Translational oncology · 2025
TCEB2 promotes M2 polarization of macrophages in triple negative breast cancer by mediating ubiquitination degradation of Slit2 through recruiting NEDD4.
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Liu Li, Xiao Wang, Zeng Jie, Yi Jianing, Gong Haoli, Liu Luyao
Аннотация
BACKGROUND: M2-polarized tumor-associated macrophage infiltration is a key risk factor for poor prognosis in triple-negative breast cancer (TNBC). This study investigated the role of transcription elongation factor B polypeptide 2 (TCEB2) in regulating M2 macrophage polarization during TNBC development.
METHODS: The expression of gene or protein was tested by qRT-PCR, western blot, and IHC. CCK8, colony formation, wound healing, and Transwell assays were used to evaluate TNBC cell malignant behaviors, including cell viability, proliferation, migration, and invasion. The secretion levels of cytokines were detected by ELISA. Ubiquitin-based IP assays were used to detect Slit2 ubiquitination. The combined relation between TCEB2, Slit2, and NEDD4 was investigated using Co-IP assay.
RESULTS: Our results demonstrated that M2 macrophage polarization was activated in TNBC, which might be related to TCEB2 upregulation. TCEB2 knockdown reduced TNBC cell growth, migration, invasion, and their ability to induce M2 macrophage polarization. Mechanistically, TCEB2 mediated Slit2 K63 ubiquitination degradation in TNBC by interacting with NEDD4. As expected, the inhibitory effect of TCEB2 silencing on the ability of TNBC cells to induce M2 macrophage polarization was reversed by Slit2 knockdown. Finally, TCEB2 knockdown inhibited TNBC tumor growth and TNBC-induced M2 macrophage polarization in vivo.
CONCLUSION: TCEB2 upregulation promoted TNBC-induced M2 macrophage polarization to accelerate TNBC development by mediating Slit2 K63-ubiquitination degradation through interacting with NEDD4.
METHODS: The expression of gene or protein was tested by qRT-PCR, western blot, and IHC. CCK8, colony formation, wound healing, and Transwell assays were used to evaluate TNBC cell malignant behaviors, including cell viability, proliferation, migration, and invasion. The secretion levels of cytokines were detected by ELISA. Ubiquitin-based IP assays were used to detect Slit2 ubiquitination. The combined relation between TCEB2, Slit2, and NEDD4 was investigated using Co-IP assay.
RESULTS: Our results demonstrated that M2 macrophage polarization was activated in TNBC, which might be related to TCEB2 upregulation. TCEB2 knockdown reduced TNBC cell growth, migration, invasion, and their ability to induce M2 macrophage polarization. Mechanistically, TCEB2 mediated Slit2 K63 ubiquitination degradation in TNBC by interacting with NEDD4. As expected, the inhibitory effect of TCEB2 silencing on the ability of TNBC cells to induce M2 macrophage polarization was reversed by Slit2 knockdown. Finally, TCEB2 knockdown inhibited TNBC tumor growth and TNBC-induced M2 macrophage polarization in vivo.
CONCLUSION: TCEB2 upregulation promoted TNBC-induced M2 macrophage polarization to accelerate TNBC development by mediating Slit2 K63-ubiquitination degradation through interacting with NEDD4.