title: CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A.
abstract: C-terminal binding protein-2 (CtBP2), as a transcriptional co-repressor, has been shown to mediate the repression of p16(INK4A) , a tumor suppressor gene product, in primary human cells. Here we aimed to investigate how the correlation between CtBP2 and p16(INK4A) influenced the development of esophageal squamous cell carcinoma (ESCC). Immunohistochemistry of ESCC tissue sections indicated that the CtBP2 and p16(INK4A) expressions were inversely correlated to each other with a linear regression coefficient of -0.747 (P < 0.05), and Western blot analysis revealed that CtBP2 was higher expressed in tumorous tissues than in adjacent non-tumorous tissues. Either CtBP2 or p16(INK4A) expression was significantly related to histological differentiation (P = 0.016 or 0.001) and to the expression of Ki-67, a proliferating marker (P = 0.006 or 0.02), and patients with higher CtBP2 and lower p16(INK4A) expressions had shorter overall survival. We also observed that CtBP2 modulated the cell proliferation and cell cycle in ECA109 cells, an ESCC cell line, by inhibiting p16(INK4A) . Overexpression or knockdown of CtBP2 in ECA109 cells was found to inhibit or activate the mRNA or protein expression of p16(INK4A) , which in turn altered the cell proliferation and cell cycle in ECA109 cells, as measured by flow cytometry and cell count assay. Additionally, after ECA109 cells silenced for CtBP2 were treated with cisplatin (an anti-ESCC agent), the p16(INK4A) expression was up-regulated, and the cell apoptosis was promoted, thus confirming the repression of p16(INK4A) by CtBP2. Collectively, all results suggested that CtBP2 might contribute to the progression of ESCC through a negative transcriptional regulation of p16(INK4A).
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China.
authors.forename: Chengqi
authors.initials: C
authors.lastname: Guan
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.forename: Huijie
authors.initials: H
authors.lastname: Wang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.forename: Wenkai
authors.initials: W
authors.lastname: Ni
authors.forename: Buyou
authors.initials: B
authors.lastname: Chen
authors.forename: Sicong
authors.initials: S
authors.lastname: Hou
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.forename: Runzhou
authors.initials: R
authors.lastname: Ni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000429:Alcohol Oxidoreductases / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D056970:Co-Repressor Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents; D056970:Co-Repressor Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009419:Nerve Tissue Proteins; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; D002945:Cisplatin