Abstract
Bmi-1 is a transcriptional regulator that promotes tumor cell self-renewal and epithelial to mesenchymal transition and its upregulation is associated with tumor progression, AMPK is an intracellular fuel-sensing enzyme and plays important roles in tumor cell growth and progression. Thus, the present study aims to examine the regulation of Bmi-1 by AMPK. First, our data revealed that, as compared to adjacent normal tissue, Bmi-1 was highly expressed in gastric cancer, whereas phosphorylation of AMPK (p-AMPK) was reduced. Similar findings were observed in lung adenocarcinomas and appeared that the expression of Bmi-1 was correlated with pathological grades of the cancer, where opposite changes were found in p-AMPK. Second, Metformin, a pharmacological AMPK activator and anti-diabetic drug, or ectopic expression of LKB1, diminished expression of Bmi-1 in cancer cells, an event that was reversed by silencing LKB1. Third, knockdown of LITAF, previously identified as a downstream target of AMPK, upregulated Bmi-1, associated with increased cell viability, colony formation, and migration of cancer cells in vitro. Fourth, metformin increased the abundance of miR-15a, miR-128, miR-192, and miR-194, which was prevented by knockdown of LITAF. Accordingly, transfection of these individual miRNAs downregulated Bmi-1. Altogether, our data for the first time suggest a regulatory axis in cancer cells: AMPK upregulates LITAF, which in turn increases miRNAs, leading to attenuation of Bmi-1 expression.
Highlights
B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1), a member of the Polycomb transcription repressors, participates in various biological processes, including embryonic development, organ formation, tumorigenesis, and stem cell self-renewal and differentiation [1]
We found that expression of Bmi-1 was increased whereas phospho-AMPK was decreased in gastric cancer and lung adenocarcinoma specimens
We attempted to depict the linear relationship of AMPK, Lipopolysaccharide-induced TNFa factor (LITAF) and Bmi-1 in cancer cells
Summary
B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1), a member of the Polycomb transcription repressors, participates in various biological processes, including embryonic development, organ formation, tumorigenesis, and stem cell self-renewal and differentiation [1]. Bmi-1 is accepted as an oncogene that alters cell cycle, senescence, and apoptosis by promoting tumor cell self-renewal and epithelial to mesenchymal transition (EMT) [5]. Bmi-1 cooperates with c-myc to repress expression of tumor suppressor genes including p16Ink4a and p19Arf, thereby preventing apoptosis and stimulating cell proliferation [7]. Recent studies have shown that multiple microRNAs could repress translation of Bmi-1 and block proliferation and metastasis of tumor cells [9,10,11,12,13]
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