Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer
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Background Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial bifunctional enzyme encoded in the nucleus. It plays a significant role in the regulation of glucose, nucleic acid, and folate metabolism, and maintains redox balance in the cells. The present study aimed at elucidating the potential function and mechanisms of MTHFD2 and explored the correlation between ferroptosis and MTHFD2 in triple-negative breast cancer. Methods MTHFD2 expression, survival analysis, and clinical correlation were performed using data from various online databases including TCGA, GEO, HPA, GTEX, Kaplan–Meier Plotter, PrognoScan, and UALCAN databases. Genomic alterations and CNV analysis were performed using the cBioPortal and GSCA databases. Potential functions and mechanisms were explored by enrichment analysis. The tumor microenvironment was identified by the TIMER database. In vitro, RT-qPCR and western blot assays were utilized to identify the MTHFD2 expression and the knockdown effects in breast cancer. CCK8, cell wound healing, transwell, and flow cytometry assays were used to identify the potential function of MTHFD2 in TNBC cells. MDA, GSH detection, and flow cytometry assays were performed to identify ferroptosis. Western blot assays were performed to measure the protein expression of all target genes. Results MTHFD2 expression levels were up-regulated in the majority of cancers and particularly in TNBC, in which higher expression levels indicated a poorer prognosis. Enrichment analyses showed that MTHFD2 is involved in various tumor-related biological processes. MTHFD2 expression was found to strongly correlate with multiple immune cell infiltration. In vitro, the knockdown of MTHFD2 suppresses the proliferation, apoptosis, migration, and invasion in TNBC cells. In addition, the MTHFD2 knockdown significantly enhanced intracellular ROS and lipid peroxidation and decreased intracellular GSH. The expressions of SLC7A11, GPX4, and NRF2 were down-regulated by the MTHFD2 knockdown. Conclusion MTHFD2 could be a crucial molecular biomarker for predicting patient prognosis and a novel therapeutic target in TNBC. In addition, MTHFD2 is a potential ferroptosis regulatory gene in TNBC.
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High expression of genes coding for these enzymes and their transcriptional regulators is strongly associated with shortened patient survival in different types of malignancies.
“The high expression of genes coding for all of these enzymes and their transcriptional regulators is strongly associated with a shortened patient survival in different types of malignancies [66,67,68,69,70,71,72,73,74].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [67]
The up-regulation of glycolysis and one-carbon metabolism, and increased expression of corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.
“The up-regulation of glycolysis and one-carbon metabolism, and the increased expression of genes coding for corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [67]
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- Authors
- Zhang, H., Zhu, S., Zhou, H., Li, R., Xia, X., & Xiong, H.
- Affiliations
- Tongji Hospital (CN)
- Corresponding author
- Xiong, Huihua
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2023-01-16
- Volume
- 13
- Pages
- 1098357-1098357
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC9885267
- OpenAlex
- W4316466479
- Cited by
- 46
- References
- 54
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 16 · 2023: 6
- FWCI
- 8.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Chinese Society of Clinical Oncology
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- MTHFD2, triple-negative breast cancer, ferroptosis, prognostic factors, tumor immune cell infiltration, reactive oxygen species, lipid peroxidation, glutathione, SLC7A11, GPX4, Nrf2, folate metabolism, cell proliferation and invasion
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