Causal association between systemic inflammatory factors and the risk of hepatocellular carcinoma based on Mendelian randomization

Published on Sep. 04, 2024Total Views: 1367 times Total Downloads: 264 times Download Mobile

Author: LI Xinyu ^1, ² NIE Duorui ¹ XIAO Tingfen ^1, ² CAO Jun ¹ WANG Zhiqi ^1, ² XU Fei ^1, ²  CHEN Chang ¹

Affiliation: 1. School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China 2. National First-Class Major Construction Point of Chinese Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China

Keywords: Inflammatory factors Hepatocellular carcinoma Mendelian randomization analysis GWAS

DOI: 10.12173/j.issn.1004-4337.202405145

Reference: Li XY, Nie DR, Xiao TF, Cao J, Wang ZQ, Xu F, Chen C. Causal association between systemic inflammatory factors and the risk of hepatocellular carcinoma based on Mendelian randomization[J]. Journal of Mathematical Medicine, 2024, 37(8): 592-599. DOI: 10.12173/j.issn.1004-4337.202405001[Article in Chinese]  Copied

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Abstract

Objective To explore the causal relationship between systemic inflammatory factors and the risk of hepatocellular carcinoma.

Methods This study was based on the published genome-wide association study (GWAS) database. The exposure factor was 41 systemic inflammatory regulators. The data were derived from a Finland study with a sample size of 8 293 people. The outcome variable was hepatocellular carcinoma, which was derived from the Finnish database (FINNGen). Two-sample Mendelian randomization analysis was performed using inverse variance weighted (IVW), MR-Egger, weighted median estimator (WME), and weighted mode (WM) MR-Egger was carried out for pleiotropy analysis, Cochran's Q test was used for heterogeneity analysis, and leave-one-out method was used for sensitivity analysis.

Results IVW results of two-sample Mendelian randomization analysis showed that TNF-related apoptosis-inducing ligand (TRAIL) level (OR=0.77, 95%CI=0.61-0.97, P=0.025), macrophage-stimulating factor (MCSF) level (OR=0.69, 95%CI=0.50-0.95, P=0.024) and interleukin-18 (IL-18) level (OR=0.77, 95%CI=0.61-0.97, P=0.026) were negatively correlated with the risk of hepatocellular carcinoma.

Conclusion TRAIL, IL-18 and MCSF had potential negative causal association with hepatocellular carcinoma, which migh be protective factors for hepatocellular carcinoma.

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References

1.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.

2.张顺娟, 夏运风. 炎症因子在血液透析患者合并抑郁中的研究进展[J]. 中国血液净化, 2023, 22(12): 916-919. [Zhang SJ, Xia YF. Research progress in inflammatory factors in hemodialysis patients complicated with depression[J]. Chinese Journal of Blood Purification, 2023, 22(12): 916-919.] DOI: 10.3969/j.issn.1671-4091.2023.12.007.

3.El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma[J]. Gastroenterology, 2012, 142(6): 1264-1273. DOI: 10.1053/j.gastro.2011.12.061.

4.赵枭卿, 周虎, 冷静. 肝癌细胞外泌体诱导肝癌细胞炎症因子的表达[J]. 免疫学杂志, 2020, 36(5): 410-415. [Zhao XQ, Zhou H, Leng J. Hepatocellular carcinoma cells-derived exosomes induce the expression of inflammatory cytokines in hepatocellular carcinoma cells[J]. Immunological Journal, 2020, 36(5): 410-415.] DOI: 10.13431/j.cnki.immunol.j.20200066.

5.沈国定, 姜润秋, 孙倍成. 炎症相关因子IL-1β, TGF-β及MCP-1在肝细胞肝癌的表达[J]. 江苏医药, 2011, 37(7): 797-799. [Shen GD, Jiang RQ, Sun BC. Expressions of inflammation-associated factors IL-1β, TGF-β and MCP-1 in human hepatocellular carcinoma[J]. Jiangsu Medical Journal, 2011, 37(7): 797-799.] DOI: 10.19460/j.cnki.0253-3685.2011.07.018.

6.黄高铂, 连建奇, 张野. 白细胞介素22与肝脏疾病关系的研究进展[J]. 细胞与分子免疫学杂志, 2015, 31(9): 1280-1283. [Huang GB, Lian JQ, Zhang Y. Research progress on the relationship between interleukin-22 and liver disease[J]. Chinese Journal of Cellular and Molecular Immunology, 2015, 31(9): 1280-1283.] DOI: 10.13423/j.cnki.cjcmi.007470.

