{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T01:48:08Z","timestamp":1792374488807,"version":"4.4.0"},"reference-count":43,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2013,7,13]],"date-time":"2013-07-13T00:00:00Z","timestamp":1373673600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2013,11,15]]},"abstract":"<jats:p>Apart from \u03b2\u2010catenin accumulation, loss of 3p21 is one of the most frequent genetic alterations in numerous malignancies including nasopharyngeal carcinoma (NPC). Herein, we characterized a novel candidate tumor suppressor gene (TSG) <jats:italic>CACNA2D3,<\/jats:italic> a voltage\u2010dependent subunit alpha 2 delta 3 of a calcium channel complex. Downregulation of <jats:italic>CACNA2D3<\/jats:italic> was frequently detected in primary NPCs and NPC cell lines compared with their nontumorigenic counterparts. Attenuated <jats:italic>CACNA2D3<\/jats:italic> expression may be associated with loss of heterozygosity (LOH) at intragenic single\u2010nucleotide polymorphism sites (rs589281, rs1449325 and rs6797113) and\/or epigenetic silencing by methylation and histone deacetylation. Given the extensive effects of calcium in cancer, we then investigated the tumor suppressive role and underlying mechanism of <jats:italic>CACNA2D3<\/jats:italic> in the development and progression of NPC. <jats:italic>CACNA2D3<\/jats:italic> was stably transfected into NPC cell lines (C666 and SUNE1) at levels comparative with the normal nasopharynx, alongside siRNA\u2010mediated silencing in an immortalized nasopharyngeal epithelial cell line (NP69) to conduct <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> functional assays. Our findings show that <jats:italic>CACNA2D3\u2010<\/jats:italic>mediated increase in intracellular calcium (Ca2+) can induce mitochondrial\u2010mediated apoptosis and activation of <jats:italic>NLK<\/jats:italic> (through the Wnt\/Ca2+ pathway) to antagonize Wnt signaling\u2010mediated anchorage\u2010dependent and independent cell proliferation (<jats:italic>via CCND1<\/jats:italic> and <jats:italic>CMYC<\/jats:italic>), invasion (<jats:italic>via MMP7<\/jats:italic>) and epithelial\u2010to\u2010mesynchemal transition (<jats:italic>via SNAIL<\/jats:italic>). As the expression pattern of calcium channels and their degree of functionality can change with the progression of cancer, <jats:italic>CACNA2D3<\/jats:italic> may indeed be a promising biomarker for NPC. Our study also warrants further exploration in the potential therapeutic use of existing epigenetic targeting drugs (<jats:italic>e.g.,<\/jats:italic> 5\u2010azacytidine, SAHA) to reconstitute <jats:italic>CACNA2D3\u2010<\/jats:italic>associated tumor suppression in NPC.<\/jats:p>","DOI":"10.1002\/ijc.28252","type":"journal-article","created":{"date-parts":[[2013,5,3]],"date-time":"2013-05-03T16:43:26Z","timestamp":1367599406000},"page":"2284-2295","source":"Crossref","is-referenced-by-count":42,"title":["Characterization of <i>CACNA2D3<\/i> as a putative tumor suppressor gene in the development and progression of nasopharyngeal carcinoma"],"prefix":"10.1002","volume":"133","author":[{"given":"Alissa Michelle Go","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kar 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