RNA结合蛋白LSM7通过介导CD44的替代剪接促进乳腺癌转移
RNA-binding protein LSM7 facilitates breast cancer metastasis through mediating alternative splicing of CD44
影响因子:5.10000
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
摘要
RNA结合蛋白LSM7对于RNA剪接是必不可少的，它是剪接体复合物的关键组成部分。然而，尚未广泛研究其在乳腺癌（BC）中的具体作用。通过生物信息学分析和免疫组织化学评估了BC样品中的LSM7表达。使用Transwell和伤口愈合测定法以及原位异种移植模型检查了LSM7对促进转移性肿瘤特征的影响。另外，通过RNA免疫沉淀和第三代测序探索了LSM7参与CD44的替代剪接。使用荧光素酶报告基因测定和染色质免疫沉淀，进一步阐明了TCF3在调节LSM7基因表达中的调节作用。我们的发现表明，在BC患者中，LSM7在转移性BC组织中显着表达了LSM7在转移性BC组织中明显过表达，并且与预后不良有关。 LSM7的过表达显着增加了BC细胞体外的迁移和侵入性能力，并在体内显着促进了自发性的肺转移。此外，RIP-seq分析表明，LSM7绑定到CD44 RNA，增强其剪接的同工型CD44S的表达，从而驱动BC转移和入侵。此外，发现转录因子TCF3通过直接结合其启动子来激活LSM7转录。总而言之，这项研究突出了LSM7在CD44S同型生产中的关键作用和乳腺癌转移的促进。靶向TCF3/LSM7/CD44S轴可能会为乳腺癌治疗提供有希望的治疗策略。
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.