Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Expression, Prognostic Value, and Immune Infiltration of MTHFD Family in Bladder Cancer

Author(s): Bai Shu Zheng, Shun De Wang, Jun Yong Zhang and Cheng Guo Ge*

Volume 24, Issue 2, 2024

Published on: 28 August, 2023

Page: [178 - 191] Pages: 14

DOI: 10.2174/1568009623666230804152603

Price: $65

Abstract

Background: The Methylenetetrahydrofolate Dehydrogenase (MTHFD) family plays an important role in the development and prognosis of a variety of tumors; however, the role of the MTHFD family in bladder cancer is unclear.

Methods: R software, cBioPortal, GeneMANIA, and online sites such as String-LinkedOmics were used for bioinformatics analysis.

Results: MTHFD1/1L/2 was significantly upregulated in bladder cancer tissues compared with normal tissues, high expression of the MTHFD family was strongly associated with poorer clinical grading and staging, and bladder cancer patients with upregulated expression of MTHFD1L/2 had a significantly worse prognosis. Gene function and PPI network analysis revealed that the MTHFD family and related genes play synergistic roles in the development of bladder cancer. 800 co-expressed genes related to the MTHFD family were used for functional enrichment analysis, and the results showed that many genes were associated with various oncogenic pathways such as cell cycle and DNA replication. More importantly, the MTHFD family was closely associated with multiple infiltrating immune lymphocytes, including Treg cells, and immune molecules such as TNFSF9, CD274, and PDCD1.

Conclusion: Our study shows that MTHFD family genes may be potential prognostic markers and therapeutic targets for patients with bladder cancer.

