Research progress of thymidylate synthase gene in tumorigenesis and development

doi:10.3760/cma.j.cn441417-20241118-08007

Abstract

Abstract:

Protein encoded by the thymidylate synthase (TYMS) gene is a rate-limiting enzyme necessary for DNA synthesis and is an important enzyme for DNA damage repair, and plays an important role in a variety of physiological and pathological conditions. This article mainly reviews the expression and clinical significance of TYMS gene in various types of tumors, the effect and mechanism of TYMS gene on the malignant biological behaviors and the sensitivity to chemotherapeutic drugs of tumor cells, various factors regulating TYMS gene expression, and the anti-tumor application of TYMS gene targeting.

Key words:

Tumor, Thymidylate synthase, Tumorigenesis, Development, Mechanism, Progress

摘要：

胸苷酸合成酶（thymidylate synthase，TYMS）基因编码蛋白是DNA合成必需的限速酶，也是重要的DNA损伤修复酶，在多种生理病理情况下发挥重要作用。本文主要对TYMS基因在不同类型肿瘤中的表达和临床意义、对肿瘤细胞恶性生物学行为及化疗药物敏感性的影响和作用机制、调控TYMS基因表达的多种因子以及靶向TYMS基因的抗肿瘤应用进行综述。

关键词:

肿瘤, 胸苷酸合成酶, 发生, 发展, 机制, 进展

Hong Jinquan, Huang Zhenyu, Huang Huiwen, Huang Haobo.

Research progress of thymidylate synthase gene in tumorigenesis and development [J]. International Medicine and Health Guidance News, 2025, 31(8): 1260-1265.

洪金全黄震宇黄惠炆黄豪博.

胸苷酸合成酶基因在肿瘤发生发展中的研究进展 [J]. 国际医药卫生导报, 2025, 31(8): 1260-1265.

