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.

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.

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.

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