Although renal cell carcinoma (RCC) is the most malignant urological cancer, its pathogenesis remains unclear, and effective treatments for advanced RCC are still lacking. Here we report that a novel E2F1-miR-520/372/373-SPOP axis controls RCC carcinogenesis. Speckle-type POZ protein (SPOP) was upregulated in over 90% of RCC tissues, whereas the miR-520/372/373 family was downregulated and correlated inversely with SPOP protein levels in RCC tissues. The miR-520/372/373 family targeted the SPOP 3'-UTR and suppressed SPOP protein expression, leading to elevation of PTEN and DUSP7 levels and, consequently, decreased proliferation, invasion/migration, and metastasis of RCC cells in vitro and in vivo. Tail vein delivery of therapeutic miR-520/372/373 family significantly decreased both tumor size and lung metastasis ratio in mice bearing orthotopic xenograft tumors. Decreased expression of miR-520/372/373 family was mediated by transcription factor E2F1. In conclusion, our results demonstrate that the E2F1-miR-520/372/373-SPOP axis functions as a key signalling pathway in RCC progression and metastasis and represents a promising opportunity for targeted therapies.
Cancer research. 2018 Oct 22 [Epub ahead of print]
Meng Ding, Xiaolan Lu, Cheng Wang, Quan Zhao, Jingping Ge, Qiuyuan Xia, Junjun Wang, Ke Zen, Chen-Yu Zhang, Chunni Zhang
Department of Clinical Laboratory, Jinling Hospital, Nanjing University., Clinical Laboratory, Jinling Hospital, Clinical School of Medical College, Nanjing University., School of Life Sciences, Nanjing University., Clinical School of Medical College, Nanjing University., Nanjing Jinling Hospital., Department of Clinical Laboratory, Jinling Hospital, Nanjing University .