7.何松青, 陈孝平. 肝细胞肝癌病人血清IL-12、IL-2、sIL-2R水平的相关性[J]. 中华普通外科杂志, 2002, 17(4): 18-20. [He SQ, Chen XP. Interleukin-2 in its relation with interleukin-12 and soluble interleukin-2 receptor in patients with hepatocellular carcinoma[J]. Chinese Journal of General Surgery, 2002, 17(4): 18-20.] DOI: 10.3760/j.issn:1007-631X.2002.04.007.

8.Hu M, Tong Y, Fang H, et al. IL36 indicating good prognosis in human hepatocellular carcinoma[J]. J Cancer, 2020, 11(21): 6248-6255. DOI: 10.7150/jca.47106.

9.刘明, 高亚, 杨珂璐, 等. 孟德尔随机化研究的报告规范(STROBE-MR)解读[J]. 中国循证医学杂志, 2022, 22(8): 978-987. [Liu M, Gao Y, Yang KL, et al. Interpretation of STROBE-MR: a statement for strengthening the reporting ofobservational studies in epidemiology using Mendelian randomization[J]. Chinese Journal of Evidence-Based Medicine, 2022, 22(8): 978-987.] http://qikan.cqvip.com/Qikan/Article/Detail?id=7107921163.

10.Zheng J, Baird D, Borges MC, et al. Recent developments in Mendelian randomization studies[J]. Curr Epidemiol Rep, 2017, 4(4): 330-345. DOI: 10.1007/s40471-017-0128-6.

11.Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944): 508-518. DOI: 10.1038/s41586-023-05837-8.

12.Ahola-Olli AV, Würtz P, Havulinna AS, et al. Genome-wide association study identifies 27 loci influencing concentrations of circulating cytokines and growth factors[J]. Am J Hum Genet, 2017, 100(1): 40-50. DOI: 10.1016/j.ajhg.2016.11.007.

13.Slatkin M. Linkage disequilibrium-understanding the evolutionary past and maping the medical future[J]. Nat Rev Genet, 2008, 9(6): 477-485. DOI: 10.1038/nrg2361.

14.Burgess S, Thompson SG, CRP CHD genetics collaboration. Avoiding bias from weak instruments in mendelian randomization studies[J]. Int J Epidemiol, 2011, 40(3): 755-764. DOI: 10.1093/ije/dyr036.

15.Chen H, Zhang Y, Li S, et al. The association between genetically predicted systemic inflammatory regulators and polycystic ovary syndrome: a mendelian randomization study[J]. Front Endocrinol (Lausanne), 2021, 12: 731569. DOI: 10.3389/fendo.2021.731569.

16.Yuan X, Gajan A, Chu Q, et al. Developing TRAIL/TRAIL death receptor-based cancer therapies[J]. Cancer Metastasis Rev, 2018, 37(4): 733-748. DOI: 10.1007/s10555-018-9728-y.

17.Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis[J]. Immunity, 1995, 3(6): 673-682. DOI: 10.1016/1074-7613(95)90057-8.

18.Allen JE, El-Deiry WS. Regulation of the human TRAIL gene[J]. Cancer Biol Ther, 2012, 13(12): 1143-1151. DOI: 10.4161/cbt.21354.

19.Piras-Straub K, Khairzada K, Trippler M, et al. TRAIL expression levels in human hepatocellular carcinoma have implications for tumor growth, recurrence and survival[J]. Int J Cancer, 2015, 136(4): E154-E160. DOI: 10.1002/ijc.29139.

20.Oikonomou E, Pintzas A. The TRAIL of oncogenes to apoptosis[J]. Biofactors, 2013, 39(4): 343-354. DOI: 10.1002/biof.1112.

21.代雪飞, 吕雄文. TRAIL及其受体在肝脏疾病中的作用研究进展[J]. 安徽医科大学学报, 2017, 52(2): 304-307. [Dai XF, Lyu XW. Research progress on the role of TRAIL and its receptors in liver disease[J]. Acta Universitatis Medicinalis Anhui, 2017, 52(2): 304-307.] DOI: 10.19405/j.cnki.issn1000-1492.2017.02.037.

22.Helmy SA, El-Mesery M, El-Karef A, et al. Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model[J]. Life Sci, 2019, 233: 116673. DOI: 10.1016/j.lfs.2019.116673.

23.冯全林, 曹晓蕾. TRAIL重组蛋白诱导肝癌细胞HepG2凋亡的研究[J]. 苏州大学学报(医学版), 2009, 29(6): 1072-1075. [Feng QL, Cao XL. Apoptpsis-inducing effect of HrsTRAIL on hepatoma cell line HepG2[J]. Suzhou University Journal of Medical Science, 2009, 29(6): 1072-1075.] https://d.wanfangdata.com.cn/periodical/ChlQZXJpb2RpY2FsQ0hJTmV3UzIwMjQwNzA0EhBzenl4eXhiMjAwOTA2MDE0GghpcGdiYWVjcA%3D%3D.