« Previous Next »
Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[2]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Grayson, M. Bladder cancer. Nature, 2017, 551(7679), S33.
[http://dx.doi.org/10.1038/551S33a] [PMID: 29117156]
[4]
Vasekar, M.; Degraff, D.; Joshi, M. Immunotherapy in bladder cancer. Curr. Mol. Pharmacol., 2016, 9(3), 242-251.
[http://dx.doi.org/10.2174/1874467208666150716120945] [PMID: 26177642]
[5]
Lenis, A.T.; Lec, P.M.; Chamie, K.; Mshs, M. Bladder Cancer. JAMA, 2020, 324(19), 1980-1991.
[http://dx.doi.org/10.1001/jama.2020.17598] [PMID: 33201207]
[6]
Ducker, G.S.; Rabinowitz, J.D. One-carbon metabolism in health and disease. Cell Metab., 2017, 25(1), 27-42.
[http://dx.doi.org/10.1016/j.cmet.2016.08.009] [PMID: 27641100]
[7]
Pietzke, M.; Meiser, J.; Vazquez, A. Formate metabolism in health and disease. Mol. Metab., 2020, 33, 23-37.
[http://dx.doi.org/10.1016/j.molmet.2019.05.012] [PMID: 31402327]
[8]
Li, A.M.; Ye, J. Reprogramming of serine, glycine and one-carbon metabolism in cancer. Biochim. Biophys. Acta Mol. Basis Dis., 2020, 1866(10), 165841.
[http://dx.doi.org/10.1016/j.bbadis.2020.165841] [PMID: 32439610]
[9]
Dekhne, A.S.; Hou, Z.; Gangjee, A.; Matherly, L.H. Therapeutic targeting of mitochondrial one-carbon metabolism in cancer. Mol. Cancer Ther., 2020, 19(11), 2245-2255.
[http://dx.doi.org/10.1158/1535-7163.MCT-20-0423] [PMID: 32879053]
[10]
Labuschagne, C.F.; van den Broek, N.J.F.; Mackay, G.M.; Vousden, K.H.; Maddocks, O.D.K. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep., 2014, 7(4), 1248-1258.
[http://dx.doi.org/10.1016/j.celrep.2014.04.045] [PMID: 24813884]
[11]
He, D.; Yu, Z.; Liu, S.; Dai, H.; Xu, Q.; Li, F. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) is underexpressed in clear cell renal cell carcinoma tissue and transfection and overexpression in caki-1 cells inhibits cell proliferation and increases apoptosis. Med. Sci. Monit., 2018, 24, 8391-8400.
[http://dx.doi.org/10.12659/MSM.911124] [PMID: 30459299]
[12]
Cui, L.; Zhao, X.; Jin, Z.; Wang, H.; Yang, S.F.; Hu, S. Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L-formate axis. J. Pineal Res., 2021, 71(4), e12767.
[http://dx.doi.org/10.1111/jpi.12767] [PMID: 34533844]
[13]
Chen, J.; Yang, J.; Xu, Q.; Wang, Z.; Wu, J.; Pan, L.; Huang, K.; Wang, C. Integrated bioinformatics analysis identified MTHFD1L as a potential biomarker and correlated with immune infiltrates in hepatocellular carcinoma. Biosci. Rep., 2021, 41(2), BSR20202063.
[http://dx.doi.org/10.1042/BSR20202063] [PMID: 33605411]
[14]
Yang, Y.S.; Yuan, Y.; Hu, W.P.; Shang, Q.X.; Chen, L.Q. The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma. Scand. J. Gastroenterol., 2018, 53(5), 533-540.
[http://dx.doi.org/10.1080/00365521.2017.1407440] [PMID: 29171320]
[15]
Agarwal, S.; Behring, M.; Hale, K.; Al Diffalha, S.; Wang, K.; Manne, U.; Varambally, S. MTHFD1L, a folate cycle enzyme, is involved in progression of colorectal cancer. Transl. Oncol., 2019, 12(11), 1461-1467.
[http://dx.doi.org/10.1016/j.tranon.2019.07.011] [PMID: 31421459]
[16]
Shi, L.; Zhang, Q.; Shou, X.; Niu, H. Expression and prognostic value identification of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in brain low-grade glioma. Int. J. Gen. Med., 2021, 14, 4517-4527.
[http://dx.doi.org/10.2147/IJGM.S323858] [PMID: 34421310]
[17]
Huang, J.; Qin, Y.; Lin, C.; Huang, X.; Zhang, F. MTHFD2 facilitates breast cancer cell proliferation via the AKT signaling pathway. Exp. Ther. Med., 2021, 22(1), 703.
[http://dx.doi.org/10.3892/etm.2021.10135] [PMID: 34007312]
[18]
Shi, Y.; Xu, Y.; Yao, J.; Yan, C.; Su, H.; Zhang, X.; Chen, E.; Ying, K. MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK-3β/β-catenin signalling. J. Cell. Mol. Med., 2021, 25(14), 7013-7027.
[http://dx.doi.org/10.1111/jcmm.16715] [PMID: 34121323]
[19]
Cerami, E.; Gao, J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, B.A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; Antipin, Y.; Reva, B.; Goldberg, A.P.; Sander, C.; Schultz, N. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov., 2012, 2(5), 401-404.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0095] [PMID: 22588877]
