ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly.

Autor:	Wu S; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Chen M; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Huang J; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Zhang F; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Lv Z; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Jia Y; Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China., Cui YZ; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Sun LZ; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; Department of Biology, Southern University of Science and Technology, Shenzhen, China.; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, China., Wang Y; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.; State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China., Tang Y; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Verhoeft KR; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Li Y; Department of Biology, Southern University of Science and Technology, Shenzhen, China.; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, China., Qin Y; Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China., Lin X; School of Chinese Medicine, The University of Hong Kong, Hong Kong, China., Guan XY; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. lamkaon@hku.hk xyguan@hku.hk., Lam KO; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. lamkaon@hku.hk xyguan@hku.hk.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Feb 15; Vol. 81 (4), pp. 986-1000. Date of Electronic Publication: 2020 Dec 11.
DOI:	10.1158/0008-5472.CAN-20-0049
Abstrakt:	The ubiquitous second messenger Ca 2+ has long been recognized as a key regulator in cell migration. Locally confined Ca 2+ , in particular, is essential for building front-to-rear Ca 2+ gradient, which serves to maintain the morphologic polarity required in directionally migrating cells. However, little is known about the source of the Ca 2+ 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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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