title: The role of the REG4 gene and its encoding product in ovarian epithelial carcinoma.
abstract: BACKGROUND
  Although its biological function remains poorly understood, REG4 is reported to be a potent activator of the EGFR/Akt/AP-1 signaling pathway in colon cancer cells and closely linked with the inhibition of apoptosis.
  
  
  METHODS
  SKOV3 cells were transfected with a REG4-expressing plasmid or treated with recombinant REG4. We then analyzed proliferation, cell cycle, apoptosis, invasion and metastasis or expression of related molecules. REG4 expression was examined in normal ovarian tissue, benign and borderline tumors, and cancers by immunohistochemistry or real-time PCR.
  
  
  RESULTS
  REG4 overexpression and the recombinant protein inhibited cell apoptosis, enhanced G2/S progression, proliferation, migration and invasion. Furthermore, expression of Wnt5a, p70s6k, survivin and VEGF expression was increased, while Bax expression was decreased at both the mRNA and protein levels compared to control or mock cells (P<0.05). REG4 mRNA levels were higher in benign tumors and primary cancer compared to those in normal ovarian tissue (P<0.05) while, REG4 protein expression was higher in all three tumor types than that in normal ovarian tissue (P<0.05). Higher REG4 mRNA expression was observed in mucinous carcinomas than serous carcinomas (P<0.05), and in well- and moderately-differentiated carcinomas than poorly-differentiated carcinomas (P<0.05). Survival analysis revealed an inverse relationship between REG4 expression and cumulative or relapse-free survival rates of the patients with ovarian cancer as an independent factor (P<0.05).
  
  
  CONCLUSIONS
  Our findings indicate that aberrant REG4 expression plays an essential role in early ovarian carcinogenesis and is closely linked to mucinous ovarian tumors, differentiation and adverse prognosis of ovarian cancer by modulating proliferation, apoptosis, migration and invasion.
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China. chenshuo077003@163.com.
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China. xiaogouaeiou@163.com.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Gou
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China. zhaoshuang1235@163.com.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China. nzf870617@126.com.
authors.forename: Zhe-Feng
authors.initials: ZF
authors.lastname: Niu
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China. yida.zhaoyang@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Clinical Cancer Institute, Kanagawa Cancer Center, Yokohama, 241-0815, Japan. ytakano@gancen.asahi.yokohama.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China. zheng_huachuan@hotmail.com.
authors.forename: Hua-Chuan
authors.initials: HC
authors.lastname: Zheng
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D000073718:Pancreatitis-Associated Proteins; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human