Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Science, Nanjing University, Nanjing, China.
Cancer Res. 2018 Dec 15;78(24):6771-6784. doi: 10.1158/0008-5472.CAN-18-1662. Epub 2018 Oct 22.
: 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 and . 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.
尽管肾细胞癌（RCC）是最恶性的泌尿系统癌症，但它的发病机制仍不清楚，且晚期 RCC 的有效治疗方法仍然缺乏。在这里，我们报告了一个新的 E2F1-miR-520/372/373-SPOP 轴控制 RCC 癌变。斑点型 POZ 蛋白（SPOP）在超过 90%的 RCC 组织中上调，而 miR-520/372/373 家族则下调，并与 RCC 组织中的 SPOP 蛋白水平呈负相关。miR-520/372/373 家族靶向 SPOP 3'-UTR，并抑制 SPOP 蛋白表达，导致 PTEN 和 DUSP7 水平升高，从而降低 RCC 细胞的增殖、侵袭/迁移和转移。静脉内递送治疗性 miR-520/372/373 家族显著降低了荷同位移植瘤小鼠的肿瘤大小和肺转移比例。miR-520/372/373 家族的表达减少是由转录因子 E2F1 介导的。总之，我们的结果表明，E2F1-miR-520/372/373-SPOP 轴作为 RCC 进展和转移的关键信号通路发挥作用，为靶向治疗提供了有前途的机会。意义：这些发现表明，E2F1-miR-520/372/373 家族-SPOP 轴促进了 RCC 的进展，从而有助于我们理解 RCC 的发病机制，并为更有效的靶向治疗开辟了新途径。
