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Pan-cancer pervasive upregulation of 3′ UTR splicing drives tumourigenesis
Nature Cell Biology ( IF 17.3 ) Pub Date : 2022-05-26 , DOI: 10.1038/s41556-022-00913-z
Jia Jia Chan 1 , Bin Zhang 1, 2, 3 , Xiao Hong Chew 1 , Adil Salhi 2, 3 , Zhi Hao Kwok 1, 4 , Chun You Lim 1 , Ng Desi 1 , Nagavidya Subramaniam 5 , Angela Siemens 1, 6 , Tyas Kinanti 1 , Shane Ong 1 , Avencia Sanchez-Mejias 1, 7 , Phuong Thao Ly 8 , Omer An 1 , Raghav Sundar 9, 10, 11, 12 , Xiaonan Fan 1 , Shi Wang 13 , Bei En Siew 14 , Kuok Chung Lee 14, 15 , Choon Seng Chong 14, 15 , Bettina Lieske 14, 15 , Wai-Kit Cheong 14, 15 , Yufen Goh 1 , Wee Nih Fam 1 , Melissa G Ooi 9, 16 , Bryan T H Koh 17 , Shridhar Ganpathi Iyer 14, 18 , Wen Huan Ling 19 , Jianbin Chen 20 , Boon-Koon Yoong 21 , Rawisak Chanwat 22 , Glenn Kunnath Bonney 14, 18 , Brian K P Goh 23 , Weiwei Zhai 19, 24 , Melissa J Fullwood 1, 8, 25 , Wilson Wang 17 , Ker-Kan Tan 14, 15 , Wee Joo Chng 1, 9, 16 , Yock Young Dan 16 , Jason J Pitt 1, 26 , Xavier Roca 8 , Ernesto Guccione 27 , Leah A Vardy 5 , Leilei Chen 1, 28 , Xin Gao 2, 3, 29 , Pierce K H Chow 19, 23, 30 , Henry Yang 1 , Yvonne Tay 1, 26, 31
Affiliation  

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3′ UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3′ UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3′ UTR splicing and present this in SpUR (http://www.cbrc.kaust.edu.sa/spur/home/). 3′ UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3′ UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3′ UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3′ UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3′ UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.



中文翻译:

3' UTR 剪接的泛癌普遍上调驱动肿瘤发生

大多数哺乳动物基因产生具有可变非翻译区 (UTR) 的信使 RNA,这些区域是重要的转录后调节因子。在癌症中,通过选择性聚腺苷酸化缩短 3' UTR 末端可以激活癌基因。然而,内部 3' UTR 剪接仍然知之甚少,因为剪接研究传统上侧重于蛋白质编码改变。在这里,我们系统地绘制了 3' UTR 剪接的泛癌景观,并将其呈现在 SpUR (http://www.cbrc.kaust.edu.sa/spur/home/) 中。3' UTR 剪接广泛存在,在癌症中上调,与不良预后相关,在癌基因中更为普遍。我们表明,反义寡核苷酸介导的 3' UTR 剪接抑制有效地降低了癌基因表达并阻碍了肿瘤进展。值得注意的是,CTNNB13' UTR 剪接是癌症中最一致的失调事件。我们验证了它在肝细胞癌和结肠腺癌中的上调,并表明剪接的 3' UTR 变体是其致癌功能的主要贡献者。总的来说,我们的研究强调了 3' UTR 剪接在癌症中的重要性,并可能为基于 RNA 的抗癌疗法开辟新途径。

更新日期:2022-05-27
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