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

Peiyuan Zhang,Yuan Wang,Xuan Cao,Xue Zhang,Yingjie Liu,Tong Liu,Min Cong,Gang Wei,Guohong Hu,Cheng Lian,Xiaoxun Li,Pu Tian

doi:10.1038/s41467-020-16051-9

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.

Highlights

Cancer stem-like cells (CSCs) are the tumorigenic cell subpopulation and contribute to cancer recurrence and metastasis
We found SH3RF3 could upregulate the expression of Pentraxin 3 (PTX3) to promote stem-like traits of breast cancer cells
To identify regulatory molecules in breast cancer stem-like cells (BCSCs), we sorted HMLER, a human breast cancer cell line often used in CSC studies[23], into a CD44+CD24− subpopulation and a CD44−CD24+ subpopulation via flow cytometry (Fig. 1a)

Summary

Introduction

Cancer stem-like cells (CSCs) are the tumorigenic cell subpopulation and contribute to cancer recurrence and metastasis. We found SH3RF3 could upregulate the expression of Pentraxin 3 (PTX3) to promote stem-like traits of breast cancer cells. We show that the scaffold protein SH3RF3 is highly expressed in breast cancer CSCs and reveal its function to enhance the cancer cell stemness by regulating PTX3.

Results

Conclusion