91种炎症蛋白与胆道癌发病风险的因果关系

Journal: Basic Medical Theory Research DOI: 10.12238/bmtr.v6i5.10088

赵亚军1, 冯立2

1. 内蒙古医科大学
2. 北京大学肿瘤医院内蒙古医院

Abstract

背景:胆道恶性肿瘤(BTC)是一种极为恶性的肿瘤,其5年生存率通常低于5%。炎症在BTC的发病机制中扮演重要角色,但目前关于炎症与BTC之间的因果关系研究仍较为匮乏。目的:本研究旨在通过两样本双向孟德尔随机化分析,评估炎症相关蛋白与BTC之间的潜在因果关系。方法:我们使用GWAS数据中的遗传变异(SNP)作为工具变量,依据关联性、独立性和排他性假设筛选有效的工具变量。炎症相关蛋白的数据来源于GWAS Catalog(包含14824名欧洲人),而BTC的数据则来自IEU数据库(包括196084名东亚人)。工具变量筛选标准为SNP阈值P<5×10-8,排除连锁不平衡影响,F统计量>10。分析采用R软件包,包括IVW法、WM法和MR-Egger回归等方法。敏感性分析通过Cochran's Q统计量检验异质性,并使用MR-Egger回归和MR-PRESSO评估水平多效性。结果:我们发现7种炎症相关蛋白与BTC存在显著的因果关系,其中4种为BTC的危险因素,包括CD40L受体、成纤维细胞生长因子23(FGF23)、胶质细胞源性神经营养因子(GDNF)和白介素7(IL-7);另外3种为BTC的保护因素,包括神经生长因子β(β-NGF)、S100A12蛋白(S100-A12)和γ干扰素(INFγ)。结论:这些发现对于深入理解BTC的发病机制及其预防和治疗策略具有重要指导意义。

