NSrp70 suppresses metastasis in triple-negative breast cancer by modulating Numb/TβR1/EMT axis.

Abstract

Alternative splicing of mRNA precursors allows cancer cells to create different protein isoforms that promote growth and survival. Compared to normal cells, cancer cells frequently exhibit a higher diversity of their transcriptomes. A comprehensive understanding of splicing regulation is required to correct the splicing alterations for the future precision oncology. A quantitative proteomic screen was performed to identify the regulators associated the metastasis in triple-negative breast cancer. Multiple in vitro and in vivo functional analyses were used to study the effects of NSrp70 on breast cancer metastasis. Next, transcriptomic sequencing (RNA-seq) and alternative splicing bioinformatics analysis was applied to screen the potential targets of NSrp70. Moreover, in vitro splicing assays, RNA pull-down, and RNA immunoprecipitation assay were used to confirm the specific binding between NSrp70 and downstream target genes. Furthermore, the prognostic value of NSrp70 was analyzed in a cohort of patients by performing IHC. We uncovered NSrp70 as a novel suppressor of breast cancer metastasis. We discovered that NSrp70 inhibited the skipped exon alternative splicing of NUMB, promoted the degradation of transforming growth factor receptor 1 through lysosome pathway, and regulated TGFβ/SMAD-mediated epithelial-mesenchymal transition phenotype in breast cancer cells. Furthermore, high NSrp70 expression correlated with a better prognosis in breast cancer patients. Our findings revealed that splicing regulator NSrp70 serves as a metastasis suppressor.

• Authors: Yang Zhao, Hefen Sun, Yuanyuan Zhao, Qiqi Liu, Yang Liu, Yifeng Hou, Wei Jin
• Journal: Oncogene (Oncogene) Vol. 41 Issue 25 Pg. 3409-3422 (06 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35568738 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Membrane Proteins
• NSRP1 protein, human
• Nerve Tissue Proteins
• Nuclear Proteins
• NUMB protein, human
• RNA Precursors
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Alternative Splicing
• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Proteins (genetics, metabolism)
• Neoplasm Metastasis
• Nerve Tissue Proteins (genetics)
• Nuclear Proteins (metabolism)
• Precision Medicine
• Proteomics
• RNA Precursors
• Receptor, Transforming Growth Factor-beta Type I (metabolism)
• Triple Negative Breast Neoplasms (pathology)