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.
Highlights
Renal cell carcinoma (RCC) accounts for approximately 4% of all cancers and is the third most common urologic malignancy, which has the highest fatality rate among all urologic cancers [1, 2]
Upregulation of Speckle-type POZ protein (SPOP) correlates with poor prognosis in clear-cell renal cell carcinoma (ccRCC) To demonstrate the clinical significance of SPOP expression in ccRCC, we firstly examined SPOP expression in ccRCC tissue specimens from a cohort of 120 patients with ccRCC by IHC staining using a specific anti-SPOP antibody
We observed that 95% (114/120) of ccRCC tissue samples showed significantly elevated SPOP levels compared with matched normal adjacent tissues (NAT; Fig. 1A and B)
Summary
Renal cell carcinoma (RCC) accounts for approximately 4% of all cancers and is the third most common urologic malignancy, which has the highest fatality rate among all urologic cancers [1, 2]. RCC is notorious for its resistance to routine chemotherapy and radiotherapy [3]. When metastasis occurs, it is mostly incurable with a very low 5-year survival rate [3]. The most commonly observed RCC subtype is clear-cell renal cell carcinoma (ccRCC), which accounts for approximately 75%–85% of all cases of RCC, with the highest rates of local invasion, metastasis, mortality, and refraction to current treatments [4, 5]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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