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KLHL1 suppresses triple-negative breast cancer progression by promoting M1 macrophage polarization via APOC2
Ziran He1, Zhenhua Zhang2, Li Ding1
1Department of Breast and Thyroid Surgery, Hunan University of Medicine General Hospital, Huaihua, 418000, Hunan, China.
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by an immunosuppressive tumor microenvironment and resistance to chemotherapy. Previous studies have indicated that apolipoprotein C-II (APOC2) is involved in the immune microenvironment of several malignancies and is upregulated in breast cancer; however, the molecular mechanisms through which APOC2 regulates the immune microenvironment in TNBC remain poorly understood. In the present study, we found that APOC2 was upregulated in TNBC tissues and was negatively correlated with M1 macrophage infiltration. APOC2 overexpression in 4 T1 cells promoted tumor progression by enhancing cell proliferation, migration, and invasion, while suppressing M1 macrophage polarization. In addition, KLHL1, a substrate adaptor for the Cullin3-RING E3 ubiquitin ligase complex, was found to interact with APOC2, and KLHL1 overexpression reversed the biological effects induced by APOC2. Mechanistically, KLHL1 promoted APOC2 protein degradation through the ubiquitin-proteasome pathway, thereby enhancing M1 macrophage polarization and suppressing the malignant behavior of tumor cells. Finally, in vivo xenograft experiments demonstrated that APOC2 reduced M1 macrophage polarization and increased tumor weight and volume, whereas KLHL1 overexpression counteracted the oncogenic effects of APOC2. Collectively, these findings reveal that activation of the KLHL1/APOC2 axis enhances M1 macrophage polarization and inhibits TNBC progression, providing novel insights into the immune regulatory mechanisms underlying TNBC development.
Insights
The KLHL1/APOC2 pathway regulates the immune microenvironment in triple-negative breast cancer (TNBC). Activating this axis enhances M1 macrophage polarization, inhibiting TNBC progression and tumor growth.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive, with an immunosuppressive tumor microenvironment and chemotherapy resistance.
- Apolipoprotein C-II (APOC2) is implicated in malignancy immune microenvironments and upregulated in breast cancer.
- The specific roles of APOC2 in TNBC's immune microenvironment are not fully understood.
Purpose of the Study:
- Investigate the molecular mechanisms of APOC2 in regulating the TNBC immune microenvironment.
- Determine the relationship between APOC2, macrophage infiltration, and TNBC progression.
- Identify potential therapeutic targets within the APOC2 regulatory pathway.
Main Methods:
- Analysis of APOC2 expression in TNBC tissues and correlation with M1 macrophage infiltration.
- In vitro studies using 4T1 cells to assess the effects of APOC2 overexpression on tumor cell behavior and macrophage polarization.
- Investigation of the interaction between APOC2 and KLHL1 (Cullin3-RING E3 ubiquitin ligase substrate adaptor).
- Ubiquitin-proteasome pathway analysis to elucidate APOC2 degradation mechanism.
- In vivo xenograft experiments to evaluate the impact of APOC2 and KLHL1 on tumor growth and M1 macrophage polarization.
Main Results:
- APOC2 was upregulated in TNBC tissues and negatively correlated with M1 macrophage infiltration.
- APOC2 overexpression promoted proliferation, migration, and invasion of 4T1 cells while suppressing M1 macrophage polarization.
- KLHL1 interacted with APOC2 and promoted its degradation via the ubiquitin-proteasome pathway, reversing APOC2's effects.
- KLHL1 overexpression enhanced M1 macrophage polarization and suppressed tumor cell malignancy.
- In vivo, APOC2 reduced M1 macrophage polarization and increased tumor growth; KLHL1 counteracted these effects.
Conclusions:
- The KLHL1/APOC2 axis plays a critical role in regulating the immune microenvironment of TNBC.
- Activation of KLHL1 enhances M1 macrophage polarization by promoting APOC2 degradation, thereby inhibiting TNBC progression.
- Targeting the KLHL1/APOC2 pathway offers a potential therapeutic strategy for TNBC.
