Our most recent studies demonstrate that RhoGDIβ is able to promote human bladder cancer (BC) invasion and metastasis in an XIAP-dependent fashion accompanied with the increased levels of MMP-2 protein expression. We also found that RhoGDIβ 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 RhoGDIβ inhibited MMP-2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of RhoGDIβ upregulated MMP-2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP-2 was upregulated by RhoGDIβ at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp-2 promoter region. Further investigation revealed that RhoGDIβ overexpression led to downregulation of miR-200c, whereas miR-200c was able to directly target 3'-UTR of jnk2 mRNA and attenuated JNK2 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 RhoGDIβ overexpression inhibits miR-200c abundance, which consequently results in increases of JNK2 protein translation, Sp1 expression, mmp-2 transcription, and BC invasion. These findings, together with our previous results showing XIAP mediating mRNA stabilization of both RhoGDIβ and mmp-2, reveal the nature of the MMP-2 regulatory network, which leads to MMP-2 overexpression and BC invasion.
Molecular oncology. 2017 Aug 28 [Epub ahead of print]
Haishan Huang, Honglei Jin, Huirong Zhao, Jingjing Wang, Xin Li, Huiying Yan, Shuai Wang, Xirui Guo, Lei Xue, Jingxia Li, Minggang Peng, Annette Wang, Junlan Zhu, Xue-Ru Wu, Changyan Chen, Chuanshu Huang
Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms,School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China, 325035., Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, 10987, USA., Departments of Urology, New York University School of Medicine, New York, NY, 10016, USA., The Center of Drug Discovery, Northeastern University, Boston, 02115, USA.