Role of p38γ MAPK in Regulation of EMT and Cancer Stem Cells

Mei Xu; Siying Wang; Yongchao Wang; Huaxun Wu; Jacqueline A Frank; Zhuo Zhang; Jia Luo

doi:10.1016/j.bbadis.2018.08.024

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Role of p38γ MAPK in Regulation of EMT and Cancer Stem Cells

Journal article

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Role of p38γ MAPK in Regulation of EMT and Cancer Stem Cells

Mei Xu, Siying Wang, Yongchao Wang, Huaxun Wu, Jacqueline A Frank, Zhuo Zhang and Jia Luo

Biochimica et biophysica acta. Molecular basis of disease, Vol.1864(11), pp.3605-3617

11/2018

DOI: 10.1016/j.bbadis.2018.08.024

PMCID: PMC6428452

PMID: 30251680

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Abstract

p38γ is a member of p38 MAPK family which contains four isoforms p38α, p38β, p38γ and p38δ. p38γ MAPK has unique function and is less investigated. Recent studies revealed that p38γ MAPK may be involved in tumorigenesis and cancer aggressiveness. However, the underlying cellular/molecular mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) is a process that epithelial cancer cells transform to facilitate the loss of epithelial features and gain of mesenchymal phenotype. EMT promotes cancer cell progression and metastasis, and is involved in the regulation of cancer stem cells (CSCs) which have self-renewal capacity and are resistant to chemotherapy and target therapy. We showed that p38γ MAPK positively increased EMT in breast cancer cells; over-expression of p38γ MAPK enhanced EMT while its down-regulation inhibited EMT. Meanwhile, p38γ MAPK augmented CSC population while knock down of p38γ MAPK decreased CSC ratio in breast cancer cells. MicroRNA-200b (miR-200b) was down-stream of p38γ MAPK and negatively regulated by p38γ MAPK; miR-200b mimics blocked p38γ MAPK-induced EMT while miR-200b inhibitors promoted EMT. p38γ MAPK regulated miR-200b through inhibiting GATA3. p38γ MAPK induced GATA3 ubiquitination, leading to its proteasome-dependent degradation. Suz12, a Polycomb group protein, was down-stream of miR-200b and involved in miR-200b regulation of EMT. Thus, our study established an important role of p38γ MAPK in EMT and identified a novel signaling pathway for p38γ MAPK–mediated tumor promotion.

Cancer stem cells

metastasis

microRNA

p38γ MAPK

Details

Title: Subtitle: Role of p38γ MAPK in Regulation of EMT and Cancer Stem Cells
Creators: Mei Xu - University of Kentucky
Siying Wang - Anhui Medical University
Yongchao Wang - University of Kentucky
Huaxun Wu - Anhui Medical University
Jacqueline A Frank - University of Kentucky
Zhuo Zhang - University of Kentucky
Jia Luo - University of Kentucky
Resource Type: Journal article
Publication Details: Biochimica et biophysica acta. Molecular basis of disease, Vol.1864(11), pp.3605-3617
DOI: 10.1016/j.bbadis.2018.08.024
PMID: 30251680
PMCID: PMC6428452
NLM abbreviation: Biochim Biophys Acta Mol Basis Dis
ISSN: 0925-4439
eISSN: 1879-260X
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: AA017226, AA015407; DOI: 10.13039/100006379, name: Office of Research and Development, award: BX001721
Language: English
Date published: 11/2018
Academic Unit: Pathology
Record Identifier: 9984186560602771

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