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WNK4 restrains endometrial cancer progression by reprogramming macrophage polarization toward an M1-like phenotype
Jiarong He1, Tian Zhang1, Menglan Xiong1
1NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, No.53 Xiangchun Road, Changsha city, 410008, Hunan province, China.
Background:
Endometrial cancer lacks robust immune-linked biomarkers that can be translated into tractable therapeutic strategies. WNK4, a member of the with-no-lysine (WNK) kinase family, is involved in cancer-relevant signaling pathways; however, its immunological significance in endometrial cancer has yet to be defined.
Methods:
Immune deconvolution and gene-immune correlation analyses were performed to relate WNK4 to immune-cell-associated signatures. WNK4 expression was assessed in clinical endometrial cancer tissues and cell lines by immunoblotting. Macrophage polarization was modeled using phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages with interleukin-4 (IL-4) induction, followed by WNK4 overexpression. Polarization status was evaluated by marker expression and flow cytometry. Conditioned macrophage states were tested in Transwell co-culture with Ishikawa and HEC-1-A cells to assess viability, clonogenicity, migration/invasion, and apoptosis. To confirm the impact on tumor growth and macrophage-marker expression within tumors, we established a nude-mouse xenograft model.
Results:
WNK4 was reduced in endometrial cancer tissues and malignant endometrial cell lines. Correlation analyses linked WNK4 to immune-state features, including an inverse association with M2-like macrophage signatures. In THP-1-derived macrophages, WNK4 overexpression counteracted IL-4-driven M2-like polarization and shifted cells toward an M1-like profile. In co-culture, WNK4-modified macrophages suppressed proliferative and motile phenotypes of endometrial cancer cells and increased apoptotic signaling. In vivo, WNK4 overexpression inhibited xenograft growth and was accompanied by macrophage-marker changes consistent with reduced M2-like features.
Conclusions:
WNK4 acts as an immune-relevant suppressor in endometrial cancer, partly by limiting M2-like polarization and weakening macrophage-driven tumor support.
Insights
With-no-lysine kinase 4 (WNK4) acts as an immune suppressor in endometrial cancer by reducing M2-like macrophages, thereby inhibiting tumor growth and support. This finding offers potential new therapeutic strategies for endometrial cancer.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Endometrial cancer lacks effective immune biomarkers for targeted therapies.
- The immunological role of with-no-lysine kinase 4 (WNK4) in endometrial cancer remains undefined.
Purpose of the Study:
- To investigate the immunological significance of WNK4 in endometrial cancer.
- To determine WNK4's effect on immune cell signatures and macrophage polarization.
- To assess WNK4's impact on endometrial cancer cell behavior and tumor growth.
Main Methods:
- Immune deconvolution and gene-immune correlation analyses were performed.
- WNK4 expression was assessed in clinical tissues and cell lines.
- Macrophage polarization was modeled in vitro, and WNK4's effects were studied in co-culture and a nude-mouse xenograft model.
Main Results:
- WNK4 expression was reduced in endometrial cancer tissues and cell lines.
- WNK4 inversely correlated with M2-like macrophage signatures.
- WNK4 overexpression counteracted M2-like polarization, suppressed cancer cell proliferation and migration, and induced apoptosis, inhibiting tumor growth in vivo.
Conclusions:
- WNK4 functions as an immune-relevant suppressor in endometrial cancer.
- WNK4 limits M2-like macrophage polarization, thereby reducing tumor-promoting macrophage functions.
- WNK4 represents a potential therapeutic target for endometrial cancer treatment.