MTHFD2 overexpression predicts poor prognosis in renal cell carcinoma and is associated with cell proliferation and vimentin-modulated migration and invasion
Open accessAbstract
BACKGROUND/AIMS: To investigate the role of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in the clinical prognosis and cell biology of renal cell carcinoma (RCC). METHODS: A total of 137 RCC tissues were evaluated by immunohistochemistry. The relationship between MTHFD2 overexpression and clinical parameters and vimentin expression was assessed. Kaplan-Meier curves and the log-rank test were applied for survival analysis according to MTHFD2 and vimentin expression in RCC tissues. The expression of MTHFD2 mRNA and protein was examined by quantitative reverse transcription PCR and western blotting, respectively. To determine further the biological activity of MTHFD2 in RCC, 786-O cells were transfected with short hairpin RNA specifically targeting MTHFD2 (shMTHFD2) with or without tumor necrosis factor (TNF)-α stimulation. Cell proliferation, cell migration and invasion and drug sensitivity were subsequently assessed using Cell Counting Kit-8, wound healing, and Transwell assays. RESULTS: Immunohistochemical analysis demonstrated that both MTHFD2 and vimentin overexpression was positively associated with clinical staging, pathological grade, and poor overall survival (all P < 0.05). MTHFD2 expression was closely correlated with vimentin overexpression in RCC (r = 0.402, P < 0.001). After knocking down MTHFD2 expression in 786-O cells, decreased cell proliferation, migration, and invasion were observed and accompanied by the reduced expression of vimentin. The effects of MTHFD2 down-regulation could be partially restrained by TNF-α treatment. Vimentin expression and cell migration and invasion, but not cell proliferation, were reversed by TNF-α stimulation. Furthermore, treatment of 786-O cells with shMTHFD2 increased their sensitivity to chemotherapy drugs. CONCLUSION: The current results demonstrated that MTHFD2 was overexpressed in RCC and associated with poor clinical characteristics, vimentin expression, and cellular features connected to malignant disease, thus, implicating MTHFD2 as a potential target for RCC therapy.
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The paper's TCGA pan-disease survival analysis corroborated previous findings for pancreatic adenocarcinoma (PAAD), kidney renal clear cell carcinoma (KIRC), and kidney renal papillary cell carcinoma (KIRP).
“Our analysis corroborated previous findings with pancreatic (pancreatic adenocarcinoma, PAAD), kidney renal clear cell carcinoma (KIRC), and kidney renal papillary cell carcinoma (KIRP) malignancies.214,215”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [215]
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- Authors
- Lin, H., Huang, B., Wang, H., Liu, X., Hong, Y., Qiu, S., & Zheng, J.
- Affiliations
- Shantou University (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Second Affiliated Hospital of Shantou University Medical College (CN)
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2018
- Volume
- 51
- Issue
- 2
- Pages
- 991-1000
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2900667726
- Cited by
- 73
- References
- 0
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 7 · 2022: 11 · 2021: 14 · 2020: 11 · 2019: 8
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Guangdong Medical Research Foundation
- Shantou Science and Technology Project
- Sun Yat-sen University Cancer Center
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- MTHFD2, renal cell carcinoma, vimentin, prognostic factors, cell proliferation, cell migration, cell invasion, TNF-α, chemosensitivity, 786-O cells, gene knockdown
- MeSH terms
- Aged, Aminohydrolases, Antineoplastic Agents, Carcinoma, Renal Cell, Cell Movement, Female, Humans, Kidney Neoplasms, Male, Methylenetetrahydrofolate Dehydrogenase (NADP), Middle Aged, Prognosis, Tumor Necrosis Factor-alpha, Vimentin, Down-Regulation, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Kaplan-Meier Estimate, Neoplasm Grading, Multifunctional Enzymes
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