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

Oncogene volume 41, pages 3409–3422 (2022)Cite this article

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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.

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Fig. 1: NSrp70 expression is downregulated in highly metastatic breast cancer cells.
Fig. 2: Loss of NSrp70 promotes breast cancer cell migration and metastasis in vitro and in vivo.
Fig. 3: NSrp70 inhibits SE alternative splicing of target pre-mRNA.
Fig. 4: Knockdown of NSrp70 promotes TGFβ–induced EMT.
Fig. 5: NSrp70 levels correlate with TβR1 degradation.
Fig. 6: Low NSrp70 expression correlates with poor patient prognosis.

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Acknowledgements

This work was supported by a grant from National Natural Science Foundation of China (81972727) and the Municipal Human Resources Development Program for Outstanding Leaders in Medical Disciplines in Shanghai (2017BR028). We gratefully acknowledge the help of professor Igor Vladimirovich Reshetov (I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation) for the support of clinical statistical analysis.

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  1. These authors contributed equally: Yang Zhao, Hefen Sun.

Authors and Affiliations

  1. Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Yang Zhao, Hefen Sun, Yuanyuan Zhao, Qiqi Liu, Yang Liu, Yifeng Hou & Wei Jin

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Yang Zhao, Hefen Sun, Yuanyuan Zhao, Qiqi Liu, Yifeng Hou & Wei Jin

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  1. Yang Zhao
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Contributions

WJ, Yang Z, and HS contributed to the study design. Yang Z, Yuanyuan Z, and QL contributed to the methodology. YL and YH performed statistical analysis and interpretation. Yang Z wrote the original draft. WJ and HS revised the manuscript. WJ supervised the study and provided financial support.

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Correspondence to Hefen Sun or Wei Jin.

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Zhao, Y., Sun, H., Zhao, Y. et al. NSrp70 suppresses metastasis in triple-negative breast cancer by modulating Numb/TβR1/EMT axis. Oncogene 41, 3409–3422 (2022). https://doi.org/10.1038/s41388-022-02349-z

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