叶酸与肝癌发生发展的关系

李应雯; 师丽; 刘敏; 袁浩; 郑亚; 王玉平; 郭庆红

doi:10.3969/j.issn.1001-5256.2023.03.033

叶酸与肝癌发生发展的关系

DOI: 10.3969/j.issn.1001-5256.2023.03.033

李应雯^{1, 2a, 2b},
师丽^{1, 2a, 2b},
刘敏^{2a, 2b},
袁浩^{2a, 2b},
郑亚^{2a, 2b},
王玉平^{2a, 2b},
郭庆红^{2a, 2b, , ,}

1.
兰州大学第一临床医学院, 兰州 730000
2a.
兰州大学第一医院消化科, 兰州 730000
2b.
兰州大学第一医院甘肃省胃肠病重点实验室, 兰州 730000

基金项目:

甘肃省自然科学基金 (21JR1RA117);

甘肃省自然科学基金 (20JR5RA347);

兰州大学第一医院院内基金 (ldyyyn2019-28);

兰州大学第一医院院内基金 (ldyyyn2018-54)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：李应雯负责课题设计，资料分析，撰写论文；师丽、刘敏、袁浩参与收集数据，修改论文；郑亚、王玉平、郭庆红负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
郭庆红，gqh@lzu.edu.cn (ORCID: 0000-0002-0438-3948)

计量
- 文章访问数: 590
- HTML全文浏览量: 429
- PDF下载量: 110
- 被引次数: 0
出版历程
- 收稿日期: 2022-09-01
- 录用日期: 2022-10-20
- 出版日期: 2023-03-20

Association of folic acid with the development and progression of liver cancer

Yingwen LI^{1, 2a, 2b},
Li SHI^{1, 2a, 2b},
Min LIU^{2a, 2b},
Hao YUAN^{2a, 2b},
Ya ZHENG^{2a, 2b},
Yuping WANG^{2a, 2b},
Qinghong GUO^{2a, 2b
, ,
,}

1.
The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
2a.
Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
2b.
Gansu Key Laboratory of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China

Research funding:

Natural Science Foundation of Gansu Province (21JR1RA117);

Natural Science Foundation of Gansu Province (20JR5RA347);

In Hospital Fund of the First Hospital of Lanzhou University (ldyyyn2019-28);

In Hospital Fund of the First Hospital of Lanzhou University (ldyyyn2018-54)

More Information

Corresponding author: GUO Qinghong, gqh@lzu.edu.cn (ORCID: 0000-0002-0438-3948)

摘要

摘要: 迄今为止，肝癌仍是我国高发、恶性程度极高的肿瘤，严重影响我国人民的生命和健康。以往研究发现，肝癌的发生与病毒、吸烟、饮酒及非酒精性脂肪性肝病等诸多因素相关。随着不断探索，越来越多的研究指出，营养因素及生活环境与肝癌的发生发展相关。叶酸作为机体细胞生长和繁殖所必需的营养物质，其在人体内的水平高低均对肿瘤细胞的生长产生影响，与肝癌的关系密不可分。本文对近年来叶酸与肝癌之间关系的研究进展予以综述，以期为肝癌的预防和治疗提供新的参考和依据。
- 肝肿瘤 /
- 叶酸 /
- DNA甲基化 /
- 治疗学
Abstract: So far, liver cancer is still a highly malignant tumor with a high incidence rate in China, and it seriously affects the life and health of Chinese people. Previous studies have shown that the development of liver cancer is associated with various factors such as virus, smoking, drinking, and nonalcoholic fatty liver disease. With continuous exploration, more and more studies have pointed out that nutritional factors and living environment are associated with the development and progression of liver cancer. Folic acid is a necessary nutrient for cell growth and reproduction, and its level in human body has an impact on the growth of tumor cells and is closely associated with liver cancer. This article reviews the research advances in the association between folic acid and liver cancer in recent years, so as to provide new reference and basis for the prevention and treatment of liver cancer.
- Liver Neoplasms /
- Folic Acid /
- DNA Methylation /
- Therapeutics

