title: Investigation of tumor suppressing function of CACNA2D3 in esophageal squamous cell carcinoma.
abstract: BACKGROUND
  Deletion of 3p is one of the most frequent genetic alterations in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes (TSGs) within these regions. In this study, one TSG, CACNA2D3 at 3p21.1, was characterized.
  
  
  METHODS
  Expression of CACNA2D3 in ESCCs was tested by quantitative real-time PCR and tissue microarray. The mechanism of CACNA2D3 downregulation was investigated by methylation-specific polymerase chain reaction (MS-PCR). The tumor suppressive function of CACNA2D3 was characterized by both in vitro and in vivo tumorigenic assays, cell migration and invasion assays.
  
  
  RESULTS
  CACNA2D3 was frequently downregulated in ESCCs (24/48, 50%), which was significantly associated with promoter methylation and allele loss (P<0.05). Tissue microarray result showed that downregulation of CACNA2D3 was detected in (127/224, 56.7%) ESCCs, which was significantly associated with lymph node metastasis (P = 0.01), TNM staging (P = 0.003) and poor outcome of ESCC patients (P<0.05). Functional studies demonstrated that CACNA2D3 could inhibit tumorigenicity, cell motility and induce apoptosis. Mechanism study found that CACNA2D3 could arrest cell cycle at G1/S checkpoint by increasing expressions of p21 and p53 and decreasing expression of CDK2. In addition, CACNA2D3 could upregulate intracellular free cytosolic Ca(2+) and subsequently induce apoptosis.
  
  
  CONCLUSIONS
  CACNA2D3 is a novel TSG responsible to the 3p21 deletion event and plays a critical suppressing role in the development and progression of ESCC.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China. liy6@mail.sysu.edu.cn
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Cai-Lei
authors.initials: CL
authors.lastname: Zhu
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Nie
authors.forename: Jiang-Chao
authors.initials: JC
authors.lastname: Li
authors.forename: Ting-ting
authors.initials: TT
authors.lastname: Zeng
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Jinna
authors.initials: J
authors.lastname: Chen
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.forename: Haibo
authors.initials: H
authors.lastname: Liu
authors.forename: Yanru
authors.initials: Y
authors.lastname: Qin
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002893:Chromosomes, Human, Pair 3; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C531012:CACNA2D3 protein, human; D015220:Calcium Channels; D016159:Tumor Suppressor Protein p53; D054462:p21-Activated Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D002118:Calcium
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