Related Experiment Video
Updated: Jul 6, 2025
Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis
Published on: November 28, 2015
Glycolysis Induced by METTL14 Is Essential for Macrophage Phagocytosis and Phenotype in Cervical Cancer
Bingyu Wang1, Zhonghao Mao1, Jinwen Ye1
1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
Abstract:
N 6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and it plays a vital role in various biological processes. However, the roles of m6A on cervical cancer tumorigenesis, especially macrophages infiltrated in the tumor microenvironment of cervical cancer, are still unclear. We analyzed the abnormal m6A methylation in cervical cancer, using CaSki and THP-1 cell lines, that might influence macrophage polarization and/or function in the tumor microenvironment. In addition, C57BL/6J and BALB/c nude mice were used for validation in vivo. In this study, m6A methylated RNA immunoprecipitation sequencing analysis revealed the m6A profiles in cervical cancer. Then, we discovered that the high expression of METTL14 (methyltransferase 14, N6-adenosine-methyltransferase subunit) in cervical cancer tissues can promote the proportion of programmed cell death protein 1 (PD-1)-positive tumor-associated macrophages, which have an obstacle to devour tumor cells. Functionally, changes of METTL14 in cervical cancer inhibit the recognition and phagocytosis of macrophages to tumor cells. Mechanistically, the abnormality of METTL14 could target the glycolysis of tumors in vivo and vitro. Moreover, lactate acid produced by tumor glycolysis has an important role in the PD-1 expression of tumor-associated macrophages as a proinflammatory and immunosuppressive mediator. In this study, we revealed the effect of glycolysis regulated by METTL14 on the expression of PD-1 and phagocytosis of macrophages, which showed that METTL14 was a potential therapeutic target for treating advanced human cancers.
Insights
N 6-methyladenosine (m6A) modification and METTL14 expression in cervical cancer impact tumor-associated macrophages. METTL14 abnormality impairs macrophage phagocytosis by targeting tumor glycolysis, suggesting METTL14 as a potential cancer therapy target.
Area of Science:
- Epigenetics and Cancer Biology
- Immunology and Tumor Microenvironment
Background:
- N 6-methyladenosine (m6A) is a crucial mRNA modification in mammalian biology.
- The role of m6A in cervical cancer, particularly its influence on tumor-infiltrating macrophages, remains largely unexplored.
Purpose of the Study:
- To investigate the aberrant m6A methylation patterns in cervical cancer.
- To elucidate the functional impact of METTL14 on macrophage polarization and phagocytosis within the cervical cancer tumor microenvironment.
- To explore the underlying molecular mechanisms linking METTL14, tumor glycolysis, and macrophage immunosuppression.
Main Methods:
- Analysis of m6A profiles using m6A-RNA immunoprecipitation sequencing in cervical cancer cell lines (CaSki, THP-1) and mouse models (C57BL/6J, BALB/c nude).
- Assessment of METTL14 expression and its correlation with PD-1 positive tumor-associated macrophages.
- In vitro and in vivo studies to evaluate the effect of METTL14 on macrophage recognition and phagocytosis of tumor cells.
- Investigation of the role of tumor glycolysis and lactate acid in regulating macrophage PD-1 expression.
Main Results:
- High METTL14 expression in cervical cancer promotes PD-1 positive tumor-associated macrophages, hindering tumor cell phagocytosis.
- METTL14 abnormality inhibits macrophage recognition and phagocytosis of cervical cancer cells.
- METTL14 dysregulation targets tumor glycolysis, leading to increased lactate acid production.
- Lactate acid mediates PD-1 expression on tumor-associated macrophages, contributing to immunosuppression.
Conclusions:
- METTL14 plays a significant role in cervical cancer progression by modulating macrophage function via glycolysis.
- Targeting METTL14 and its downstream effects on tumor glycolysis and macrophage PD-1 expression presents a promising therapeutic strategy for advanced cervical cancer.
Related Concept Videos
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:17Phagocytosis of Apoptotic Cells
Normal cells contain receptors that prevent them from being recognized...