HTML全文

图 1 叶酸缺乏促进肿瘤发生的机制

注：ELOVL2，长链脂肪酸延长酶2；Lpl，脂蛋白脂肪酶；Slpi，分泌型白细胞肽酶抑制剂；Sctr^{1, 2}，分泌素受体；Ly49i6，Ly49抑制受体-6。

Figure 1. The mechanism of folic acid deficiency promoting tumorigenesis

下载: 全尺寸图片幻灯片

参考文献(44)

[1]	BRAY F, LAVERSANNE M, WEIDERPASS E, et al. The ever-increasing importance of cancer as a leading cause of premature death worldwide[J]. Cancer, 2021, 127(16): 3029-3030. DOI: 10.1002/cncr.33587.
[2]	SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[3]	ANWANWAN D, SINGH SK, SINGH S, et al. Challenges in liver cancer and possible treatment approaches[J]. Biochim Biophys Acta Rev Cancer, 2020, 1873(1): 188314. DOI: 10.1016/j.bbcan.2019.188314.
[4]	HEATH AK, CLASEN JL, JAYANTH NP, et al. Soft drink and juice consumption and renal cell carcinoma incidence and mortality in the European prospective investigation into cancer and nutrition[J]. Cancer Epidemiol Biomarkers Prev, 2021, 30(6): 1270-1274. DOI: 10.1158/1055-9965.EPI-20-1726.
[5]	KENNEDY OJ, RODERICK P, BUCHANAN R, et al. Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis[J]. BMJ Open, 2017, 7(5): e013739. DOI: 10.1136/bmjopen-2016-013739.
[6]	FARVID MS, SIDAHMED E, SPENCE ND, et al. Consumption of red meat and processed meat and cancer incidence: a systematic review and meta-analysis of prospective studies[J]. Eur J Epidemiol, 2021, 36(9): 937-951. DOI: 10.1007/s10654-021-00741-9.
[7]	PARK SH, HOANG T, KIM J. Dietary factors and breast cancer prognosis among breast cancer survivors: A systematic review and meta-analysis of cohort studies[J]. Cancers (Basel), 2021, 13(21): 5329. DOI: 10.3390/cancers13215329.
[8]	PIEROTH R, PAVER S, DAY S, et al. Folate and its impact on cancer risk[J]. Curr Nutr Rep, 2018, 7(3): 70-84. DOI: 10.1007/s13668-018-0237-y.
[9]	LIU Y, SUN CJ, ZHANG YH, et al. Effect of combined treatment with folic acid and teprenone on the prognosis of precancerous lesion of chronic atrophic antral gastritis after Helicobacter pylori eradication[J]. Clin J Med Offic, 2021, 49(11): 1267-1269, 1272. DOI: 10.16680/j.1671-3826.2021.11.29. 刘燕, 孙陈静, 张月华, 等. 叶酸与替普瑞酮联合治疗对幽门螺杆菌根除后慢性萎缩性胃窦炎癌前病变转归影响[J]. 临床军医杂志, 2021, 49(11): 1267-1269, 1272. DOI: 10.16680/j.1671-3826.2021.11.29.
[10]	LEE D, XU IM, CHIU DK, et al. Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma[J]. J Clin Invest, 2017, 127(5): 1856-1872. DOI: 10.1172/JCI90253.
[11]	SHARMA R, ALI T, NEGI I, et al. Dietary modulations of folic acid affect the development of diethylnitrosamine induced hepatocellular carcinoma in a rat model[J]. J Mol Histol, 2021, 52(2): 335-350. DOI: 10.1007/s10735-020-09955-9.
[12]	SHARMA R, ALI T, KAUR J. Tumor suppressor genes are differentially regulated with dietary folate modulations in a rat model of hepatocellular carcinoma[J]. Mol Cell Biochem, 2021, 476(1): 385-399. DOI: 10.1007/s11010-020-03915-3.
[13]	CUI LH, QUAN ZY, PIAO JM, et al. Plasma folate and vitamin B12 levels in patients with hepatocellular carcinoma[J]. Int J Mol Sci, 2016, 17(7): 1032. DOI: 10.3390/ijms17071032.
[14]	KUO CS, LIN CY, WU MY, et al. Relationship between folate status and tumour progression in patients with hepatocellular carcinoma[J]. Br J Nutr, 2008, 100(3): 596-602. DOI: 10.1017/S0007114508911557.
