ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly
| Autor: | Miao Chen, Feifei Zhang, Zhaojie Lv, Yan Li, Ka-On Lam, Yuzhu Cui, Liangzhan Sun, Jiao Huang, Yongxu Jia, Krista Roberta Verhoeft, Ying Wang, Ying Tang, Shayi Wu, Yanru Qin, Xiang Lin, Xin Yuan Guan |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Male Cancer Research Carcinogenesis MAP Kinase Signaling System Cell ORAI2 Protein Mice Nude Adenocarcinoma Metastasis Focal adhesion 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Movement Stomach Neoplasms Cell Line Tumor medicine Animals Humans Neoplasm Metastasis Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Focal Adhesions Mice Inbred BALB C Cell growth Chemistry medicine.disease 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer research. 81(4) |
| ISSN: | 1538-7445 |
| Popis: | The ubiquitous second messenger Ca2+ has long been recognized as a key regulator in cell migration. Locally confined Ca2+, in particular, is essential for building front-to-rear Ca2+ gradient, which serves to maintain the morphologic polarity required in directionally migrating cells. However, little is known about the source of the Ca2+ and the mechanism by which they crosstalk between different signaling pathways in cancer cells. Here, we report that calcium release–activated calcium modulator 2 (ORAI2), a poorly characterized store-operated calcium (SOC) channel subunit, predominantly upregulated in the lymph node metastasis of gastric cancer, supports cell proliferation and migration. Clinical data reveal that a high frequency of ORAI2-positive cells in gastric cancer tissues significantly correlated with poor differentiation, invasion, lymph node metastasis, and worse prognosis. Gain- and loss-of-function showed that ORAI2 promotes cell motility, tumor formation, and metastasis in both gastric cancer cell lines and mice. Mechanistically, ORAI2 mediated SOC activity and regulated tumorigenic properties through the activation of the PI3K/Akt signaling pathways. Moreover, ORAI2 enhanced the metastatic ability of gastric cancer cells by inducing FAK-mediated MAPK/ERK activation and promoted focal adhesion disassembly at rear-edge of the cell. Collectively, our results demonstrate that ORAI2 is a novel gene that plays an important role in the tumorigenicity and metastasis of gastric cancer. Significance: These findings describe the critical role of ORAI2 in gastric cancer cell migration and tumor metastasis and uncover the translational potential to advance drug discovery along the ORAI2 signaling pathway. |
| Databáze: | OpenAIRE |
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