Role of p38? MAPK in regulation of EMT and cancer stem cells.

ABSTRACT: p38? is a member of p38 MAPK family which contains four isoforms p38?, p38?, p38?, and p38?. p38? MAPK has unique function and is less investigated. Recent studies revealed that p38? 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 p38? MAPK significantly increased EMT in breast cancer cells; over-expression of p38? MAPK enhanced EMT while its down-regulation inhibited EMT. Meanwhile, p38? MAPK augmented CSC population while knock down of p38? MAPK decreased CSC ratio in breast cancer cells. MicroRNA-200b (miR-200b) was down-stream of p38? MAPK and inhibited by p38? MAPK; miR-200b mimics blocked p38? MAPK-induced EMT while miR-200b inhibitors promoted EMT. p38? MAPK regulated miR-200b through inhibiting GATA3. p38? 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 p38? MAPK in EMT and identified a novel signaling pathway for p38? MAPK-mediated tumor promotion.

SUBMITTER: Xu M 

PROVIDER: S-EPMC6428452 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature