastric cancer (GC), an aggressive disease with heterogeneous features. It ranks as the world’s 5th most common malignancy worldwide. GC is highly characterized by a skewed geographical distribution pattern of which Eastern Asia has particularly high incidence and mortality rates. Despite advances in diagnostic techniques and treatment strategies, GC still remains as the 3rd leading cause of cancer-related deaths worldwide, in which the median survival time of GC is only around 8-10 months, primarily due to tumor metastasis and chemoresistance. Patients with GCs are usually diagnosed at the advanced/late stages, and even for those who were diagnosed at earlier stages, regional metastasis is found in the majority. Therefore, it is prudent to investigate the metastatic mechanisms underlying GC and identify novel metastatic biomarker for the treatment of GC.

The ubiquitous second messenger Ca2+ has long been described as a key regulator in cell survival, proliferation and motility. Locally confined Ca2+, in particular, is essential for building front-to-rear Ca2+ gradient which serves to maintain the morphological polarity required in directionally migrating cells. However, little knowledge is known about the source of the Ca2+ and the mechanism by which they crosstalk between different signaling pathways in cancer cells. In this project, we demonstrated that ORAI2, a poorly characterized store-operated calcium (SOC) channel subunit, is predominantly upregulated in the lymph node (LN) of GC, enhancing the abilities of cancer cells to tolerate chemotherapy, proliferate and disseminate to distant organs. Clinical evaluation reveals that a high frequency of ORAI2-positive cells in GC tissues is critically correlated with poor differentiation, invasion, LN metastasis and poor prognosis. Through functional investigations by overexpression or knockdown of ORAI2 in selected GC cell lines, we found that ORAI2 could facilitate cell survival, tumor formation and metastasis in both GC cell lines and mice. Mechanistically, ORAI2 promotes the ability of GC cells to tolerate chemotherapy by eliciting FAK/Akt upregulation. Moreover, it could mediate SOC activity to induce tumorigenesis through the activation of the PI3K/Akt transduction pathways. Lastly, ORAI2 enhances the metastatic ability of GC cells by triggering FAK-mediated MAPK/ERK activation and promotes focal adhesion (FA) disassembly at the rear-edge of the cell. These findings describe the critical role of ORAI2 in GC cell survival, proliferation, migration and invasion, while uncovering the translational potential to advance drug discovery along the ORAI2 signaling pathway.