RNA结合蛋白LSM7通过调节CD44的选择性剪接促进乳腺癌转移

RNA-binding protein LSM7 facilitates breast cancer metastasis through mediating alternative splicing of CD44

LIFE SCIENCES

影响因子:5.1

分区:医学3区 / 药学2区医学：研究与实验3区

发表日期:2024 Nov 01

作者: Chenxin Li, Yuhao Zhang, Yun Wang, Jing Ouyang, Yingqian Yang, Qingqing Zhu, Yingsi Lu, Tingting Kang, Yan Li, Ming Xia, Jinrun Chen, Qiji Li, Chengming Zhu, Liping Ye

DOI: 10.1016/j.lfs.2024.123013

摘要

RNA结合蛋白LSM7在RNA剪接中起着关键作用，作为剪接体复合物的核心组成部分，然而其在乳腺癌（BC）中的具体作用尚未被广泛研究。我们通过生物信息学分析和免疫组化评估了BC样本中LSM7的表达。利用Transwell迁移和伤口愈合实验以及正位异种移植模型，探究了LSM7在促进转移性肿瘤特性中的作用。此外，通过RNA免疫沉淀和三代测序，研究了LSM7在CD44的选择性剪接中的参与。利用荧光素酶报告和染色质免疫沉淀进一步阐明了转录因子TCF3在调控LSM7基因表达中的作用。研究发现，LSM7在转移性BC组织中显著过表达，并与患者预后较差相关。LSM7过表达显著增强了BC细胞的迁移和侵袭能力，并在体内明显促进了自发性肺转移。此外，RIP-seq分析显示LSM7结合于CD44RNA，促进其可变剪接异构体CD44s的表达，从而驱动BC的转移和侵袭。TFC3转录因子则通过直接结合其启动子激活LSM7转录。综上所述，本研究强调了LSM7在产生CD44s异构体及促进乳腺癌转移中的关键作用。靶向TFC3/LSM7/CD44s轴可能为乳腺癌治疗提供新的策略。

Abstract

The RNA-binding protein LSM7 is essential for RNA splicing, acting as a key component of the spliceosome complex; however, its specific role in breast cancer (BC) has not been extensively investigated.LSM7 expression in BC samples was evaluated through bioinformatics analysis and immunohistochemistry. The impact of LSM7 on promoting metastatic tumor characteristics was examined using transwell and wound healing assays, as well as an orthotopic xenograft model. Additionally, the involvement of LSM7 in alternative splicing of CD44 was explored via RNA immunoprecipitation and third-generation sequencing. The regulatory role of TCF3 in modulating LSM7 gene expression was further elucidated using luciferase reporter assays and chromatin immunoprecipitation.Our findings demonstrate that LSM7 was significantly overexpressed in metastatic BC tissues and was associated with poor prognostic outcomes in patients with BC. LSM7 overexpression markedly increased the migratory and invasive capabilities of BC cells in vitro and significantly promoted spontaneous lung metastasis in vivo. Furthermore, RIP-seq analysis revealed that LSM7 binded to CD44 RNA, enhancing the expression of its alternatively spliced isoform CD44s, thereby driving BC metastasis and invasion. Additionally, the transcription factor TCF3 was found to activate LSM7 transcription by directly binding to its promoter.In summary, this study highlights the pivotal role of LSM7 in the production of the CD44s isoform and the promotion of breast cancer metastasis. Targeting the TCF3/LSM7/CD44s axis may offer a promising therapeutic strategy for breast cancer treatment.