The E2F1–miR-520/372/373–SPOP Axis Modulates Progression of Renal Carcinoma

Abstract Although renal cell carcinoma (RCC) is the most malignant urologic 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 signaling pathway in RCC progression and metastasis and represents a promising opportunity for targeted therapies. Significance: These findings show that the E2F1-miR-520/372/373 family–SPOP axis promotes RCC progression, thereby contributing to our understanding of RCC pathogenesis and unveiling new avenues for more effective targeted therapies.