Non‐metabolic function of MTHFD2 activates CDK2 in bladder cancer

Liu, Xi; Liu, Shuangjie; Piao, Chiyuan; Zhang, Zhe; Zhang, Xiaolin; Jiang, Yufei; Kong, Chuize

doi:10.1111/cas.15159

Cited by 18 publications

(19 citation statements)

References 30 publications

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“…Meanwhile, MTHFD2 could accelerate tumorigenesis and metastasis via the AKT/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway in lung adenocarcinoma [ 19 ] and via the STAT3 signaling pathway in ovarian cancer [ 20 ]. Recently, MTHFD2 was found to affect bladder cancer cell growth by activating CDK2 [ 21 ]. All these observations indicated that MTHFD2 is tightly associated with the tumorigenesis of various cancer types.…”

Section: Introductionmentioning

confidence: 99%

MTHFD2 is a potential oncogene for its strong association with poor prognosis and high level of immune infiltrates in urothelial carcinomas of bladder

et al. 2022

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Background The bifunctional methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase (MTHFD2) has been reported to play an oncogenic role in various types of cancers. However, the function of MTHFD2 in urothelial carcinomas of bladder (UCB) and its association with tumor immune infiltration remains unknown. We aim to examine the suitability of MTHFD2 to be a novel biomarker of bladder cancer and whether MTHFD2 is linked to immune infiltration. Methods RNA sequencing data and clinical information (bladder cancer samples: normal samples = 414: 19) were downloaded from The Cancer Genome Atlas official website. Western blot analysis was performed to detect MTHFD2 expression in human bladder cancer (BLCA) cells and normal urothelial cell line SV-HUC-1. Associations between MTHFD2 expression and clinicopathological features were analyzed using Mann Whitney U test or Kruskal-Wallis H test. The “survival” and “survminer” packages were utilized to plot Kaplan-Meier survival curves. Moreover, the gene set enrichment analysis (GSEA) was conducted using a clusterProfiler package. The correlation of MTHFD2 expression with immune infiltration level was estimated using the single sample GSEA (ssGSEA) algorithm. Furthermore, associations between MTHFD2 and immune checkpoint genes were evaluated using the correlation analysis. Results Transcriptome analysis manifested that MTHFD2 was highly expressed in UCB tissues than normal bladder tissues, which was further confirmed by western blot analysis in human BLCA cells and SV-HUC-1 cells. Moreover, MTHFD2 high expression was significantly associated with the advanced disease progression. Also, the high expression of MTHFD2 was correlated with poor prognosis, and MTHFD2 was considered as an independent prognostic factor for disease specific survival. Furthermore, a number of cancer-related pathways were enriched in MTHFD2 high group, including NF-κB activation, JAK/STAT, and cancer immunotherapy by PD1 blockade. Several immune checkpoint molecules were also strongly associated with MTHFD2 expression, including PDCD1, CD274, CTLA4, CD276, LAG3, HAVCR2, and TIGIT. Conclusions MTHFD2 expression was remarkably elevated in UCB, suggesting that MTHFD2 could be a promising biomarker for BLCA as well as novel target for anti-cancer immunotherapy since its close association with immune infiltration.

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Section: Introductionmentioning

confidence: 99%

MTHFD2 is a potential oncogene for its strong association with poor prognosis and high level of immune infiltrates in urothelial carcinomas of bladder

et al. 2022

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“…MTHFD2 is also a metabolic checkpoint linking purine metabolism to autoimmune responses ( Sugiura et al, 2022 ). It is highly expressed in various cancers, playing a role in metabolic remodeling and regulating of the cell cycle in the mitochondria and nucleus, respectively ( Lee et al, 2021b ; Liu et al, 2021 ; Yao et al, 2021 ; Ren et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

et al. 2022

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Renal cell carcinoma (RCC) is the most common type of renal cancer, characterized by the dysregulation of metabolic pathways. RCC is the second highest cause of death among patients with urologic cancers and those with cancer cell metastases have a 5-years survival rate of only 10–15%. Thus, reliable prognostic biomarkers are essential tools to predict RCC patient outcomes. This study identified differentially expressed genes (DEGs) in the gene expression omnibus (GEO) database that are associated with pre-and post-metastases in clear cell renal cell carcinoma (ccRCC) patients and intersected these with metabolism-related genes in the Kyoto encyclopedia of genes and genomes (KEGG) database to identify metabolism-related DEGs (DEMGs). GOplot and ggplot packages for gene ontology (GO) and KEGG pathway enrichment analysis of DEMGs with log (foldchange) (logFC) were used to identify metabolic pathways associated with DEMG. Upregulated risk genes and downregulated protective genes among the DEMGs and seven independent metabolic genes, RRM2, MTHFD2, AGXT2, ALDH6A1, GLDC, HOGA1, and ETNK2, were found using univariate and multivariate Cox regression analysis, intersection, and Lasso-Cox regression analysis to establish a metabolic risk score signature (MRSS). Kaplan-Meier survival curve of Overall Survival (OS) showed that the low-risk group had a significantly better prognosis than the high-risk group in both the training cohort (p < 0.001; HR = 2.73, 95% CI = 1.97–3.79) and the validation cohort (p = 0.001; HR = 2.84, 95% CI = 1.50–5.38). The nomogram combined with multiple clinical information and MRSS was more effective at predicting patient outcomes than a single independent prognostic factor. The impact of metabolism on ccRCC was also assessed, and seven metabolism-related genes were established and validated as biomarkers to predict patient outcomes effectively.

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“…These observations have been associated with advanced tumor stage and grade [ 105 ]. In breast cancer, up-regulation of MTHFD2, which contributes in the cell cycle through binding to CDK2, has been associated with shorter OS, tumor grade and stage [ 107 ]. Other studies have shown up-regulation of a number of CDK2-interactiong circRNAs such as hsa_circ_0000520 [ 128 ], circ_0084927 [ 129 ] and circZFR [ 130 ] in cervical cancer patients.…”

Section: Cyclin-dependent Kinase 2 (Cdk2)mentioning

confidence: 99%

A review on the role of cyclin dependent kinases in cancers

et al. 2022

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The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.

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Non‐metabolic function of MTHFD2 activates CDK2 in bladder cancer

Cited by 18 publications

References 30 publications

MTHFD2 is a potential oncogene for its strong association with poor prognosis and high level of immune infiltrates in urothelial carcinomas of bladder

MTHFD2 is a potential oncogene for its strong association with poor prognosis and high level of immune infiltrates in urothelial carcinomas of bladder

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

A review on the role of cyclin dependent kinases in cancers

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