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METTL3 recruiting M2-type immunosuppressed macrophages by targeting m6A-SNAIL-CXCL2 axis to promote colorectal cancer pulmonary metastasis

Authors :
Peng Ouyang
Kang Li
Wei Xu
Caiyun Chen
Yangdong Shi
Yao Tian
Jin Gong
Zhen Bao
Source :
Journal of Experimental & Clinical Cancer Research, Vol 43, Iss 1, Pp 1-14 (2024)
Publication Year :
2024
Publisher :
BMC, 2024.

Abstract

Abstract Background The regulatory role of N6-methyladenosine (m6A) modification in the onset and progression of cancer has garnered increasing attention in recent years. However, the specific role of m6A modification in pulmonary metastasis of colorectal cancer remains unclear. Methods This study identified differential m6A gene expression between primary colorectal cancer and its pulmonary metastases using transcriptome sequencing and immunohistochemistry. We investigated the biological function of METTL3 gene both in vitro and in vivo using assays such as CCK-8, colony formation, wound healing, EDU, transwell, and apoptosis, along with a BALB/c nude mouse model. The regulatory mechanisms of METTL3 in colorectal cancer pulmonary metastasis were studied using methods like methylated RNA immunoprecipitation quantitative reverse transcription PCR, RNA stability analysis, luciferase reporter gene assay, Enzyme-Linked Immunosorbent Assay, and quantitative reverse transcription PCR. Results The study revealed high expression of METTL3 and YTHDF1 in the tumors of patients with pulmonary metastasis of colorectal cancer. METTL3 promotes epithelial-mesenchymal transition in colorectal cancer by m6A modification of SNAIL mRNA, where SNAIL enhances the secretion of CXCL2 through the NF-κB pathway. Additionally, colorectal cancer cells expressing METTL3 recruit M2-type macrophages by secreting CXCL2. Conclusion METTL3 facilitates pulmonary metastasis of colorectal cancer by targeting the m6A-Snail-CXCL2 axis to recruit M2-type immunosuppressive macrophages. This finding offers new research directions and potential therapeutic targets for colorectal cancer treatment.

Details

Language :
English
ISSN :
17569966
Volume :
43
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Journal of Experimental & Clinical Cancer Research
Publication Type :
Academic Journal
Accession number :
edsdoj.7de7ad2a90b84c349d2390c3db3851a0
Document Type :
article
Full Text :
https://doi.org/10.1186/s13046-024-03035-6