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Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup>exchanger 2 (NCX2) is expressed only in the normal brain and not in other tissues or glioma. We constructed a hypoxic microenvironment to more accurately understand the effect of NCX2 in glioma. Our previous experiments confirmed that NCX2 inhibited the growth of U87 cells in nude mice, indicating that NCX2 is a potential tumor suppressor gene. Malignant tumor cells are often exposed to an anoxic environment. To more accurately understand the effect of NCX2 in glioma, we constructed a hypoxic microenvironment. To detect the localization of NCX2 in transfected U87 cells, immunofluorescence was used. We tested the function of NCX2 in glioma, i.e., how it contributes to the cytosolic Ca<jats:sup>2+<\/jats:sup>homeostasis by X-Rhod-1. We tested the cell proliferation of NCX2 in glioma in hypoxic using Cell counting kit-8 (CCK8). Cell migration and invasion were evaluated in 24-well transwell matrigel-coated or non-matrigel-coated in hypoxia. NCX2 promoted the proliferation of U87 cells in the hypoxic microenvironment. It inhibited the invasion and migration abilities of U87 cells. We demonstrated that NCX2 was located on the cell membrane and that it reduced intracellular Ca<jats:sup>2+<\/jats:sup>levels and reactivated P53 and PTEN. We further demonstrated that NCX2 impaired cell invasion through the HIF-1\u03b1 pathway in glioma. The results indicated that NCX2 plays a key role in glioma formation and tumor invasion functionality.<\/jats:p>","DOI":"10.1007\/s10528-022-10274-9","type":"journal-article","created":{"date-parts":[[2022,11,5]],"date-time":"2022-11-05T08:02:48Z","timestamp":1667635368000},"page":"979-994","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["NCX2 Regulates Intracellular Calcium Homeostasis and Translocation of HIF-1\u03b1 into the Nucleus to Inhibit Glioma Invasion"],"prefix":"10.1007","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9580-9715","authenticated-orcid":false,"given":"Hongyuan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liling","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,5]]},"reference":[{"issue":"19","key":"10274_CR1","doi-asserted-by":"publisher","first-page":"16846","DOI":"10.1074\/jbc.M110.187559","volume":"286","author":"P Andrikopoulos","year":"2011","unstructured":"Andrikopoulos P, Fraser SP, Patterson L et al (2011a) Angiogenic functions of voltage-gated Na+ channels in human endothelial cells: modulation of vascular endothelial growth factor (VEGF) signaling. 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