Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, China.
Department of Gynecology, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, China.
Funct Integr Genomics. 2023 Oct 25;23(4):326. doi: 10.1007/s10142-023-01255-1.
Renal cell carcinoma (RCC) is the most lethal of the urologic malignancies. We previously discovered that DAB2IP, a novel Ras GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. In this study, we determined the biological functions of DAB2IP in clear cell RCC (ccRCC) and its potential mechanisms of action. Correlations between DAB2IP expression level and ccRCC tumor size and patient survival were analyzed, and the results showed that ccRCC patients with high DAB2IP mRNA level exhibited smaller tumor size and better survival than the patients with low DAB2IP. Compared to control, DAB2IP knockdown significantly increased cell proliferation, promoted cell cycle progression in G1/S phase, and decreased p27 expression. Mechanism studies demonstrated that loss of DAB2IP promoted p27 protein phosphorylation, cytosolic sequestration, and subsequently ubiquitination-mediated degradation in ccRCC cells. Further studies confirmed that the proline-rich domain in C terminal (CPR) of DAB2IP suppressed AKT phosphorylation and p27 phosphorylation on S10. Hence, DAB2IP is essential for p27 protein stabilization in ccRCC, which is at less partly mediated by PI3K/AKT signaling pathway.
肾细胞癌（RCC）是最致命的泌尿系统恶性肿瘤之一。我们之前发现，DAB2IP，一种新型的 Ras GTPase 激活蛋白，在 RCC 中经常被表观遗传沉默，DAB2IP 的缺失与 RCC 患者的总生存相关。在这项研究中，我们确定了 DAB2IP 在透明细胞肾细胞癌（ccRCC）中的生物学功能及其潜在的作用机制。分析了 DAB2IP 表达水平与 ccRCC 肿瘤大小和患者生存的相关性，结果表明，DAB2IP mRNA 水平高的 ccRCC 患者肿瘤体积较小，生存状况较好。与对照相比，DAB2IP 敲低显著增加了细胞增殖，促进了 G1/S 期细胞周期进程，并降低了 p27 的表达。机制研究表明，DAB2IP 的缺失促进了 ccRCC 细胞中 p27 蛋白的磷酸化、细胞质隔离，随后被泛素化介导降解。进一步的研究证实，DAB2IP 的 C 端富含脯氨酸结构域（CPR）抑制了 AKT 磷酸化和 p27 在 S10 上的磷酸化。因此，DAB2IP 对 ccRCC 中 p27 蛋白的稳定是必不可少的，这部分是由 PI3K/AKT 信号通路介导的。
