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Dysregulation of systemic calcium homeostasis and changing levels of calcium-binding proteins have been shown to be associated with the malignant behavior of tumors. However, the precise molecular mechanism underlying Nasopharyngeal carcinoma (NPC) remains uncertain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Reticulocalbin (RCN2) expression in NPC was assessed using GEO database, western blot analysis and qRT-PCR. Apoptosis was assessed using flow cytometric analysis and the expression levels of apoptosis-related proteins were determined using western blot analysis. Intracellular calcium ion concentrations were measured using fluorescence imaging. The findings from these analyses were validated in vitro using nude mice models. Luciferase and ChIP assays were used to measure transcriptional regulation. Clinical significance was evaluated using tissue microarray analysis (n=150).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results showed that RCN2 promotes malignancy by causing Ca2+ flow imbalance, which leads to the initiation of the stress-mediated mitochondrial apoptosis pathway. We demonstrate that calreticulin (CALR) resides primarily in the endoplasmic reticulum and interacts with RCN2. Moreover, the transcription factors YY1 and homeobox protein goosecoid (GSC) both contribute to the initiation of RCN2 transcription by directly binding to the predicted promoter region of RCN2. Finally, high expression of RCN2 combined with high expression of GSC and YY1 may serve as an important clinical biomarker of poor prognosis in patients with NPC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>YY1 and GSC are upstream regulators of RCN2, involved in mitochondrial calcium overload and stress-induced mitochondrial apoptosis. Thus, they can play significant role in the malignant development of NPCs.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s13402-023-00796-8","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T10:03:04Z","timestamp":1679565784000},"page":"1031-1048","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["RCN2 promotes Nasopharyngeal carcinoma progression by curbing Calcium flow and Mitochondrial apoptosis"],"prefix":"10.1007","volume":"46","author":[{"given":"Hui","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"issue":"1","key":"796_CR1","doi-asserted-by":"crossref","first-page":"5009","DOI":"10.1038\/s41467-018-07308-5","volume":"9","author":"T XIANG","year":"2018","unstructured":"T. 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All mouse experiments were conducted according to NIH Guidelines and were approved by the Administration Committee of Experimental Animals, Jiangsu Province, China (Approval ID: SYXK (SU) 2007-0021). Tissue samples were obtained from patients with pathologically confirmed NPC at the Affiliated Hospital of Nantong University with the approval of the hospital\u2019s ethics committee (IRB number: 2020-L160).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Statements and declarations"}}]}}