Negative regulation of Bmi-1 by AMPK and implication in cancer progression
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Deqiang Huang1, Xiaoling He2,3, Junrong Zou2,3, Pei Guo2,3, Shanshan Jiang2,3, Nonghua Lv1, Yuriy Alekseyev4, Lingyu Luo1, Zhijun Luo3,5
1Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
2Graduate Program, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, P.R. China
3Institute of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, P.R. China
4Departments of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
5Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
Zhijun Luo, e-mail: email@example.com
Lingyu Luo, e-mail: firstname.lastname@example.org
Keywords: AMPK, Bmi-1, LITAF, cancer progression, miRNA
Received: July 24, 2015 Accepted: November 15, 2015 Published: December 23, 2015
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.
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