BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer.
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.
Zhang
Xiao-Wei
XW
Department of Medical Oncology, Cancer Hospital of Fudan University, 270 Dong An Road, Shanghai 200032, China.
Sheng
Ya-Ping
YP
Li
Qian
Q
Qin
Wei
W
Lu
You-Wei
YW
Cheng
Yu-Fan
YF
Liu
Bing-Ya
BY
Zhang
Feng-Chun
FC
Li
Jin
J
Dimri
Goberdhan P
GP
Guo
Wei-Jian
WJ
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*
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