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Article: ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis Through PI3K/Akt Signaling and MAPK-dependent Focal Adhesion Disassembly

TitleORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis Through PI3K/Akt Signaling and MAPK-dependent Focal Adhesion Disassembly
Authors
Issue Date2021
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2021, v. 81 n. 4, p. 986-1000 How to Cite?
AbstractThe 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.
Persistent Identifierhttp://hdl.handle.net/10722/295520
ISSN
2023 Impact Factor: 12.5
2023 SCImago Journal Rankings: 3.468
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWU, S-
dc.contributor.authorCHEN, M-
dc.contributor.authorHUANG, J-
dc.contributor.authorZHANG, F-
dc.contributor.authorLYU, Z-
dc.contributor.authorJIA, Y-
dc.contributor.authorCUI, YZ-
dc.contributor.authorSUN, LZ-
dc.contributor.authorWANG, Y-
dc.contributor.authorTANG, Y-
dc.contributor.authorVERHOEFT, KR-
dc.contributor.authorLI, Y-
dc.contributor.authorQIN, Y-
dc.contributor.authorLin, X-
dc.contributor.authorGuan, X-
dc.contributor.authorLam, KO-
dc.date.accessioned2021-01-25T11:16:02Z-
dc.date.available2021-01-25T11:16:02Z-
dc.date.issued2021-
dc.identifier.citationCancer Research, 2021, v. 81 n. 4, p. 986-1000-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/295520-
dc.description.abstractThe 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.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titleORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis Through PI3K/Akt Signaling and MAPK-dependent Focal Adhesion Disassembly-
dc.typeArticle-
dc.identifier.emailLin, X: linxiang@hku.hk-
dc.identifier.emailGuan, X: xyguan@hku.hk-
dc.identifier.emailLam, KO: lamkaon@hku.hk-
dc.identifier.authorityLin, X=rp02623-
dc.identifier.authorityGuan, X=rp00454-
dc.identifier.authorityLam, KO=rp01501-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/0008-5472.CAN-20-0049-
dc.identifier.pmid33310726-
dc.identifier.scopuseid_2-s2.0-85102194311-
dc.identifier.hkuros320989-
dc.identifier.volume81-
dc.identifier.issue4-
dc.identifier.spage986-
dc.identifier.epage1000-
dc.identifier.isiWOS:000620166400021-
dc.publisher.placeUnited States-

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