MET/SMAD3/SNAIL circuit mediated by miR-323a-3p is involved in regulating epithelial-mesenchymal transition progression in bladder cancer

作者：Li, Jiangfeng; Xu, Xin; Meng, Shuai; Liang, Zhen; Wang, Xiao; Xu, Mingjie; Wang, Song; Li, Shiqi; Zhu, Yi; Xie, Bo; Lin, Yiwei; Zheng, Xiangyi; Liu, Ben^*; Xie, Liping^*

来源：Cell Death & Disease, 2017, 8(8): e3010.

DOI：10.1038/cddis.2017.331

• GLOBAL GENE-EXPRESSION
• GROWTH-FACTOR RECEPTOR
• CELL LUNG-CANCER
• INHIBITS PROLIFERATION
• TGF-BETA
• MET
• INVASION
• METASTASIS
• PATHWAYS
• MOTILITY

Bladder cancer (BCa) is the one of the most common cancers with high incidence, occurrence and low 5-year survival rate. Emerging evidence indicates that DLK1-DIO3 genomic region especially the miRNA cluster in this region is involved in several pathologic processes and various cancers, and miR-323a-3p is a member of this miRNA cluster. In this study, we investigate the function and regulatory network of miR-323a-3p in BCa. miR-323a-3p is frequently downregulated in BCa tissues and three cell lines compared with adjacent non-tumorous tissues and bladder normal cell line (SV-HUC-1). Besides, downregulation of miR-323a-3p is significantly associated with poor overall survival rate of BCa. Methylation of DLK1-MEG3 intergenic DMR (IG-DMR) contributes to the reduction of miR-323a-3p. Overexpression of miR-323a-3p significantly inhibits the epithelial-mesenchymal transition (EMT) progression of BCa. Both upregulated MET and SMAD3 are direct targets of miR-323a-3p, and the knockdown of MET and SMAD3 also represses the EMT progression consistently with overexpression of miR-323a-3p. SNAIL is detected in the last targeted confocal protein of both MET and SMAD3 signaling that trigger EMT consequently. Hence, a miR-323a-3p/MET/SMAD3/SNAIL circuit is established to regulate the EMT progression of BCa. And a mutual regulatory mechanism between miR-323a-3p/miR-433/miR-409 and MET also participates in this circuit. In conclusion, our study demonstrates a novel regulatory mechanism of the miR-323a-3p/MET/SMAD3/SNAIL circuit that is involved in the EMT regulation of BCa, which may be a potential therapy target for BCa.

• 出版日期2017-8
• 单位浙江省人民医院; 浙江大学