| Summary: | 博士 === 中山醫學大學 === 生化微生物免疫研究所 === 106 === Metastasis Associated 1 Family Member 2 (MTA2) is a central components of the Mi-2/NuRD complex, which possesses both nucleosome remodeling and histone deacetylase activities. Recent studies have indicated that MTA2 was associated with cells proliferation and metastasis in many cancer cells. The present study investigated the effect of MTA2 knockdown in cell proliferation and metastasis of human cervical cancer cells and the specific mechanism. Herein, we showed that MTA2 expression was correlated significantly with tumor differentiation and Gleason''s grade in cervical cancer tissue. Lentivirus mediated short hairpin RNA (shRNA) was used to knockdown MTA2 expression in cervical cancer cell lines. In vitro migration and invasion assay demonstrated MTA2 depletion inhibited cells metastasis ability, but not affect of the cells proliferation. In addition, MTA2 knockdown decreased MMP-12 protein levels and increased KLK10 in cervical cancer cells, as determined by proteinase microarray analysis. Furthermore, western blot analysis indicated ASK1, MEK3/6, and p38 signaling pathways were activated, then induced p-YB1 (phosphorylated of Y box-binding protein 1) nuclear translocation, significantly inhibited AP-1 activity binding to the MMP-12 promoter, and trans-suppressed the expression of MMP-12. In vivo studies using tail intravenous injection in mice models indicated that MTA2 knockdown significantly inhibited metastasis to lung. In addtion, MTA2 depletion increased mirR-7 expression, which targets Sp1, by MicroRNA Sequencing analysis. Mechanistic investigations suggested that MTA2 knockdown inhibited Sp1 expression and interaction with the KLK10 5’-flank region via regulating miR-7 expression. Moreover, the protein levels of Sp1 were up-regulated and down-regulated of KLK10 after transfection with miR-7 inhibitor that reversed cell metastasis and invasion in cervical cancer cells. In conclusion, our findings suggest that MTA2 is important for tumor metastasis through knockdown of MTA2 will regulate p38/YB1/MMP-12 signaling pathway and induce miR-7 expression by targeting Sp1 mediated KLK10 expression.
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