References

[1] Wilson PM, Danenberg PV, Johnston PG, et al. Standing the test of time: targeting thymidylate biosynthesis in cancer therapy[J]. Nat Rev Clin Oncol, 2014,11(5):282-298. DOI: 10.1038/nrclinonc.2014.51.
[2] Zhang F, Ye J, Guo W, et al. TYMS-TM4SF4 axis promotes the progression of colorectal cancer by EMT and upregulating stem cell marker[J]. Am J Cancer Res, 2022,12(3):1009-1026.
[3] Ramadan RA, Moghazy TF, Hafez R, et al. Significance of expression of pyrimidine metabolizing genes in colon cancer[J]. Arab J Gastroenterol, 2020,21(3):189-193. DOI: 10.1016/j.ajg.2020.07.006.
[4] Jiang L, Li S, Yuan M, et al. Genetic variants in the Folic acid metabolic pathway genes predict outcomes of metastatic colorectal cancer patients receiving first-line chemotherapy[J]. J Cancer, 2020,11(22):6507-6515. DOI: 10.7150/jca.44580.
[5] Pereira MA, Ramos MFKP, Dias AR, et al. Immunohistochemical expression of thymidylate synthase and prognosis in gastric cancer patients submitted to fluoropyrimidine-based chemotherapy[J]. Chin J Cancer Res, 2018,30(5):526-536. DOI: 10.21147/j.issn.1000-9604.2018.05.06.
[6] Song S, Tian B, Zhang M, et al. Diagnostic and prognostic value of thymidylate synthase expression in breast cancer[J]. Clin Exp Pharmacol Physiol, 2021,48(2):279-287. DOI: 10.1111/1440-1681.13415.
[7] Wang L, Wu Z, Wang Y, et al. TYMS knockdown suppresses cells proliferation, promotes ferroptosis via Inhibits PI3K/Akt/mTOR signaling pathway activation in triple negative breast cancer[J]. Cell Biochem Biophys, 2024,82(3):2717-2726. DOI: 10.1007/s12013-024-01388-5.
[8] Rahimi Z, Bozorgi Zarini M, Rahimi Z, et al. Variants of genes involved in metabolism of folate among patients with breast cancer: association of TYMS 3R allele with susceptibility to breast cancer and metastasis[J]. Iran J Pathol, 2021,16(1):62-68. DOI: 10.30699/ijp.2020. 117676.2283.
[9] 周文,王佳丽,谭碧波,等. ERCC1、TYMS和RRM1在宫颈癌组织中的表达及与化疗疗效的关系[J]. 中国癌症防治杂志,2019,11(6):513-517. DOI:10.3969/j.issn.1674-5671. 2019.06.12.
[10] Rakic A, Anicic R, Rakic M, et al. Integrated bioinformatics investigation of novel biomarkers of uterine leiomyosarcoma diagnosis and outcome[J]. J Pers Med, 2023,13(6):985. DOI: 10.3390/jpm13060985.
[11] Donner DB, Nakakura EK, Venook AP, et al. High thymidylate synthase gene expression predicts poor outcome after resection of hepatocellular carcinoma[J]. PLoS One, 2019,14(7):e0219469. DOI: 10.1371/journal.pone.0219469.
[12] Gandhi M, Groß M, Holler JM, et al. The lncRNA lincNMR regulates nucleotide metabolism via a YBX1 - RRM2 axis in cancer[J]. Nat Commun, 2020,11(1):3214. DOI: 10.1038/s41467-020-17007-9.
[13] Li S, Zhao J, Lv L, et al. Identification and validation of TYMS as a potential biomarker for risk of metastasis development in hepatocellular carcinoma[J]. Front Oncol, 2021,11:762821. DOI: 10.3389/fonc.2021.762821.
[14] Chamizo C, Zazo S, Dómine M, et al. Thymidylate synthase expression as a predictive biomarker of pemetrexed sensitivity in advanced non-small cell lung cancer[J]. BMC Pulm Med, 2015,15:132. DOI: 10.1186/s12890-015- 0132-x.
[15] Kulda V, Hrda K, Houdek Z, et al. Predictive significance of thymidylate synthase expression in non-small cell lung cancer[J]. Anticancer Res, 2017,37(12):6953-6958. DOI: 10.21873/anticanres.12161.
[16] Yin Y, Li D, He M, et al. The identification of hub biomarkers and pathways in lung cancer and prognostic evaluation[J]. Transl Cancer Res, 2022,11(8):2622-2635. DOI: 10.21037/tcr-22-245.
[17] Li Y, Li X, Dai H, et al. Thymidylate synthase was associated with patient prognosis and the response to adjuvant therapy in bladder cancer[J]. BJU Int, 2009,103(4):547-552. DOI: 10.1111/j.1464-410X. 2008.08099.x.
[18] Zhang S, Yan L, Cui C, et al. Identification of TYMS as a promoting factor of retroperitoneal liposarcoma progression: bioinformatics analysis and biological evidence[J]. Oncol Rep, 2020,44(2):565-576. DOI: 10.3892/or.2020.7635.
[19] Zhao M, Tan B, Dai X, et al. DHFR/TYMS are positive regulators of glioma cell growth and modulate chemo-sensitivity to temozolomide[J]. Eur J Pharmacol, 2019,863:172665. DOI: 10.1016/j.ejphar.2019.172665.
[20] Wu M, Ou-Yang DJ, Wei B, et al. A prognostic model of differentiated thyroid cancer based on up-regulated glycolysis-related genes[J]. Front Endocrinol (Lausanne), 2022,13:775278. DOI: 10.3389/fendo.2022.775278.
