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FBXW7 Inhibited M2 Macrophage Polarization in Endometrial Cancer by Reducing CCL2 Secretion Through Ubiquitination of

Jing Wu¹, Xiaomei Zhang¹, Wei Xu²

¹Obstetrics and Gynecology, Dongtai Traditional Chinese Medicine Hospital, No. 198, Yaju Road, High-Tech Zone, Dongtai, 224200, Jiangsu Province, P.R. China.

Biochemical Genetics

|January 4, 2026

Abstract:

Impeding M2 macrophage polarization has been suggested to slow the progression of endometrial cancer (EC). F-box and WD repeat domain containing 7 (FBXW7) reportedly regulates the polarization and migration of macrophages in a multitude of cancers. Our pre-existing bioinformatics predictions showed a negative association between FBXW7 and M2-TAM infiltration in EC. This study aimed to investigate the role of FBXW7 in M2 macrophage polarization in EC by regulating the MYBL2/CCL2 axis. Cancer and adjacent cancerous tissues from patients with EC were collected to detect the differential expression of each factor. CCL2 levels in the cell culture medium were examined using enzyme-linked immunosorbent assay. Immunofluorescence staining was performed to determine the localization of FBXW7 and MYBL2 in EC cells. The number of M2 macrophages marker was determined by flow cytometry. The protein levels of FBXW7, MYBL2, CCL2, CD206, CD163, Arg1, and IL-10 were assessed using western blotting. The ubiquitination level of MYBL2 and the binding relationship between FBXW7 and MYBL2 were verified using co-immunoprecipitation. The effect of FBXW7/MYBL2/CCL2 axis on the malignant progression of EC in vivo was evaluated using tumor xenografts in nude mice. FBXW7 levels were decreased, whereas MYBL2 levels were increased in EC. Overexpression of FBXW7 downregulated CCL2 secretion in EC and inhibited M2 macrophage polarization. FBXW7 promoted the degradation of MYBL2 in a ubiquitination-dependent manner. FBXW7 knockdown inhibited CCL2 secretion by EC cells to restrain M2 macrophage polarization, which was countered by MYBL2 downregulation. In vivo functional assays demonstrated that FBXW7 overexpression significantly suppressed EC xenograft growth and enhanced tumor cell apoptosis. FBXW7 enhanced the ubiquitination and degradation of MYBL2 to reduce CCL2 secretion from EC, which inhibited macrophage polarization to the M2 type.

Insights

Targeting M2 macrophage polarization is key for endometrial cancer (EC) treatment. This study reveals F-box and WD repeat domain containing 7 (FBXW7) suppresses EC by degrading MYBL2, reducing CCL2 and inhibiting M2 macrophage infiltration.

Area of Science:

Oncology
Immunology
Molecular Biology

Background:

M2 macrophage polarization promotes endometrial cancer (EC) progression.
F-box and WD repeat domain containing 7 (FBXW7) is implicated in macrophage regulation across cancers.
Bioinformatics data suggest FBXW7 negatively correlates with M2 tumor-associated macrophage (TAM) infiltration in EC.

Purpose of the Study:

To investigate the role of FBXW7 in M2 macrophage polarization within EC.
To elucidate the mechanism involving the MYBL2/CCL2 axis regulated by FBXW7.
To evaluate FBXW7's therapeutic potential in EC progression.

Main Methods:

Analysis of FBXW7, MYBL2, and CCL2 expression in EC tissues.
Enzyme-linked immunosorbent assay (ELISA) for CCL2 quantification.
Immunofluorescence, flow cytometry, and western blotting for protein analysis.
Co-immunoprecipitation to verify protein interactions and ubiquitination.
In vivo tumor xenograft models in nude mice.

Main Results:

FBXW7 expression was decreased, while MYBL2 expression was increased in EC tissues.
FBXW7 overexpression reduced CCL2 secretion and M2 macrophage polarization.
FBXW7 promoted MYBL2 ubiquitination and degradation, consequently decreasing CCL2.
FBXW7 overexpression suppressed tumor growth and increased apoptosis in vivo.

Conclusions:

FBXW7 acts as a tumor suppressor in EC by targeting the MYBL2/CCL2 axis.
FBXW7 enhances MYBL2 ubiquitination and degradation, reducing CCL2 secretion from EC cells.
This mechanism inhibits M2 macrophage polarization, offering a potential therapeutic strategy for EC.

Read full analysis

Keywords:

Endometrial cancer FBXW7 M2 macrophages MYBL2 Ubiquitination

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