叶酸及其代谢在宫颈癌中的研究进展

doi:10.12280/gjfckx.20200699

摘要/Abstract

摘要：

叶酸又名蝶酰谷氨酸,其本身并没有生理功能,需要在机体内进行一系列的代谢和转化后才能发挥作用,是参与一碳代谢的关键营养素,在基因合成修复和DNA甲基化中起着重要作用,因此被认为与癌症的发生发展有关。叶酸缺乏和代谢障碍可以作为一个解释宫颈癌多因素致病理论的新角度。但目前叶酸和宫颈癌的相关机制研究尚处于初步阶段,尚需进一步的研究阐明叶酸缺乏和代谢障碍在宫颈癌发生发展的分子内机制。近年来叶酸在宫颈癌的预防、诊断和治疗中的研究都有显著的进展,如叶酸补充或强化对宫颈病变的预防和治疗作用的探索,基于叶酸生物化学特性的宫颈筛查新方法,以及叶酸修饰或功能化的新型靶向药物。综述叶酸及其代谢在宫颈癌中的研究进展。

关键词: 叶酸, 代谢, 宫颈肿瘤, 乳头状瘤病毒科, 宫颈上皮内瘤样病变

Abstract:

Folic acid, also known as pteroyl glutamate, has no physiological function, which needs a series of metabolism and transformation in the body to play biological role. It is an essential nutrient involved in the one-carbon metabolism pathway, which plays a critical role in the synthesis and repair of genes and DNA methylation, so it is considered to be related to the occurrence and development of cancer. Folic acid deficiency and metabolic disorders could be a new angle to explain the multifactorial pathogenic theory of cervical cancer. However, the research on the related mechanisms of folic acid and cervical cancer is unclear, and further research is needed to clarify the molecular mechanism of folic acid deficiency and metabolic disorders in the occurrence and development of cervical cancer. Folic acid has made significant progress in the prevention, diagnosis and treatment of cervical cancer in recent years, such as the exploration of folic acid supplementation or fortification on the prevention and treatment of cervical lesions, new cervical screening method based on the biochemical properties of folic acid, and novel targeted drugs modified or functionalized by folic acid. This article reviews the research progress of folic acid and its metabolism in cervical cancer.

Key words: Folic acid, Metabolism, Uterine cervical neoplasms, Papillomaviridae, Cervical intraepithelial neoplasia

李元幸, 王伟, 郝敏. 叶酸及其代谢在宫颈癌中的研究进展[J]. 国际妇产科学杂志, 2021, 48(1): 47-50.

LI Yuan-xing, WANG Wei, HAO Min. Research Progress of Folic Acid and Its Metabolism in Cervical Cancer[J]. Journal of International Obstetrics and Gynecology, 2021, 48(1): 47-50.