[20]
Warde-Farley, D. The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res., 2010, 38(Web Server issue), W214-20.
[http://dx.doi.org/10.1093/nar/gkq537]
[21]
Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res., 2021, 49(D1), D605-D612.
[22]
Vasaikar, S.V.; Straub, P.; Wang, J.; Zhang, B. LinkedOmics: Analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res., 2018, 46(D1), D956-D963.
[http://dx.doi.org/10.1093/nar/gkx1090] [PMID: 29136207]
[23]
Ru, B.; Wong, C.N.; Tong, Y.; Zhong, J.Y.; Zhong, S.S.W.; Wu, W.C.; Chu, K.C.; Wong, C.Y.; Lau, C.Y.; Chen, I.; Chan, N.W.; Zhang, J. TISIDB: An integrated repository portal for tumor–immune system interactions. Bioinformatics, 2019, 35(20), 4200-4202.
[http://dx.doi.org/10.1093/bioinformatics/btz210] [PMID: 30903160]
[24]
Kan, J.; Moran, R.G. Intronic polyadenylation in the human glycinamide ribonucleotide formyltransferase gene. Nucleic Acids Res., 1997, 25(15), 3118-3123.
[http://dx.doi.org/10.1093/nar/25.15.3118] [PMID: 9224613]
[25]
Kawamura, T.; Takehora, Y.; Hori, N.; Takakura, Y.; Yamaguchi, N.; Takano, H.; Yamaguchi, N. VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression. J. Cell. Biochem., 2022, 123(6), 1064-1076.
[http://dx.doi.org/10.1002/jcb.30251] [PMID: 35434822]
[26]
Skrajnowska, D.; Bobrowska-Korczak, B. Role of zinc in immune system and anti-cancer defense mechanisms. Nutrients, 2019, 11(10), 2273.
[http://dx.doi.org/10.3390/nu11102273] [PMID: 31546724]
[27]
Parkin, J.; Cohen, B. An overview of the immune system. Lancet, 2001, 357(9270), 1777-1789.
[http://dx.doi.org/10.1016/S0140-6736(00)04904-7] [PMID: 11403834]
[28]
Wang, W.; Gu, W.; Tang, H.; Mai, Z.; Xiao, H.; Zhao, J.; Han, J. The emerging role of MTHFD family genes in regulating the tumor immunity of oral squamous cell carcinoma. J. Oncol., 2022, 2022, 1-18.
[http://dx.doi.org/10.1155/2022/4867730] [PMID: 35693982]
[29]
Yu, H.; Wang, H.; Xu, H.R.; Zhang, Y.C.; Yu, X.B.; Wu, M.C.; Jin, G.Z.; Cong, W.M. Overexpression of MTHFD1 in hepatocellular carcinoma predicts poorer survival and recurrence. Future Oncol., 2019, 15(15), 1771-1780.
[http://dx.doi.org/10.2217/fon-2018-0606] [PMID: 30997850]
[30]
Li, H.; Fu, X.; Yao, F.; Tian, T.; Wang, C.; Yang, A. MTHFD1L-mediated redox homeostasis promotes tumor progression in tongue squamous cell carcinoma. Front. Oncol., 2019, 9, 1278.
[http://dx.doi.org/10.3389/fonc.2019.01278] [PMID: 31867267]
[31]
Li, G. p53 deficiency induces MTHFD2 transcription to promote cell proliferat ion and restrain DNA damage. Proc. Natl. Acad. Sci., 118(28), e2019822118.
[32]
Shang, M. The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation. Nat Commun., 2011, 12(1), 1940.
[33]
Nishimura, T.; Nakata, A.; Chen, X.; Nishi, K.; Meguro-Horike, M.; Sasaki, S.; Kita, K.; Horike, S.; Saitoh, K.; Kato, K.; Igarashi, K.; Murayama, T.; Kohno, S.; Takahashi, C.; Mukaida, N.; Yano, S.; Soga, T.; Tojo, A.; Gotoh, N. Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2. Oncogene, 2019, 38(14), 2464-2481.
[http://dx.doi.org/10.1038/s41388-018-0589-1] [PMID: 30532069]
[34]
Li, Q.; Yang, F.; Shi, X.; Bian, S.; Shen, F.; Wu, Y.; Zhu, C.; Fu, F.; Wang, J.; Zhou, J.; Chen, Y. MTHFD2 promotes ovarian cancer growth and metastasis via activation of the STAT3 signaling pathway. FEBS Open Bio, 2021, 11(10), 2845-2857.
[http://dx.doi.org/10.1002/2211-5463.13249] [PMID: 34231329]
[35]
Zeng, Y.; Zhang, J.; Xu, M.; Chen, F.; Zi, R.; Yue, J.; Zhang, Y.; Chen, N.; Chin, Y.E. Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis. J. Cancer, 2021, 12(19), 5888-5894.
[http://dx.doi.org/10.7150/jca.60170] [PMID: 34476002]
[36]
Zhang, P.; Yang, Q. Overexpression of SHMT2 predicts a poor prognosis and promotes tumor cell growth in bladder cancer. Front. Genet., 2021, 12, 682856.
[http://dx.doi.org/10.3389/fgene.2021.682856] [PMID: 34149818]
[37]
Hinshaw, D.C.; Shevde, L.A. The tumor microenvironment innately modulates cancer progression. Cancer Res., 2019, 79(18), 4557-4566.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3962] [PMID: 31350295]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy