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Negative regulation of Bmi-1 by AMPK and implication in cancer progression.

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.

SUBMITTER: Huang D

PROVIDER: S-EPMC4868749 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Negative regulation of Bmi-1 by AMPK and implication in cancer progression.

Huang Deqiang D He Xiaoling X Zou Junrong J Guo Pei P Jiang Shanshan S Lv Nonghua N Alekseyev Yuriy Y Luo Lingyu L Luo Zhijun Z

Oncotarget 20160201 5

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 ...[more]

PMID: 26717043

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Project description:BackgroundThe RNA-binding protein Musashi-2 (MSI2) has been implicated in the tumorigenesis and tumor progression of some human cancers. MSI2 has also been reported to suppress tumor epithelial-to-mesenchymal transition (EMT) progression in breast cancer, and low MSI2 expression is associated with poor outcomes for breast cancer patients; however, the underlying mechanisms have not been fully investigated. This study investigated the expression and phenotypic functions of two major alternatively spliced MSI2 isoforms (MSI2a and MSI2b) and the potential molecular mechanisms involved in triple-negative breast cancer (TNBC) progression.MethodsThe Illumina sequencing platform was used to analyze the mRNA transcriptomes of TNBC and normal tissues, while quantitative reverse transcription-polymerase chain reaction and immunohistochemistry validated MSI2 isoform expression in breast cancer tissues. The effects of MSI2a and MSI2b on TNBC cells were assayed in vitro and in vivo. RNA immunoprecipitation (RIP) and RNA sequencing were performed to identify the potential mRNA targets of MSI2a, and RIP and luciferase analyses were used to confirm the mRNA targets of MSI2.ResultsMSI2 expression in TNBC tissues was significantly downregulated compared to that in normal tissues. In TNBC, MSI2a expression was associated with poor overall survival of patients. MSI2a overexpression in vitro and in vivo inhibited TNBC cell invasion as well as extracellular signal-regulated kinase 1/2 (ERK1/2) activity. However, MSI2b overexpression had no significant effects on TNBC cell migration. Mechanistically, MSI2a expression promoted TP53INP1 mRNA stability by its interaction with the 3'-untranslated region of TP53INP1 mRNA. Furthermore, TP53INP1 knockdown reversed MSI2a-induced suppression of TNBC cell invasion, whereas ectopic expression of TP53INP1 and inhibition of ERK1/2 activity blocked MSI2 knockdown-induced TNBC cell invasion.ConclusionsThe current study demonstrated that MSI2a is the predominant functional isoform of MSI2 proteins in TNBC, that its downregulation is associated with TNBC progression and poor prognosis and that MSI2a expression inhibited TNBC invasion by stabilizing TP53INP1 mRNA and inhibiting ERK1/2 activity. Overall, our study provides new insights into the isoform-specific roles of MSI2a and MSI2b in the tumor progression of TNBC, allowing for novel therapeutic strategies to be developed for TNBC.

Dataset Information

Negative regulation of Bmi-1 by AMPK and implication in cancer progression.

Publications

Negative regulation of Bmi-1 by AMPK and implication in cancer progression.

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