PDF(Pubmed)
Abstract：
As the second most common malignant tumor in the urinary system, renal cell carcinoma (RCC) is imperative to explore its early diagnostic markers and therapeutic targets. Numerous studies have shown that AURKB promotes tumor development by phosphorylating downstream substrates. However, the functional effects and regulatory mechanisms of AURKB on clear cell renal cell carcinoma (ccRCC) progression remain largely unknown. In the current study, we identified AURKB as a novel key gene in ccRCC progression based on bioinformatics analysis. Meanwhile, we observed that AURKB was highly expressed in ccRCC tissue and cell lines and knockdown AURKB in ccRCC cells inhibit cell proliferation and migration in vitro and in vivo. Identified CDC37 as a kinase molecular chaperone for AURKB, which phenocopy AURKB in ccRCC. AURKB/CDC37 complex mediate the stabilization of MYC protein by directly phosphorylating MYC at S67 and S373 to promote ccRCC development. At the same time, we demonstrated that the AURKB/CDC37 complex activates MYC to transcribe CCND1, enhances Rb phosphorylation, and promotes E2F1 release, which in turn activates AURKB transcription and forms a positive feedforward loop in ccRCC. Collectively, our study identified AURKB as a novel marker of ccRCC, revealed a new mechanism by which the AURKB/CDC37 complex promotes ccRCC by directly phosphorylating MYC to enhance its stability, and first proposed AURKB/E2F1-positive feedforward loop, highlighting AURKB may be a promising therapeutic target for ccRCC.
摘要：
作为泌尿系统第二常见的恶性肿瘤，肾细胞癌(RCC)的早期诊断标志物和治疗靶点的探索势在必行。大量研究表明，AURKB通过磷酸化下游底物促进肿瘤发展。然而,AURKB对肾透明细胞癌(ccRCC)进展的功能作用和调节机制尚不清楚.在目前的研究中,基于生物信息学分析,我们将AURKB鉴定为ccRCC进展的新关键基因。同时,我们观察到AURKB在ccRCC组织和细胞系中高表达，敲低ccRCC细胞中的AURKB在体外和体内抑制细胞增殖和迁移。确定CDC37为AURKB的激酶分子伴侣，ccRCC中的表型AURKB。AURKB/CDC37复合物通过在S67和S373处直接磷酸化MYC来介导MYC蛋白的稳定以促进ccRCC的发展。同时,我们证明了AURKB/CDC37复合物激活MYC转录CCND1，增强Rb磷酸化，并促进E2F1的发布，进而激活AURKB转录并在ccRCC中形成正前馈环。总的来说，我们的研究将AURKB确定为ccRCC的新标记，揭示了AURKB/CDC37复合物通过直接磷酸化MYC以增强其稳定性来促进ccRCC的新机制，首先提出了AURKB/E2F1正前馈环，突出显示AURKB可能是ccRCC的有希望的治疗靶标。
