title: BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer.
abstract: BACKGROUND
  The BMI1 oncogene is overexpressed in several human malignancies including gastric cancer. In addition to BMI1, mammalian cells also express Mel-18, which is closely related to BMI1. We have reported that Mel-18 functions as a potential tumor suppressor by repressing the expression of BMI1 and consequent downregulation of activated AKT in breast cancer cells. However, the mechanisms of BMI1 overexpression and the role of Mel-18 in other cancers are still not clear. The purpose of this study is to investigate the role of BMI1 and Mel-18 in gastric cancer.
  
  
  RESULTS
  BMI1 was found to be overexpressed in gastric cancer cell lines and gastric tumors. Overexpression of BMI1 correlated with advanced clinical stage and lymph node metastasis; while the expression of Mel-18 negatively correlated with BMI1. BMI1 but not Mel-18 was found to be an independent prognostic factor. Downregulation of BMI1 by Mel-18 overexpression or knockdown of BMI1 expression in gastric cancer cell lines led to upregulation of p16 (p16INK4a or CDKN2A) in p16 positive cell lines and reduction of phospho-AKT in both p16-positive and p16-negative cell lines. Downregulation of BMI1 was also accompanied by decreased transformed phenotype and migration in both p16- positive and p16-negative gastric cancer cell lines.
  
  
  CONCLUSIONS
  In the context of gastric cancer, BMI1 acts as an oncogene and Mel-18 functions as a tumor suppressor via downregulation of BMI1. Mel-18 and BMI1 may regulate tumorigenesis, cell migration and cancer metastasis via both p16- and AKT-dependent growth regulatory pathways.
authors.affiliation: Department of Medical Oncology, Cancer Hospital of Fudan University, 270 Dong An Road, Shanghai 200032, China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zhang
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Sheng
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.forename: You-Wei
authors.initials: YW
authors.lastname: Lu
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Cheng
authors.forename: Bing-Ya
authors.initials: BY
authors.lastname: Liu
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Goberdhan P
authors.initials: GP
authors.lastname: Dimri
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Guo
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
chemical_list: C069077:BMI1 protein, human; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; C489348:PCGF2 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D051057:Proto-Oncogene Proteins c-akt