SNORA37/CMTR1/ELAVL1 feedback loop drives gastric cancer progression via facilitating CD44 alternative splicing.

IF 11.4 1区医学 Q1 ONCOLOGY

Journal of Experimental & Clinical Cancer Research Pub Date : 2025-01-16 DOI:10.1186/s13046-025-03278-x

Banghe Bao, Minxiu Tian, Xiaojing Wang, Chunhui Yang, Jiaying Qu, Shunchen Zhou, Yang Cheng, Qiangsong Tong, Liduan Zheng

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引用次数: 0

Abstract

Background: Emerging evidence shows that small nucleolar RNA (snoRNA), a type of highly conserved non-coding RNA, is involved in tumorigenesis and aggressiveness. However, the roles of snoRNAs in regulating alternative splicing crucial for cancer progression remain elusive.

Methods: High-throughput RNA sequencing and comprehensive analysis were performed to identify crucial snoRNAs and downstream alternative splicing events. Biotin-labeled RNA pull-down, mass spectrometry, cross-linking RNA immunoprecipitation, and in vitro binding assays were applied to explore interaction of snoRNAs with protein partners. Alternative splicing and gene expression was observed by real-time quantitative RT-PCR and western blot assays. In vitro and in vivo studies were performed to investigate biological effects of snoRNAs and their protein partners in gastric cancer. Survival analysis was undertaken by using Kaplan-Meier method and log-rank test.

Results: SNORA37 was identified as an up-regulated snoRNA essential for tumorigenesis and aggressiveness of gastric cancer. Gain- and loss-of-function studies indicated that SNORA37 promoted the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Mechanistically, as an ELAV like RNA binding protein 1 (ELAVL1)-generated snoRNA, SNORA37 directly bound to cap methyltransferase 1 (CMTR1) to facilitate its interaction with ELAVL1, resulting in nuclear retention and activity of ELAVL1 in regulating alternative splicing of CD44. Rescue studies revealed that SNORA37 exerted oncogenic roles in gastric cancer progression via facilitating CMTR1-ELAVL1 interaction. In clinical gastric cancer cases, high levels of SNORA37, CMTR1, ELAVL1, or CD44 were associated with shorter survival and poor outcomes of patients.

Conclusions: These results indicated that SNORA37/CMTR1/ELAVL1 feedback loop drives gastric cancer progression via facilitating CD44 alternative splicing.

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SNORA37/CMTR1/ELAVL1反馈回路通过促进CD44选择性剪接驱动胃癌进展。

背景：越来越多的证据表明，小核仁RNA （small nucleolar RNA, snoRNA）是一种高度保守的非编码RNA，参与肿瘤的发生和侵袭性。然而，snorna在调节对癌症进展至关重要的选择性剪接中的作用仍然难以捉摸。方法：进行高通量RNA测序和综合分析，以确定关键的snorna和下游备选剪接事件。应用生物素标记RNA下拉、质谱、交联RNA免疫沉淀和体外结合试验来探索snoRNAs与蛋白质伴侣的相互作用。通过实时定量RT-PCR和western blot检测观察基因的选择性剪接和表达。体外和体内研究探讨了snoRNAs及其蛋白伴侣在胃癌中的生物学作用。生存率分析采用Kaplan-Meier法和log-rank检验。结果：SNORA37被鉴定为胃癌发生和侵袭所必需的上调snoRNA。功能增益和功能丧失研究表明，SNORA37在体外和体内均能促进胃癌细胞的生长、侵袭和转移。机制上，SNORA37作为ELAV样RNA结合蛋白1 （ELAVL1）生成的snoRNA，直接结合帽甲基转移酶1 (CMTR1)，促进其与ELAVL1的相互作用，导致ELAVL1的核保留和活性调节CD44的选择性剪接。救援研究显示，SNORA37通过促进CMTR1-ELAVL1相互作用，在胃癌进展中发挥致癌作用。在临床胃癌病例中，高水平的SNORA37、CMTR1、ELAVL1或CD44与患者的生存期缩短和预后不良相关。结论：这些结果表明，SNORA37/CMTR1/ELAVL1反馈回路通过促进CD44选择性剪接驱动胃癌进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.