KLF14 alleviated breast cancer invasion and M2 macrophages polarization through modulating SOCS3/RhoA/Rock/STAT3 signaling

Purpose: To study the functions and underlying network of KLF14 in breast cancer invasion and tumor-associated macrophages (TAMs).Methods: The expressions of gene or protein were assessed by qRT-PCR and western blot assays, respectively. Cell proliferation and invasion were investigated by colony formation, CCK-8 and transwell assays, respectively. Macrophage M2 polarization was identified by flow cytometry assay. The methylation level was tested by methylation Specific PCR (MSP). The molecular relationship between KLF14 and SOCS3 was validated by dual luciferase and ChIP assays. In vivo model was established to confirm effect of KLF14 on tumor growth and metastasis.Results: KLF14 was downregulated in breast cancer, and its level was modified by CpG-mediated methylation. Overexpression of KLF14 significantly inhibited the proliferation and invasion of breast cancer in vitro and in vivo. Moreover, KLF14-overexpressing breast cancer cells notably reduced M2 macrophages polarization and it related promoting factor of tumor microenvironment (EGF, TGF beta, MMP9 and VEGF). Mechanistically, KLF14 could positively activate SOCS3 transcription, then blocking the activation of RhoA/Rock/STAT3 signaling. Further rescue experiments identified that either SOCS3 silencing and activation of RhoA/Rock/STAT3 signaling dramatically restrained the regulatory roles of KLF14 overexpression in breast cancer invasion and M2 macro-phages polarization.Conclusion: Collectively, KLF14 suppressed breast cancer cell invasion and M2 macrophage polarization through modulating SOCS3/RhoA/Rock/STAT3 signaling, and these findings would provide a new potential target against breast cancer.

Automated summary

The study aimed to investigate the functions and underlying network of KLF14 in breast cancer invasion and tumor-associated macrophages. The results showed that KLF14 was downregulated in breast cancer and its overexpression inhibited breast cancer cell proliferation, invasion, and M2 macrophages polarization. Mechanistically, KLF14 modulated SOCS3/RhoA/Rock/STAT3 signaling pathway to suppress breast cancer progression.