Title: Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis.
Authors: Yang, Rui; Xu, Jiheng; Hua, Xiaohui; Tian, Zhongxian; Xie, Qipeng; Li, Jingxia; Jiang, Guosong; Cohen, Mitchell; Sun, Hong; Huang, Chuanshu
Published In Oncogene, (2020 02)
Abstract: Invasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.
PubMed ID: 31772330
MeSH Terms: Animals; Apoptosis; Biomarkers, Tumor/genetics; Biomarkers, Tumor/metabolism; Cell Proliferation; DEAD-box RNA Helicases/genetics; DEAD-box RNA Helicases/metabolism*; Gene Expression Regulation, Neoplastic*; Humans; Male; Matrix Metalloproteinase 2/genetics; Matrix Metalloproteinase 2/metabolism*; Mice; Mice, Inbred C57BL; MicroRNAs/genetics*; Mitogen-Activated Protein Kinase 9/genetics; Mitogen-Activated Protein Kinase 9/metabolism*; Neoplasm Invasiveness; Prognosis; Ribonuclease III/genetics; Ribonuclease III/metabolism*; Tumor Cells, Cultured; Urinary Bladder Neoplasms/genetics; Urinary Bladder Neoplasms/metabolism; Urinary Bladder Neoplasms/pathology*; Xenograft Model Antitumor Assays