Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University, School of Basic Medical Sciences, Jinan, Shandong, 250012, China; Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong, Jinan, Shandong, 250012, China.
Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
Int J Biochem Cell Biol. 2021 Jan;130:105887. doi: 10.1016/j.biocel.2020.105887. Epub 2020 Nov 20.
Cullin 4B (CUL4B), encoding a scaffold protein in Cullin RING ubiquitin-ligase complexes (CRL4B), is overexpressed and serves as an oncogene in various solid tumors. However, the roles and the underlying mechanisms of CUL4B in renal cell carcinoma (RCC) are still unknown. In this study, we demonstrated that CUL4B was significantly upregulated in RCC cells and clinical specimens, and its overexpression was correlated with poor survival of RCC patients. Knockdown of CUL4B resulted in the inhibition of proliferation, migration and invasion of RCC cells. Furthermore, we found that the expression of CUL4B is positively correlated with c-Met expression in RCC cells and tissues. Konckdown of c-Met or treatment with c-Met inhibitor, SU11274, could block the increase in cell proliferation, migration and invasion induced by CUL4B-overexpression. We also showed that CUL4B overexpression significantly accelerated xenograft tumor growth, and administration of SU11274 could also abrogate the accelerated tumor growth induced by CUL4B overexpression in vivo. These findings shed light on the contribution of CUL4B to tumorigenesis in RCC via activating c-Met signaling and its therapeutic implications in RCC patients.
Cullin 4B（CUL4B），作为 Cullin RING 泛素连接酶复合物（CRL4B）的支架蛋白，在各种实体瘤中过表达并作为癌基因发挥作用。然而，CUL4B 在肾细胞癌（RCC）中的作用和潜在机制尚不清楚。在这项研究中，我们证明 CUL4B 在 RCC 细胞和临床标本中显著上调，其过表达与 RCC 患者的不良预后相关。CUL4B 的敲低导致 RCC 细胞的增殖、迁移和侵袭受到抑制。此外，我们发现 CUL4B 的表达与 RCC 细胞和组织中的 c-Met 表达呈正相关。敲低 c-Met 或用 c-Met 抑制剂 SU11274 处理可阻断 CUL4B 过表达引起的细胞增殖、迁移和侵袭增加。我们还表明，CUL4B 过表达显著加速了异种移植肿瘤的生长，而 SU11274 的给药也可以消除 CUL4B 过表达在体内引起的肿瘤生长加速。这些发现揭示了 CUL4B 通过激活 c-Met 信号通路促进 RCC 肿瘤发生的作用及其在 RCC 患者中的治疗意义。