Keywords

孟德尔随机化;炎症相关蛋白;胆道恶性肿瘤;GWAS数据;因果关系

References

[1] ValleJW,KelleyRK,NerviB,etal.Biliary tract cancer[J].Lancet,2021,397(10272):428-444.
[2] RizviS,GoresGJ.Molecular pathogenesis of cholangiocar cinoma[J].Digestive Diseases,2014,32(5):564-569.
[3] LeoneV,AliA,WeberA,etal.LiverInflammationandHepatobiliaryCancers[J].TrendsinCancer,2021,7(7):606-623.
[4] LandskronG,DelaFuenteM,ThuwajitP,etal.Chronic inflam mation and cytokines in the tumor microenvironment[J].Jour nal of Immunology Research,2014,2014:149185.
[5] LiY,ZhangJ,MaH.Chronic inflammation and gallbladder cancer[J].CancerLetters,2014,345(2):242-248.
[6] BurgessS,DaveySmithG,DaviesNM,etal.Guidelines for per forming Mendelian randomization investigations: update forsummer2023[J].WellcomeOpenResearch,2023,4:186.
[7] QiuS,ZhengK,HuY,etal.Genetic correlation,causal relati onship, and shared loci between vitamin D and COVID-19: A genome-wide cross-trait analysis[J].Journal of Medical Virology,2023,95(5):e28780.
[8] ZhaoJH,StaceyD,ErikssonN,etal.Geneticsof circulating inflammatory proteins identifies drivers of immune-mediat ed disease risk and therapeutic targets[J].Nature Immunology, 2023,24(9):1540-1551.
[9] SadeghlarF,VogtA,MohrRU,etal.Inductionof cytotoxic ef fector cells towards cholangiocellular, pancreatic, and colore ctal tumor cells by activation of the immune checkpoint CD40/ CD40L on dendritic cells[J].Cancer Immunology Immunotherapy, 2021,70(5):1451-1464.
[10] TangT,ChengX,TruongB,etal.Molecular basis and thera peutic implications of CD40/CD40L immune checkpoint[J]. Phar macologicalTherapeutics,2021,219:107709.
[11] MaC,FuQ,DiggsLP,etal.Platelets control liver tumor gr owth through P2Y12-dependent CD40L release in NAFLD[J].Cancer Cell,2022,40(9):986-998.e5.
[12] ShimadaT, Hasegawa H, Yamazaki Y,etal.FGF-23 is a pot ent regulator of vitamin D metabolism and phosphate homeos tasis[J].Journal of Bone and Mineral Research,2004,19(3):429-435.
[13] EwendtF,FegerM,FöllerM.Roleof Fibroblast Growth Fac tor 23 (FGF23) and αKlotho in Cancer[J]. Frontiers in Cell and Developmental Biology,2021,8:601006.
[14] Al-HassiHO,AliNM,CookeH,etal.FGF23ExpressionIs a Pr omising Immunohistochemical Diagnostic Marker for Undiffere ntiated Pleomorphic Sarcoma of Bone (UPSb)[J].Genes,2024,15 (2):242.
[15] CotantCL,RaoPS. Elevated fibroblast growth factor 23 in a patient with metastatic prostate cancer and hypophospha temia[J]. American Journal of Kidney Diseases,2007,50(6):1033 -1036.
[16] KatohM. FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review) [J].International Journal of Molecular Medicine,2016,38(1):3 -15.
[17] FielderGC,YangTW,RazdanM,etal.TheGDNFFamily:ARoleinCancer?[J].Neoplasia,2018,20(1):99-117.
[18] WhiteleyAE,MaD,WangL,etal.Breastcancer exploits neu ral signaling pathways for bone-to-meninges metastasis[J].Science,2024,384(6702):eadh5548.
[19] GaoJ,ZhaoL,WanYY,Zhu B. Mechanism of Action of IL-7 and Its Potential Applications and Limitations in Cancer Imm unotherapy[J].International Journal of Molecular Sciences, 2015,16(5):10267-10280.
[20] MengusC,LeMagnenC,TrellaE,etal.Elevated levels of ci rculating IL-7 and IL-15 in patients with early stage pros tate cancer[J]. Journal of Translational Medicine,2011,9:162.
[21] RoatoI,CaldoD,GodioL,etal.Bone invading NSCLC cells produce IL-7:mice model and human histologic data[J].BMCCa ncer,2010,10:12.
[22] Krzystek-KorpackaM,ZawadzkiM,NeubauerK, etal.Eleva ted systemic interleukin-7 in patients with colorectal cancer and individuals at high risk of cancer: association with lymph node involvement and tumor location in the right colon[J]. Cancer Immunology Immunotherapy,2017,66(2):171-179.
[23] BradshawAR,PundavelaJ,BiarcJ,etal.NGFandProNGF:Regulation of neuronal and neoplastic responses through recep tor signaling[J]. Advances in Biological Regulation,2015,58: 16-27.
[24] 王馥丽,刘文兴,曹立瀛,等.神经生长因子NGF及其受体TrkA、p75NTR在胆管中下段癌中的表达及其与神经浸润关系的研究[J].中国煤炭工业医学杂志,2020,23(01):74-78.
[25] Nico B, Mangieri D, Benagiano V, et al. Nerve growth factor as an angiogenic factor[J]. Microvascular Research, 2008,75(2):135-141.
[26] 孟令新,丁兆军,陈希平,等.神经生长因子促进MIAPaCa-2人胰腺癌细胞的增殖[J].中国肿瘤生物治疗杂志,2010,17(1):88-92.
[27] FunkS,MarkR,BayoP,etal.High S100A8 and S100A12 pro tein expression is a favorable prognostic factor for survival of oropharyngeal squamous cell carcinoma[J].International Journal of Cancer,2015,136(9):2037-2046.
[28] MintsM,LandinD,NäsmanA,etal.Tumour inflammation si gnature and expression of S100A12 and HLA class I improve survival in HPV-negative hypopharyngeal cancer[J].Scientific Reports,2021,11(1):1782.
[29] HeL,XiaoX,YangX,etal.STING signaling in tumorigenesis and cancer therapy: A friend or foe?[J].Cancer Letters,2017, 402:203-212.
[30] AlspachE,LussierDM,Schreiber R D. Interferon γ and Its Important Roles in Promoting and Inhibiting Spontaneous and Therapeutic Cancer Immunity[J].Cold Spring Harbor Persp ectives in Biology,2019,11(3):a028480.
[31] YamashitaN,LongM,FushimiA,etal.MUC1-Cintegrates ac tivation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer[J]. Journal for Immunotherapy of Cancer,2021,9(1):e002115.
[32] CastroF,CardosoAP,GonçalvesRM,etal.Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion [J].Frontiers in Immunology,2018,9:847.
[33] LiFL,GuLH,TongYL,etal.INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN- γ signaling[J].Acta PharmacologicaSinica,2024.

Copyright © 2024 赵亚军, 冯立

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License