State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cancer Sci. 2021 May;112(5):1758-1771. doi: 10.1111/cas.14810. Epub 2021 Mar 9.
Clinically, patients with urothelial carcinoma of the bladder (UCB) with tumor metastasis are incurable. To find new therapeutic strategies, the mechanisms underlying UCB invasion and metastasis should be further investigated. In this study, zinc finger and homeobox 3 (ZHX3) was first screened as a critical oncogenic factor associated with poor prognosis in a UCB dataset from The Cancer Genome Atlas (TCGA). These results were also confirmed in a large cohort of clinical UCB clinical samples. Next, we found that ZHX3 could promote the migration and invasion capacities of UCB cells both in vitro and in vivo. Mechanistically, coimmunoprecipitation (coIP) and mass spectrometry (MS) analysis indicated that ZHX3 was a target of tripartite motif 21 (TRIM21), which mediates its ubiquitination, and subsequent degradation. Notably, RNA-seq analysis showed that ZHX3 repressed the expression of regulator of G protein signaling 2 (RGS2). Generally, our results suggest that ZHX3 plays an oncogenic role in UCB pathogenesis and might serve as a novel therapeutic target for UCB.
临床上，患有肿瘤转移的膀胱癌（UCB）患者无法治愈。为了寻找新的治疗策略，应进一步研究 UCB 侵袭和转移的机制。在这项研究中，锌指和同源盒 3（ZHX3）首先被筛选为与癌症基因组图谱（TCGA）中 UCB 数据集相关的预后不良的关键致癌因子。这些结果在大量临床 UCB 临床样本中也得到了证实。接下来，我们发现 ZHX3 可以在体外和体内均促进 UCB 细胞的迁移和侵袭能力。在机制上，免疫共沉淀（coIP）和质谱（MS）分析表明 ZHX3 是三肽基 21（TRIM21）的靶标，TRIM21 介导其泛素化和随后的降解。值得注意的是，RNA-seq 分析表明 ZHX3 抑制了 G 蛋白信号调节因子 2（RGS2）的表达。总的来说，我们的结果表明 ZHX3 在 UCB 发病机制中发挥致癌作用，可能成为 UCB 的新治疗靶点。