[21] Al-Sheikh A, Yousef AM, Alshamaseen D, et al. Effects of thymidylate synthase polymorphisms on toxicities associated with high-dose methotrexate in childhood acute lymphoblastic leukemia[J]. Cancer Chemother Pharmacol, 2021,87(3):379-385. DOI: 10.1007/s00280-020-04197-8.
[22] Chen Q, Pu N, Yin H, et al. A metabolism-relevant signature as a predictor for prognosis and therapeutic response in pancreatic cancer[J]. Exp Biol Med (Maywood), 2022,247(2):120-130. DOI: 10.1177/15353702211049220.
[23] Emelyanova M, Pokataev I, Shashkov I, et al. TYMS 3'-UTR polymorphism: a novel association with FOLFIRINOX-induced neurotoxicity in pancreatic cancer patients[J]. Pharmaceutics, 2021,14(1):77. DOI: 10.3390/pharmaceutics14010077.
[24] Tsyganov MM, Rodionov EO, Ibragimova MK, et al. Personalized prescription of chemotherapy based on assessment of mRNA expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBβ3, TYMS, and GSTP1 genes in tumors compared to standard chemotherapy in the treatment of non-small-cell lung cancer[J]. J Pers Med, 2022,12(10):1647. DOI: 10.3390/jpm12101647.
[25] Kurasaka C, Ogino Y, Sato A. Molecular mechanisms and tumor biological aspects of 5-fluorouracil resistance in HCT116 human colorectal cancer cells[J]. Int J Mol Sci, 2021,22(6):2916. DOI: 10.3390/ijms22062916.
[26] Ciszewski WM, Chmielewska-Kassassir M, Wozniak LA, et al. Thymidylate synthase overexpression drives the invasive phenotype in colon cancer cells[J]. Biomedicines, 2022,10(6):1267. DOI: 10.3390/biomedicines10061267.
[27] Yang J, Zhang J, Chen J, et al. Thymidylate synthase promotes esophageal squamous cell carcinoma growth by relieving oxidative stress through activating nuclear factor erythroid 2-related factor 2 expression[J]. PLoS One, 2023,18(9):e0290264. DOI: 10.1371/journal.pone.0290264.
[28] Chen Y, Zhang C, Jin S, et al. Pemetrexed induces ROS generation and cellular senescence by attenuating TS-mediated thymidylate metabolism to reverse gefitinib resistance in NSCLC[J]. J Cell Mol Med, 2023,27(14):2032-2044. DOI: 10.1111/jcmm.17799.
[29] Sato Y, Tomita M, Soga T, et al. Upregulation of thymidylate synthase induces pemetrexed resistance in malignant pleural mesothelioma[J]. Front Pharmacol, 2021,12:718675. DOI: 10.3389/fphar.2021.718675.
[30] Guijarro MV, Nawab A, Dib P, et al. TYMS promotes genomic instability and tumor progression in Ink4a/Arf null background[J]. Oncogene, 2023,42(23):1926-1939. DOI: 10.1038/s41388-023-02694-7.
[31] Wan S, Liu Z, Chen Y, et al. MicroRNA-140-3p represses the proliferation, migration, invasion and angiogenesis of lung adenocarcinoma cells via targeting TYMS (thymidylate synthetase)[J]. Bioengineered, 2021,12(2):11959-11977. DOI: 10.1080/21655979.2021.2009422.
[32] Mannava S, Grachtchouk V, Wheeler LJ, et al. Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells[J]. Cell Cycle, 2008,7(15):2392-2400. DOI: 10.4161/cc.6390.
[33] Zhang S, Liu N, Cao P, et al. LncRNA BC200 promotes the development of EBV-associated nasopharyngeal carcinoma by competitively binding to miR-6834-5p to upregulate TYMS expression[J]. Int J Biol Macromol, 2024,278(Pt 4):134837. DOI: 10.1016/j.ijbiomac.2024.134837.
[34] Liang J, Lu T, Chen Z, et al. Mechanisms of resistance to pemetrexed in non-small cell lung cancer[J]. Transl Lung Cancer Res, 2019,8(6):1107-1118. DOI: 10.21037/tlcr.2019.10.14.
[35] Honeywell RJ, Ruiz van Haperen VW, Veerman G, et al. Inhibition of thymidylate synthase by 2',2'-difluoro-2'-deoxycytidine (Gemcitabine) and its metabolite 2',2'-difluoro-2'-deoxyuridine[J]. Int J Biochem Cell Biol, 2015,60:73-81. DOI: 10.1016/j.biocel.2014.12.010.
[36] Chmielewska-Kassassir M, Sobierajska K, Ciszewski WM, et al. Evening primrose extract modulates TYMS expression via SP1 transcription factor in malignant pleural mesothelioma[J]. Cancers (Basel), 2023,15(20):5003. DOI: 10.3390/cancers15205003.
[37] Ciszewski WM, Włodarczyk J, Chmielewska-Kassassir M, et al. Evening primrose seed extract rich in polyphenols modulates the invasiveness of colon cancer cells by regulating the TYMS expression[J]. Food Funct, 2022,13(21):10994-11007. DOI: 10.1039/d2fo01737g.
[38] Zhu Z, Liu Y, Zeng J, et al. Diosbulbin C, a novel active ingredient in Dioscorea bulbifera L. extract, inhibits lung cancer cell proliferation by inducing G0/G1 phase cell cycle arrest[J]. BMC Complement Med Ther, 2023,23(1):436. DOI: 10.1186/s12906-023-04245-9.
[39] Kim N, Yang C. Sodium butyrate inhibits the expression of thymidylate synthase and induces cell death in colorectal cancer cells[J]. Int J Mol Sci, 2024,25(3):1572. DOI: 10.3390/ijms25031572.