title: Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.
abstract: BACKGROUND
  B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP) are involved in cancer metastasis and chemotherapeutic resistance, respectively. In this study, we evaluated the association between Bmi-1 and RKIP and outcome of gastric cancer through clinical data analysis and in vitro experiments.
  
  
  METHODS
  Bmi-1 expression and RKIP expression were observed in 107 cases of gastric cancer through use of tissue microarray technology to identify their correlations with clinicopathological parameters, patient survival, and susceptibility to chemotherapy. The correlation was confirmed in gastric cancer cell lines, analyzed further by gene overexpression and silencing analysis, a cell invasion assay, and a chemosensitivity test.
  
  
  RESULTS
  Positive expression of Bmi-1 was highly correlated with T classification and clinical stage. Diminished or lost expression of RKIP was significantly associated with T classification, lymph node metastasis, distant metastasis, and clinical stage. Bmi-1 is negatively and RKIP is positively related to patient survival. Positive expression of Bmi-1 and negative expression of RKIP are associated with poor patient survival and modest efficacy of postoperative chemotherapy. A meaningfully inverse association between Bmi-1 and RKIP was found in tissue microarray studies, and was verified further in gastric cancer cell lines. Moreover, gene overexpression and silencing analysis indicated that RKIP might be regulated by Bmi-1. Furthermore, the impacts of Bmi-1 on cell invasion and chemotherapy resistance were rescued by knockdown of RKIP.
  
  
  CONCLUSIONS
  Our study implies that detection of Bmi-1 and RKIP is valuable in predicting patient survival and therapeutic response in gastric cancer, and the inverse association between Bmi-1 and RKIP reveals the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Yinting
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Guoda
authors.initials: G
authors.lastname: Lian
authors.affiliation: Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
authors.forename: Guangsheng
authors.initials: G
authors.lastname: Ou
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Kege
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Haigang
authors.initials: H
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, China. zenglinj@mail.sysu.edu.cn.
authors.forename: Linjuan
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. huangkh@mail.sysu.edu.cn.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. huangkh@mail.sysu.edu.cn.
authors.forename: Kaihong
authors.initials: K
authors.lastname: Huang
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D046888:Tissue Array Analysis
chemical_list: C069077:BMI1 protein, human; D009944:Organoplatinum Compounds; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D000077150:Oxaliplatin; D063150:Polycomb Repressive Complex 1; D005472:Fluorouracil
keywords: B-cell-specific Moloney murine leukemia virus integration site 1; Clinical outcome; Gastric cancer; Raf kinase inhibitory protein; Tissue microarray