Ping Ji-Gen, Wang Fei, Pu Jin-Xian, Hou Ping-Fu, Chen Yan-Su, Bai Jin, Zheng Jun-Nian
Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, China.
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou, Jiangsu Province, 221002, China.
Tumour Biol. 2016 Sep;37(9):12823-12831. doi: 10.1007/s13277-016-5151-6. Epub 2016 Jul 23.
Cullin1 (Cul1) is a scaffold protein of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex, which ubiquitinates a broad range of proteins involved in cell-cycle progression, signal transduction, and transcription. To investigate the role of Cul1 in the development of renal cell carcinoma (RCC), we evaluated the Cul1 expression by immunohistochemistry using a tissue microarray (TMA) containing 307 cases of RCC tissues and 34 normal renal tissues. The Cul1 expression was increased significantly in RCC and was correlated with renal carcinoma histology grade (P = 0.007), tumor size (P = 0.013), and pT status (P = 0.023). Also, we found that silencing of Cul1 leads to increased expression of p21 and p27 that could inhibit the cyclin D and cyclin E expressions and arrest cell cycle at the G1 phase. Furthermore, knockdown of Cul1 inhibits RCC cell migration and invasion abilities by up-regulating the expression of TIMP-1 which could inhibit the expression of MMP-9. Finally, using bioluminescence imaging, we found that Cul1 knockdown significantly reduced the tumor growth in vivo. Cul1 may constitute a potential therapeutic target in RCC.
Cullin1（Cul1）是泛素E3连接酶Skp1/Cullin1/Rbx1/F-box蛋白复合物的一种支架蛋白，该复合物可使多种参与细胞周期进程、信号转导和转录的蛋白质发生泛素化。为了研究Cul1在肾细胞癌（RCC）发生发展中的作用，我们使用包含307例RCC组织和34例正常肾组织的组织芯片（TMA），通过免疫组织化学评估了Cul1的表达。Cul1在RCC中的表达显著增加，且与肾癌组织学分级（P = 0.007）、肿瘤大小（P = 0.013）和pT状态（P = 0.023）相关。此外，我们发现沉默Cul1会导致p21和p27表达增加，这两种蛋白可抑制细胞周期蛋白D和细胞周期蛋白E的表达，并使细胞周期停滞在G1期。此外，敲低Cul1可通过上调TIMP-1的表达来抑制RCC细胞的迁移和侵袭能力，而TIMP-1可抑制MMP-9的表达。最后，通过生物发光成像，我们发现敲低Cul1可显著降低体内肿瘤的生长。Cul1可能构成RCC的一个潜在治疗靶点。