[15]	FANG AP, LIU ZY, LIAO GC, et al. Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study[J]. Br J Nutr, 2019, 121(12): 1376-1388. DOI: 10.1017/S0007114519000734.
[16]	PERSSON EC, SCHWARTZ LM, PARK Y, et al. Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality[J]. Cancer Epidemiol Biomarkers Prev, 2013, 22(3): 415-421. DOI: 10.1158/1055-9965.EPI-12-1169.
[17]	DEGHAN MANSHADI S, ISHIGURO L, SOHN KJ, et al. Folic acid supplementation promotes mammary tumor progression in a rat model[J]. PLoS One, 2014, 9(1): e84635. DOI: 10.1371/journal.pone.0084635.
[18]	REN X, XU P, ZHANG D, et al. Association of folate intake and plasma folate level with the risk of breast cancer: a dose-response meta-analysis of observational studies[J]. Aging (Albany NY), 2020, 12(21): 21355-21375. DOI: 10.18632/aging.103881.
[19]	DULMAN RS, WANDLING GM, PANDEY SC. Epigenetic mechanisms underlying pathobiology of alcohol use disorder[J]. Curr Pathobiol Rep, 2020, 8(3): 61-73. DOI: 10.1007/s40139-020-00210-0.
[20]	ABBASI I, ABBASI F, WANG L, et al. Folate promotes S-adenosyl methionine reactions and the microbial methylation cycle and boosts ruminants production and reproduction[J]. AMB Express, 2018, 8(1): 65. DOI: 10.1186/s13568-018-0592-5.
[21]	LEE TY, CHIANG EP, SHIH YT, et al. Lower serum folate is associated with development and invasiveness of gastric cancer[J]. World J Gastroenterol, 2014, 20(32): 11313-11320. DOI: 10.3748/wjg.v20.i32.11313.
[22]	ALKAN A, M₁ZRAK D, UTKAN G. Lower folate levels in gastric cancer: is it a cause or a result?[J]. World J Gastroenterol, 2015, 21(13): 4101-4102. DOI: 10.3748/wjg.v21.i13.4101.
[23]	LINHART HG, TROEN A, BELL GW, et al. Folate deficiency induces genomic uracil misincorporation and hypomethylation but does not increase DNA point mutations[J]. Gastroenterology, 2009, 136(1): 227-235. DOI: 10.1053/j.gastro.2008.10.016.
[24]	TU M, FAN X, SHI J, et al. 2-Fluorofucose attenuates hydrogen peroxide-induced oxidative stress in HepG2 cells via Nrf2/keap1 and NF-κB signaling pathways[J]. Life (Basel), 2022, 12(3): 406. DOI: 10.3390/life12030406.
[25]	CUCARULL B, TUTUSAUS A, HERNÁEZ-ALSINA T, et al. Antioxidants threaten multikinase inhibitor efficacy against liver cancer by blocking mitochondrial reactive oxygen species[J]. Antioxidants (Basel), 2021, 10(9): 1336. DOI: 10.3390/antiox10091336.
[26]	BARRERA G, CUCCI MA, GRATTAROLA M, et al. Control of oxidative stress in cancer chemoresistance: spotlight on Nrf2 role[J]. Antioxidants (Basel), 2021, 10(4): 510. DOI: 10.3390/antiox10040510.
[27]	CHERN CL, HUANG RF, CHEN YH, et al. Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-kappaB in human Hep G2 cells[J]. Biomed Pharmacother, 2001, 55(8): 434-442. DOI: 10.1016/s0753-3322(01)00095-6.
[28]	LAI KG, CHEN CF, HO CT, et al. Novel roles of folic acid as redox regulator: Modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma[J]. Tumour Biol, 2017, 39(6): 1010428317702649. DOI: 10.1177/1010428317702649.
[29]	CHAGAS CE, BASSOLI BK, de SOUZA CA, et al. Folic acid supplementation during early hepatocarcinogenesis: cellular and molecular effects[J]. Int J Cancer, 2011, 129(9): 2073-2082. DOI: 10.1002/ijc.25886.
