Rho GDI β promotes Sp1/ MMP ‐2 expression and bladder cancer invasion through perturbing miR‐200c‐targeted JNK 2 protein translation

• Published in: Molecular oncology 2017-11, Vol.11 (11), p.1579-1594
• Main Authors: Huang, Haishan, Jin, Honglei, Zhao, Huirong, Wang, Jingjing, Li, Xin, Yan, Huiying, Wang, Shuai, Guo, Xirui, Xue, Lei, Li, Jingxia, Peng, Minggang, Wang, Annette, Zhu, Junlan, Wu, Xue‐Ru, Chen, Changyan, Huang, Chuanshu
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; Apoptosis; Binding sites; Bladder cancer; Breast cancer; Colorectal cancer; Ectopic expression; Gene expression; IAP protein; Immunoglobulins; Invasiveness; JNK2 protein; Kinases; Laboratories; Matrix metalloproteinase; Metalloproteinase; Metastases; Metastasis; MicroRNAs; Ovarian cancer; Proteins; Sp1 protein; Studies; Translation
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12132

Our most recent studies demonstrate that Rho GDI β is able to promote human bladder cancer ( BC ) invasion and metastasis in an X‐link inhibitor of apoptosis protein‐dependent fashion accompanied by increased levels of matrix metalloproteinase ( MMP )‐2 protein expression. We also found that Rho GDI β and MMP ‐2 protein expressions are consistently upregulated in both invasive BC tissues and cell lines. In the present study, we show that knockdown of Rho GDI β inhibited MMP ‐2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of Rho GDI β upregulated MMP ‐2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP ‐2 was upregulated by Rho GDI β at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp‐2 promoter region. Further investigation revealed that Rho GDI β overexpression led to downregulation of miR‐200c, whereas miR‐200c was able directly to target 3′‐ UTR of jnk2 mRNA and attenuated JNK 2 protein translation, which resulted in attenuation of Sp1 mRNA and protein expression in turn, inhibiting Sp1‐dependent mmp‐2 transcription. Collectively, our studies demonstrate that Rho GDI β overexpression inhibits miR‐200c abundance, which consequently results in increases of JNK 2 protein translation, Sp1 expression, mmp‐2 transcription, and BC invasion. These findings, together with our previous results showing X‐link inhibitor of apoptosis protein mediating mRNA stabilization of both Rho GDI β and mmp‐2 , reveal the nature of the MMP ‐2 regulatory network, which leads to MMP ‐2 overexpression and BC invasion.