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Updated: Mar 1, 2026
Author Spotlight: Establishing a Murine Non-Small Cell Lung Cancer Model for Developing Nanoformulations of Anticancer Drugs
Published on: May 10, 2024
MARCH1 attenuates lung adenocarcinoma by blocking macrophage M2 polarization and cisplatin resistance through
Huifeng Wang1, Yanyan Sun2, Rui Zi1
1The First Department of Oncology, Tumor Hospital, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, People's Republic of China.
Abstract:
Cisplatin (DDP) resistance constitutes a major obstacle associated with poor prognosis in patients with lung adenocarcinoma (LUAD). Membrane-associated RING-CH finger protein 1 (MARCH1) contributed to shaping an inflamed tumor microenvironment, which is linked to chemotherapy resistance in LUAD patients. However, its role and underlying mechanisms in DDP-resistant LUAD patients remains to be elucidated. Herein, we observed that MARCH1 was downregulated in DDP-resistant lung cancer tissues, and low MARCH1 expression was correlated with poor prognosis of LUAD patients. MARCH1 overexpression enhanced DDP sensitivity, suppressed proliferation and invasion, and promoted apoptosis in DDP/A549 cells. Co-culture experiments revealed that MARCH1 overexpression suppressed the polarization of tumor-associated macrophages toward the M2 phenotype, as validated by ELISA, flow cytometry, Western blotting, and immunofluorescence staining. MARCH1 contributed to shape the tumor immune microenvironment, affecting immunostimulators, MHC molecules, chemokines, and receptors. Moreover, co-immunoprecipitation and ubiquitination experiments confirmed that MARCH1 facilitated the ubiquitination and degradation of solute carrier family 25 member 17 (SLC25A17). Rescue experiments demonstrated that overexpression of SLC25A17 attenuated the enhancement of DDP sensitivity evoked by MARCH1 reintroduction through promoting M2 macrophage polarization. Additionally, the tumor-suppressive effect of MARCH1 in LUAD was confirmed in vivo. In conclusion, our findings indicated that MARCH1 suppressed lung cancer progression by blocking macrophage M2 polarization and DDP resistance through ubiquitinating SLC25A17, thus providing a new mechanism for cisplatin resistance in LUAD.
Insights
Membrane-associated RING-CH finger protein 1 (MARCH1) suppresses lung cancer progression and cisplatin resistance by blocking M2 macrophage polarization via SLC25A17 ubiquitination. This discovery offers a new therapeutic strategy for lung adenocarcinoma (LUAD).
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cisplatin (DDP) resistance is a major challenge in lung adenocarcinoma (LUAD) treatment, linked to an inflamed tumor microenvironment.
- Membrane-associated RING-CH finger protein 1 (MARCH1) influences the tumor microenvironment and chemotherapy resistance, but its specific role in DDP-resistant LUAD is unclear.
Purpose of the Study:
- To elucidate the role and underlying mechanisms of MARCH1 in DDP-resistant LUAD.
- To investigate MARCH1's impact on tumor-associated macrophage polarization and cisplatin sensitivity.
Main Methods:
- Analysis of MARCH1 expression in DDP-resistant LUAD tissues and correlation with prognosis.
- In vitro studies using DDP/A549 cells to assess MARCH1's effects on sensitivity, proliferation, invasion, and apoptosis.
- Co-culture experiments, ELISA, flow cytometry, Western blotting, immunofluorescence, co-immunoprecipitation, and ubiquitination assays to explore molecular mechanisms.
- In vivo tumor models to confirm MARCH1's therapeutic potential.
Main Results:
- MARCH1 was downregulated in DDP-resistant LUAD, with low expression correlating with poor prognosis.
- MARCH1 overexpression enhanced DDP sensitivity, suppressed cancer cell proliferation/invasion, and promoted apoptosis.
- MARCH1 suppressed M2 polarization of tumor-associated macrophages and modulated the tumor immune microenvironment.
- MARCH1 facilitated the ubiquitination and degradation of SLC25A17, a key factor in M2 polarization and DDP resistance.
Conclusions:
- MARCH1 suppresses lung cancer progression and DDP resistance by inhibiting M2 macrophage polarization through ubiquitinating SLC25A17.
- MARCH1 represents a potential therapeutic target for overcoming cisplatin resistance in LUAD.
- This study reveals a novel mechanism underlying DDP resistance in LUAD involving MARCH1 and macrophage polarization.