[30]	GUARIENTO AH, FURTADO KS, DE CONTI A, et al. Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis[J]. Int J Cancer, 2014, 135(1): 7-18. DOI: 10.1002/ijc.28642.
[31]	MENCK K, HEINRICHS S, BADEN C, et al. The WNT/ROR pathway in cancer: From signaling to therapeutic intervention[J]. Cells, 2021, 10(1): 142. DOI: 10.3390/cells10010142.
[32]	CHEN B, GU Y, SHEN H, et al. Borealin promotes tumor growth and metastasis by activating the Wnt/β-Catenin signaling pathway in hepatocellular carcinoma[J]. J Hepatocell Carcinoma, 2022, 9: 171-188. DOI: 10.2147/JHC.S336452.
[33]	BRICAMBERT J, ALVES-GUERRA MC, ESTEVES P, et al. The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity[J]. Nat Commun, 2018, 9(1): 2092. DOI: 10.1038/s41467-018-04361-y.
[34]	LOMBARDI R, IUCULANO F, PALLINI G, et al. Nutrients, genetic factors, and their interaction in non-alcoholic fatty liver disease and cardiovascular disease[J]. Int J Mol Sci, 2020, 21(22): 8761. DOI: 10.3390/ijms21228761.
[35]	CHEW TW, JIANG X, YAN J, et al. Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice[J]. J Nutr, 2011, 141(8): 1475-1481. DOI: 10.3945/jn.111.138859.
[36]	GRZĘDA E, MATUSZEWSKA J, ZIARNIAK K, et al. Animal foetal models of obesity and diabetes - from laboratory to clinical settings[J]. Front Endocrinol (Lausanne), 2022, 13: 785674. DOI: 10.3389/fendo.2022.785674.
[37]	XIA MF, BIAN H, ZHU XP, et al. Serum folic acid levels are associated with the presence and severity of liver steatosis in Chinese adults[J]. Clin Nutr, 2018, 37(5): 1752-1758. DOI: 10.1016/j.clnu.2017.06.021.
[38]	YUAN SX, ZHOU WP. Progress and hot spots of comprehensive treatment for primary liver cancer[J]. Chin J Dig Surg, 2021, 20(2): 163-170. DOI: 10.3760/cma.j.cn115610-20201211-00776. 袁声贤, 周伟平. 原发性肝癌综合治疗的进展和热点[J]. 中华消化外科杂志, 2021, 20(2): 163-170. DOI: 10.3760/cma.j.cn115610-20201211-00776.
[39]	KOIRALA N, DAS D, FAYAZZADEH E, et al. Folic acid conjugated polymeric drug delivery vehicle for targeted cancer detection in hepatocellular carcinoma[J]. J Biomed Mater Res A, 2019, 107(11): 2522-2535. DOI: 10.1002/jbm.a.36758.
[40]	LI QJ, HE MK, CHEN HW, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: A randomized phase Ⅲ trial[J]. J Clin Oncol, 2022, 40(2): 150-160. DOI: 10.1200/JCO.21.00608.
[41]	LYU N, KONG Y, MU L, et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma[J]. J Hepatol, 2018, 69(1): 60-69. DOI: 10.1016/j.jhep.2018.02.008.
[42]	TRACEY SR, SMYTH P, BARELLE CJ, et al. Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface[J]. Biochem Soc Trans, 2021, 49(5): 2253-2269. DOI: 10.1042/BST20210343.
[43]	JAIN P, HASSAN N, IQBAL Z, et al. Mesoporous silica nanoparticles: A versatile platform for biomedical applications[J]. Recent Pat Drug Deliv Formul, 2018, 12(4): 228-237. DOI: 10.2174/1872211313666181203152859.
[44]	ZHANG YL, XUE G, MIAO H, et al. Folic acid supplementation acts as a chemopreventive factor in tumorigenesis of hepatocellular carcinoma by inducing H3K9Me2-dependent transcriptional repression of LCN2[J]. Oncotarget, 2021, 12(4): 366-378. DOI: 10.18632/oncotarget.27136.