Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Clinical College of Anhui Medical University, Shenzhen, China.
Anhui Medical University, Hefei, China.
FASEB J. 2020 Aug;34(8):10623-10639. doi: 10.1096/fj.202000088RR. Epub 2020 Jun 28.
Although renal cell carcinoma (RCC) is a common malignant urological cancer, its pathogenesis remains unclear. Previous studies have indicated that miR-140-5p acts as a tumor suppressor in various tumors, including bladder cancer, hepatocellular carcinoma, and gastric cancer, but its biological function in RCC remains unknown. In the present study, we found that miR-140-5p was upregulated in RCC tissues, whereas Krüppel-like factor 9 (KLF9) was downregulated and correlated inversely with miR-140-5p in RCC tissues. miR-140-5p promoted the proliferation, migration, and invasion of RCC cells in vitro, and knockdown of miR-140-5p significantly suppressed tumor growth and lung metastasis in nude mouse model of RCC. We also found that miR-140-5p significantly suppressed the expression of KLF9 by binding to the 3'-UTR of KLF9 mRNA and that KLF9, as a transcription factor, upregulates KCNQ1 (also called K 7.1 and K LQT1) expression by binding to the site (-841/-827) in the KCNQ1 promoter region in RCC cells. Moreover, forced expression of KCNQ1 decreased the growth and metastasis of RCC cells. These results suggest that the miR-140-5p/KLF9/KCNQ1 axis functions as a key signaling pathway in RCC progression and metastasis and represents a potential target of RCC therapies.
虽然肾细胞癌 (RCC) 是一种常见的恶性泌尿系统癌症，但它的发病机制仍不清楚。先前的研究表明，miR-140-5p 在多种肿瘤中作为肿瘤抑制因子发挥作用，包括膀胱癌、肝癌和胃癌，但它在 RCC 中的生物学功能尚不清楚。在本研究中，我们发现 miR-140-5p 在 RCC 组织中上调，而 Krüppel 样因子 9 (KLF9) 下调，并与 RCC 组织中的 miR-140-5p 呈负相关。miR-140-5p 促进 RCC 细胞在体外的增殖、迁移和侵袭，并且 miR-140-5p 的敲低显著抑制 RCC 裸鼠模型中的肿瘤生长和肺转移。我们还发现，miR-140-5p 通过与 KLF9 mRNA 的 3'-UTR 结合，显著抑制 KLF9 的表达，并且 KLF9 作为转录因子，通过结合 KCNQ1 启动子区域中的位点 (-841/-827) ，上调 RCC 细胞中 KCNQ1 的表达。此外，KCNQ1 的强制表达降低了 RCC 细胞的生长和转移。这些结果表明，miR-140-5p/KLF9/KCNQ1 轴作为 RCC 进展和转移的关键信号通路发挥作用，并且是 RCC 治疗的潜在靶点。