参考文献 32

[1]	Sun LP, Yan LB, Liu ZZ, et al. Dietary factors and risk of mortality among patients with esophageal cancer: a systematic review[J]. BMC Cancer, 2020,20(1):287. doi: 10.1186/s12885-020-06767-8. doi: 10.1186/s12885-020-06767-8 pmid: 32252671
[2]	Zeng J, Gu Y, Fu H, et al. Association Between One-carbon Metabolism-related Vitamins and Risk of Breast Cancer: A Systematic Review and Meta-analysis of Prospective Studies[J]. Clin Breast Cancer, 2020,20(4):e469-e480. doi: 10.1016/j.clbc.2020.02.012. doi: 10.1016/j.clbc.2020.02.012 pmid: 32241696
[3]	Moazzen S, Dolatkhah R, Tabrizi JS, et al. Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis[J]. Clin Nutr, 2018,37(6 Pt A):1926-1934. doi: 10.1016/j.clnu.2017.10.010. doi: 10.1016/j.clnu.2017.10.010 pmid: 29132834
[4]	Zhao W, Hao M, Wang Y, et al. Association between folate status and cervical intraepithelial neoplasia[J]. Eur J Clin Nutr, 2016,70(7):837-842. doi: 10.1038/ejcn.2016.35. doi: 10.1038/ejcn.2016.35 pmid: 27026426
[5]	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019[J]. CA Cancer J Clin, 2019,69(1):7-34. doi: 10.3322/caac.21551. doi: 10.3322/caac.21551 pmid: 30620402
[6]	罗雅娟, 王丹丹, 杨清. HPV致女性生殖道疾病及HPV疫苗现况[J]. 国际生殖健康/计划生育杂志, 2019,38(3):244-248. doi: 10.3969/j.issn.1674-1889.2019.03.016.
[7]	Silva N, Silva Santos AC, Carneiro CM, et al. Association of serum folate and vitamin B12 with pre-neoplastic cervical lesions[J]. Clin Nutr ESPEN, 2020,38:223-228. doi: 10.1016/j.clnesp.2020.04.007. doi: 10.1016/j.clnesp.2020.04.007 pmid: 32690162
[8]	Badiga S, Siddiqui NR, Macaluso M, et al. Homocysteinemia is Associated with a Lower Degree of PBMC LINE-1 Methylation and a Higher Risk of CIN 2C in the U.S. Post-Folic Acid Fortification Era[J]. Nutr Cancer, 2016,68(3):446-455. doi: 10.1080/01635581.2016.1152388. doi: 10.1080/01635581.2016.1152388 pmid: 27008272
[9]	Yi K, Yang L, Lan Z, et al. The association between MTHFR polymorphisms and cervical cancer risk: a system review and meta analysis[J]. Arch Gynecol Obstet, 2016,294(3):579-588. doi: 10.1007/s00404-016-4037-6. doi: 10.1007/s00404-016-4037-6 pmid: 26879954
[10]	Bogani G, Leone Roberti Maggiore U, Signorelli M, et al. The role of human papillomavirus vaccines in cervical cancer: Prevention and treatment[J]. Crit Rev Oncol Hematol, 2018,122:92-97. doi: 10.1016/j.critrevonc.2017.12.017. doi: 10.1016/j.critrevonc.2017.12.017 pmid: 29458794
[11]	Vassilakos P, Tran PL, Sahli R, et al. HPV-negative CIN3 and cervical cancer in Switzerland: any evidence of impact on screening policies?[J]. Swiss Med Wkly, 2017,147:w14559. doi: 10.4414/smw.2017.14559. doi: 10.4414/smw.2017.14559 pmid: 29185245
[12]	Yang J, Yang A, Wang Z, et al. Interactions between serum folate and human papillomavirus with cervical intraepithelial neoplasia risk in a Chinese population-based study[J]. Am J Clin Nutr, 2018,108(5):1034-1042. doi: 10.1093/ajcn/nqy160. doi: 10.1093/ajcn/nqy160 pmid: 30247499
[13]	南晶, 丁玲, 刘学智, 等. 叶酸与HPV16E6/E7mRNA表达在宫颈癌变中的交互作用[J]. 中华流行病学杂志, 2016,37(6):852-857. doi: 10.3760/cma.j.issn.0254-6450.2016.06.022.
[14]	贾吴琳, 丁玲, 任志英, 等. 叶酸与p16蛋白在宫颈癌变中的作用及其相互效应[J]. 中华流行病学杂志, 2016,37(12):1647-1652. doi: 10.3760/cma.j.issn.0254-6450.2016.12.018.
[15]	Xiao S, Tang YS, Kusumanchi P, et al. Folate Deficiency Facilitates Genomic Integration of Human Papillomavirus Type 16 DNA In Vivo in a Novel Mouse Model for Rapid Oncogenic Transformation of Human Keratinocytes[J]. J Nutr, 2018,148(3):389-400. doi: 10.1093/jn/nxx060. doi: 10.1093/jn/nxx060 pmid: 29546304
[16]	Lamm N, Maoz K, Bester AC, et al. Folate levels modulate oncogene-induced replication stress and tumorigenicity[J]. EMBO Mol Med, 2015,7(9):1138-1152. doi: 10.15252/emmm.201404824. doi: 10.15252/emmm.201404824 pmid: 26197802
