SH3RF3 promotes breast cancer stem-like properties via JNK activation and PTX3 upregulation.
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.
Mesh Terms:
Breast Neoplasms, C-Reactive Protein, Cell Line, Cell Line, Tumor, Enzyme Activation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Neoplastic Stem Cells, Phosphorylation, Serum Amyloid P-Component, Ubiquitin-Protein Ligases, Up-Regulation
Breast Neoplasms, C-Reactive Protein, Cell Line, Cell Line, Tumor, Enzyme Activation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Neoplastic Stem Cells, Phosphorylation, Serum Amyloid P-Component, Ubiquitin-Protein Ligases, Up-Regulation
Nat Commun
Date: Dec. 19, 2019
PubMed ID: 32427938
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