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

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

作者信息

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

机构信息

Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China.

Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China.

出版信息

J Exp Clin Cancer Res. 2025 Jan 16;44(1):15. doi: 10.1186/s13046-025-03278-x.

DOI:10.1186/s13046-025-03278-x

PMID:39815331

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11737211/

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.

摘要

背景

新出现的证据表明，小核仁RNA（snoRNA）是一种高度保守的非编码RNA，参与肿瘤发生和侵袭性过程。然而，snoRNAs在调节对癌症进展至关重要的可变剪接中的作用仍不清楚。

方法

进行高通量RNA测序和综合分析以鉴定关键的snoRNAs和下游可变剪接事件。应用生物素标记的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和蛋白质免疫印迹试验观察可变剪接和基因表达。进行体外和体内研究以探讨snoRNAs及其蛋白质伴侣在胃癌中的生物学作用。采用Kaplan-Meier法和对数秩检验进行生存分析。

结果

SNORA37被鉴定为一种上调的snoRNA，对胃癌的肿瘤发生和侵袭性至关重要。功能获得和功能丧失研究表明，SNORA37在体外和体内促进胃癌细胞的生长、侵袭和转移。机制上，作为一种由ELAV样RNA结合蛋白1（ELAVL1）产生的snoRNA，SNORA37直接与帽甲基转移酶1（CMTR1）结合，促进其与ELAVL1的相互作用，导致ELAVL1在调节CD44可变剪接中的核滞留和活性。挽救研究表明，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与患者较短的生存期和不良预后相关。