[17]	Savini C, Yang R, Savelyeva L, et al. Folate Repletion after Deficiency Induces Irreversible Genomic and Transcriptional Changes in Human Papillomavirus Type 16 (HPV16)-Immortalized Human Keratinocytes[J]. Int J Mol Sci, 2019,20(5):1100. doi: 10.3390/ijms20051100. doi: 10.3390/ijms20051100
[18]	Maugeri A, Barchitta M. How Dietary Factors Affect DNA Methylation: Lesson from Epidemiological Studies[J]. Medicina(Kaunas), 2020,56(8):374. doi: 10.3390/medicina56080374.
[19]	Li Q, Ding L, Jing N, et al. Folate deficiency and aberrant DNA methylation and expression of FHIT gene were associated with cervical pathogenesis[J]. Oncol Lett, 2018,15(2):1963-1972. doi: 10.3892/ol.2017.7471. doi: 10.3892/ol.2017.7471 pmid: 29434897
[20]	Hasan T, Arora R, Bansal AK, et al. Disturbed homocysteine metabolism is associated with cancer[J]. Exp Mol Med, 2019,51(2):1-13. doi: 10.1038/s12276-019-0216-4. doi: 10.1038/s12276-018-0204-0 pmid: 30755582
[21]	Perła-Kaján J, Jakubowski H. Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia[J]. Int J Mol Sci, 2019,20(13):3140. doi: 10.3390/ijms20133140. doi: 10.3390/ijms20133140
[22]	王志莲. 叶酸及miR-224调控宫颈癌细胞自噬的作用及机制研究[D]. 太原:山西医科大学, 2017.
[23]	Crider KS, Qi YP, Devine O, et al. Modeling the impact of folic acid fortification and supplementation on red blood cell folate concentrations and predicted neural tube defect risk in the United States: have we reached optimal prevention?[J]. Am J Clin Nutr, 2018,107(6):1027-1034. doi: 10.1093/ajcn/nqy065. doi: 10.1093/ajcn/nqy065 pmid: 29767673
[24]	Piyathilake CJ, Macaluso M, Alvarez RD, et al. Lower risk of cervical intraepithelial neoplasia in women with high plasma folate and sufficient vitamin B12 in the post-folic acid fortification era[J]. Cancer Prev Res(Phila), 2009,2(7):658-664. doi: 10.1158/1940-6207.CAPR-08-0175.
[25]	Asemi Z, Vahedpoor Z, Jamilian M, et al. Effects of long-term folate supplementation on metabolic status and regression of cervical intraepithelial neoplasia: A randomized, double-blind, placebo-controlled trial[J]. Nutrition, 2016,32(6):681-686. doi: 10.1016/j.nut.2015.12.028. doi: 10.1016/j.nut.2015.12.028 pmid: 26853484
[26]	Murphy ME, Westmark CJ. Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset[J]. Nutrients, 2020,12(1):247. doi: 10.3390/nu12010247. doi: 10.3390/nu12010247
[27]	Xiao S, Xie H, Zhu X, et al. Study on the Significance of Folate Receptor-Mediated Staining Solution (FRD) Staining in Screening High Grade Cervical Lesions[J]. Med Sci Monit, 2019,25:2792-2801. doi: 10.12659/MSM.911402. doi: 10.12659/MSM.911402 pmid: 30990212
[28]	张亚丽, 靳双玲, 张春燕, 等. 亚甲基四氢叶酸还原酶基因多态性在妇产科领域的研究进展[J]. 国际妇产科学杂志, 2020,47(4):394-398.
[29]	Cheng W, Nie J, Xu L, et al. pH-Sensitive Delivery Vehicle Based on Folic Acid-Conjugated Polydopamine-Modified Mesoporous Silica Nanoparticles for Targeted Cancer Therapy[J]. ACS Appl Mater Interfaces, 2017,9(22):18462-18473. doi: 10.1021/acsami.7b02457. doi: 10.1021/acsami.7b02457 pmid: 28497681
[30]	Wang WY, Cao YX, Zhou X, et al. Delivery of folic acid-modified liposomal curcumin for targeted cervical carcinoma therapy[J]. Drug Des Devel Ther, 2019,13:2205-2213. doi: 10.2147/DDDT.S205787. pmid: 31308632
[31]	You L, Liu X, Fang Z, et al. Synjournal of multifunctional Fe₃O₄@PLGA-PEG nano-niosomes as a targeting carrier for treatment of cervical cancer[J]. Mater Sci Eng C Mater Biol Appl, 2019,94:291-302. doi: 10.1016/j.msec.2018.09.044. doi: 10.1016/j.msec.2018.09.044 pmid: 30423711
[32]	Tymon-Rosario J, Zeybek B, Santin AD. Novel antibody-drug conjugates: current and future roles in gynecologic oncology[J]. Curr Opin Obstet Gynecol, 2020 Jun 28. doi: 10.1097/GCO.0000000000000642. pmid: 33278077