SH3RF3 promotes breast cancer stem-like properties via JNK activation and PTX3 upregulation

Peiyuan Zhang, Yingjie Liu, Cheng Lian, Xuan Cao, Yuan Wang, Xiaoxun Li, Min Cong, Pu Tian, Xue Zhang, Gang Wei, Tong Liu () and Guohong Hu ()
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Peiyuan Zhang: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Yingjie Liu: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Cheng Lian: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Xuan Cao: Collaborative Innovation Center for Genetics and Developmental Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
Yuan Wang: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Xiaoxun Li: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Min Cong: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Pu Tian: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Xue Zhang: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences
Gang Wei: Collaborative Innovation Center for Genetics and Developmental Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
Tong Liu: Harbin Medical University Cancer Hospital
Guohong Hu: Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Cancer stem-like cells (CSCs) are the tumorigenic cell subpopulation and contribute to cancer recurrence and metastasis. However, the understanding of CSC regulatory mechanisms remains incomplete. By transcriptomic analysis, we identify a scaffold protein SH3RF3 (also named POSH2) that is upregulated in CSCs of breast cancer clinical tumors and cancer cell lines, and enhances the CSC properties of breast cancer cells. Mechanically, SH3RF3 interacts with the c-Jun N-terminal kinase (JNK) in a JNK-interacting protein (JIP)-dependent manner, leading to enhanced phosphorylation of JNK and activation of the JNK-JUN pathway. Further the JNK-JUN signaling expands CSC subpopulation by transcriptionally activating the expression of Pentraxin 3 (PTX3). The functional role of SH3RF3 in CSCs is validated with patient-derived organoid culture, and supported by clinical cohort analyses. In conclusion, our work elucidates the role and molecular mechanism of SH3RF3 in CSCs of breast cancer, and might provide opportunities for CSC-targeting therapy.

Date: 2020
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DOI: 10.1038/s41467-020-16051-9

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