Life sciences · 2024
RNA-binding protein LSM7 facilitates breast cancer metastasis through mediating alternative splicing of CD44.
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Li Chenxin, Zhang Yuhao, Wang Yun, Ouyang Jing, Yang Yingqian, Zhu Qingqing, Lu Yingsi, Kang Tingting, Li Yan, Xia Ming, Chen Jinrun, Li Qiji, Zhu Chengming, Ye Liping
Аннотация
AIMS: 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.
MATERIALS AND METHODS: 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.
KEY FINDINGS: 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.
SIGNIFICANCE: 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.
MATERIALS AND METHODS: 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.
KEY FINDINGS: 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.
SIGNIFICANCE: 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.