24.Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future[J]. Immunity, 2013, 39(6): 1003-1018. DOI: 10.1016/j.immuni.2013.11.010.

25.杨升, 卢辉山, 陈湘琦, 等. 白细胞介素-18对Lewis肺癌小鼠移植瘤生长及移植瘤细胞凋亡的作用[J]. 肿瘤防治研究, 2009, 36(7): 563-565. [Yang S, Lu HS, Chen XQ, et al. Effect of IL-18 on growth and apoptosis of Lewis lung cancer xenografts in C57BL/6 mice[J]. Cancer Research on Prevention and Treatment, 2009, 36(7): 563-565.] DOI: 10.3971/j.issn.1000-8578.2009.07.007.

26.李文玲, 赵文清, 周娜静, 等. 外源性IL-18基因对C6胶质瘤细胞体内致瘤抑制作用[J]. 细胞生物学杂志, 2008, 30(1): 95-99. [Li WL, Zhao WQ, Zhou NJ, et al. The exogenous IL-18 gene inhibits C6 glioma cell tumorigenesis in vivo[J]. Chinese Journal of Cell Biology, 2008, 30(1): 95-99.] DOI: 10.3969/j.issn.1674-7666. 2008.01.019.

27.崔澂, 郝淑维, 李新伟, 等. IL-18基因转染对小鼠卵巢癌OVHM体外增殖及体内成瘤的影响[J]. 细胞与分子免疫学杂志, 2008, 24(6): 577-580. [Cui C, Hao SW, Li XW, et al. Effects of IL-18 gene transfection on the proliferation in vitro and tumorigenesis in vivo of mouse ovarian cancer cell line OVHM[J]. Chinese Journal of Cellular and Molecular Immunology, 2008, 24(6): 577-580.] DOI: 10.3321/j.issn:1007-8738.2008.06.011.

28.官成浓, 廖湘晖, 罗海清, 等. 良恶性原发肝肿瘤患者血IL-18及IL-18BP含量测定及临床意义[J]. 中国肿瘤临床, 2009, 36(7): 365-367. [Guan CN, Liao XH, Luo HQ, et al. Clinical significance of serum IL-18 and IL-18BP in patients with benign or malignant primary liver tumor[J]. Chinese Journal of Clinical Oncology, 2009, 36(7): 365-367.] DOI: 10.3969/j.issn.1000-8179. 2009.07.002.

29.Markowitz GJ, Yang P, Fu J, et al. Inflammation-dependent IL18 signaling restricts hepatocellular carcinoma growth by enhancing the accumulation and activity of tumor-infiltrating lymphocytes[J]. Cancer Res, 2016, 76(8): 2394-2405. DOI: 10.1158/0008-5472.can-15-1548.

30.方艳秋, 米旭光, 李首庆, 等. 重组鼠白细胞介素18在肝癌小鼠体内的抗肿瘤作用[J]. 吉林大学学报(医学版), 2017, 43(3): 550-554. [Fang YQ, Mi XG, Li SQ, et al. Anti-tumor effect of rmIL-18 in mice with hepatocellular carcinoma[J]. Journal of Jilin University (Medicine Edition), 2017, 43(3): 550-554.] DOI: 10.13481/j.1671-587x.20170317.

31.刘磊玉, 唐圣松. 巨噬细胞集落刺激因子与肿瘤 [J]. 国外医学(肿瘤学分册), 2005, 32(7): 499-503. [Liu LY, Tang SS. Macrophage colony-stimulating factor and tumors[J]. Journal of International Oncology, 2005, 32(7): 499-503.] DOI: 10.3760/cma.j.issn.1673-422X. 2005.07.006.

32.Kirma N, Luthra R, Jones J, et al. Overexpression of the colony-stimulating factor (CSF-1) and/or its receptor c-fms in mammary glands of transgenic mice results in hyperplasia and tumor formation[J]. Cancer Res, 2004, 64(12): 4162-4170. DOI: 10.1158/0008-5472.can-03-2971.

33.Eubank TD, Galloway M, Montague CM, et al. M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes[J]. J Immunol, 2003, 171(5): 2637-2643. DOI: 10.4049/jimmunol.171.5.2637.

34.Kawakami Y, Nagai N, Ohama K, et al. Macrophage-colony stimulating factor inhibits the growth of human ovarian cancer cells in vitro[J]. Eur J Cancer, 2000, 36(15): 1991-1997. DOI: 10.1016/s0959-8049(00)00282-3.