Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Med. 2021 Jan;10(1):269-285. doi: 10.1002/cam4.3622. Epub 2020 Dec 1.
Bladder cancer (BCa) is a common malignant tumor of urinary system with few treatments, so more useful therapeutic targets are still needed. Antitumor effects of tristetraprolin (TTP) have been explored in many type tumors, but its roles in bladder cancer are still unknown until now. In this study, public expression profiles and tissue microarray analysis showed that TTP mRNA and protein levels decreased in BCa relative to the normal bladder tissue. To explore biological functions of TTP in BCa, 488 TTP target genes, which could be both suppressed and bound by TTP, were identified by comprehensively analyzing publicly available high-throughput data obtained from Gene Expression Omnibus (GEO). Gene enrichment analysis showed that these genes were enriched in pathways such as cell cycle, epithelial to mesenchymal transition (EMT), and Wnt signaling. Clustering analysis and gene set variation analysis indicated that patients with high expression of TTP target genes had poorer prognosis and stronger tumor proliferation ability relative to the BCa patients with low expression of TTP target genes. In vitro experiments validated that TTP could suppress proliferation, migration, and invasiveness of BCa cells. And TTP could suppress mRNA expression of cyclin-dependent kinase 1 (CDK1) in BCa cells by target its 3' UTR. Then, we identified a new small double-stranded RNA (dsRNA) named dsTTP-973 which could increase TTP expression in BCa cells, in vivo and in vitro experiments revealed that dsTTP-973 could suppress aggressiveness of BCa. In conclusion, TTP played a role of tumor suppressor gene in BCa like other tumors, and its dsRNA named dsTTP-973 could induce TTP expression in BCa and suppress aggressiveness of BCa. With the help of materials science, dsTTP-973 may become a potential treatment for BCa in the future.
膀胱癌（BCa）是一种常见的泌尿系统恶性肿瘤，治疗方法较少，因此仍需要更多有用的治疗靶点。Tristetraprolin（TTP）的抗肿瘤作用已在许多类型的肿瘤中得到了探索，但直到现在，其在膀胱癌中的作用仍不清楚。在这项研究中，公共表达谱和组织微阵列分析显示，TTP mRNA 和蛋白水平在膀胱癌组织中降低。为了探索 TTP 在膀胱癌中的生物学功能，通过综合分析来自基因表达综合数据库（GEO）的公开高通量数据，鉴定了 488 个 TTP 靶基因，这些基因既可以被 TTP 抑制，也可以被 TTP 结合。基因富集分析显示，这些基因富集在细胞周期、上皮间质转化（EMT）和 Wnt 信号通路等途径中。聚类分析和基因集变异分析表明，与 TTP 靶基因低表达的膀胱癌患者相比，高表达 TTP 靶基因的患者预后较差，肿瘤增殖能力较强。体外实验验证了 TTP 可抑制膀胱癌细胞的增殖、迁移和侵袭。并且 TTP 可以通过靶向其 3'UTR 抑制 CDK1（细胞周期蛋白依赖性激酶 1）mRNA 在膀胱癌细胞中的表达。然后，我们鉴定了一种新的双链 RNA（dsRNA）dsTTP-973，它可以在体内和体外增加膀胱癌细胞中的 TTP 表达，体内外实验表明 dsTTP-973 可以抑制膀胱癌的侵袭性。总之，TTP 在膀胱癌中像其他肿瘤一样发挥肿瘤抑制基因的作用，其 dsRNA 名为 dsTTP-973 可以诱导膀胱癌中 TTP 的表达，并抑制膀胱癌的侵袭性。在材料科学的帮助下，dsTTP-973 可能成为未来膀胱癌的潜在治疗方法。
