Huang Yawei, Xi Xiaoqing, Ye Zhenfeng, Zhang Chiyu, Jiang Yi, Yu Fanfan, Huang Gaomin
Department of Urology, Second Affiliated Hospital of Nanchang University, Nanchang, China.
Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanchang University, Nanchang, China.
FASEB J. 2025 Jan 31;39(2):e70330. doi: 10.1096/fj.202401910R.
Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system, and clear cell renal cell carcinoma (ccRCC) is the most common subtype. MYBL2 has been reported to be overexpressed in various tumors and associated with poor prognosis in patients, but its biological role in ccRCC remains unclear. In this study, we investigated the mRNA and protein expression levels of MYBL2 in ccRCC samples and evaluated the prognostic value of MYBL2 using TCGA dataset. In vitro functional assays were performed using CCK-8, EdU, colony formation, cell scratch, and transwell assays, as well as in vivo tumorigenesis assays to investigate the biological functions of MYBL2 in ccRCC. Additionally, gene set enrichment analysis (GSEA) was used to explore the downstream pathways of MYBL2, which were further validated. Finally, we predicted the target genes of MYBL2 using bioinformatics and validated them using ChIP and dual-luciferase reporter gene assays. MYBL2 expression was significantly higher in ccRCC than in adjacent normal tissues and was associated with poor prognosis. MYBL2 expression was positively correlated with the pathological tumor grade and clinical TNM stage of ccRCC patients. Knockdown of MYBL2 significantly inhibited the proliferation of renal cancer cells in vitro and in vivo, and knockdown of MYBL2 could inhibit cell invasion and migration, while overexpression of MYBL2 had the opposite effect. GSEA revealed that MYBL2 was associated with the mTOR signaling pathway and cell cycle pathway, which was confirmed by our study. Finally, we found that TOP2A was a target gene of MYBL2, and MYBL2 could bind to the TOP2A promoter to regulate its transcriptional activity, promoting the proliferation of clear cell renal cell carcinoma cells. MYBL2 emerges as a highly expressed factor that significantly correlates with adverse patient prognosis in ccRCC. Mechanistically, MYBL2 transcriptionally upregulates TOP2A, thereby modulating the proliferation of ccRCC cells. Furthermore, MYBL2 activates the mTOR signaling pathway, a critical node in the progression of ccRCC. Collectively, these findings position MYBL2 as a promising candidate for both a biological marker and a therapeutic target in the management of ccRCC.
肾细胞癌（RCC）是泌尿系统最常见的恶性肿瘤之一，而透明细胞肾细胞癌（ccRCC）是最常见的亚型。据报道，MYBL2在各种肿瘤中过表达，且与患者预后不良相关，但其在ccRCC中的生物学作用仍不清楚。在本研究中，我们调查了MYBL2在ccRCC样本中的mRNA和蛋白表达水平，并使用TCGA数据集评估了MYBL2的预后价值。使用CCK-8、EdU、集落形成、细胞划痕和transwell实验进行体外功能分析，以及进行体内肿瘤发生实验，以研究MYBL2在ccRCC中的生物学功能。此外，使用基因集富集分析（GSEA）来探索MYBL2的下游通路，并对其进行进一步验证。最后，我们使用生物信息学预测MYBL2的靶基因，并使用ChIP和双荧光素酶报告基因实验对其进行验证。MYBL2在ccRCC中的表达显著高于相邻正常组织，并与预后不良相关。MYBL2表达与ccRCC患者的病理肿瘤分级和临床TNM分期呈正相关。敲低MYBL2可显著抑制肾癌细胞在体外和体内的增殖，并且敲低MYBL2可抑制细胞侵袭和迁移，而MYBL2的过表达则具有相反的作用。GSEA显示MYBL2与mTOR信号通路和细胞周期通路相关，这在我们的研究中得到了证实。最后，我们发现TOP2A是MYBL2的靶基因，并且MYBL2可与TOP2A启动子结合以调节其转录活性，促进透明细胞肾癌细胞的增殖。MYBL2是一种高表达因子，与ccRCC患者的不良预后显著相关。从机制上讲，MYBL2通过转录上调TOP2A，从而调节ccRCC细胞的增殖。此外，MYBL2激活mTOR信号通路，这是ccRCC进展中的一个关键节点。总的来说，这些发现使MYBL2成为ccRCC管理中一个有前途的生物学标志物和治疗靶点候选者。
