MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion

Abstract

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.

The complexity of the serine glycine one-carbon pathway in cancer

“…Other enzymes of the SGOCP play a key role in tumorigenesis. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is consistently up-regulated in many cancer types, and its expression significantly correlates with poor clinical outcome in breast cancer, pancreatic carcinomas, renal cell carcinoma, and leukemia and in a particularly aggressive metabolic subtype of hepatocellular carcinoma (HCC; Bidkhori et al, 2018;Lehtinen et al, 2013;Lin et al, 2018;Liu et al, 2014;Nilsson et al, 2014;Noguchi et al, 2018;Reina-Campos et al, 2019;Tedeschi et al, 2015). MTHFD2 is a dual-action enzyme (dehydrogenase and cyclohydrolase) that catalyzes the reversible conversion of 5,10methylene-THF into 10-formyl-THF in the mitochondria, while MTHFD1, its cytosolic counterpart, catalyzes an extra reaction (synthetase) to convert 10-formyl-THF into THF and formate ( Fig.…”

MicroRNA‐33a‐5p suppresses colorectal cancer cell growth by inhibiting MTHFD2

“…MTHFD2 is frequently upregulated in cancer tissues, and the high expression of MTHFD2 is associated with tumour cell proliferation and with poor CRC survival . Thus, the expression patterns of MTHFD2 in CRC tissues were measured.…”

Up-regulated Expression of MTHFD2 Correlates with Favorable Prognosis in LGG Patients: A Bioinformatic Analysis

“…MTHFD2 was also significantly over-expressed in non-small cell lung cancer (NSCLC) tissues, and knockdown of MTHFD2 resulted in reduction of tumor cell growth and tumorigenicity [18]. In addition, MTHFD2 over-expression was associated with cell proliferation and vimentin-modulated migration and invasion in renal cell carcinoma (RCC) [19]. MTHFD2 expression was significantly associated with the clinical outcome of patients, and high expression of MTHFD2 resulted in poor prognosis in hepatocellular carcinoma [20], esophageal squamous cell carcinoma [21] and breast cancer [22].…”