食管癌小鼠食管组织中IL-17信号通路相关因子mRNA的表达
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摘要
目的:探讨食管癌变过程中IL-17信号通路相关因子的变化。方法:8只成年雄性C57BL/6J小鼠饮用4-硝基喹啉-1-氧化物(4-NQO)诱导食管癌模型(4-NQ组),5只正常饮水小鼠作对照。监测小鼠体重变化。28周后处死小鼠,取食管组织进行病理学观察;采用qRT-PCR方法检测小鼠食管组织中IL-17、IL-1β、IL-23、CXCL1、CXCL2、S100A8、S100A9、MMP-9和MMP-13 mRNA的表达。结果:4-NQO组小鼠体重增长缓慢;食管组织出现增生、炎症等改变,细胞异型性明显。与对照组小鼠相比,4-NQO组小鼠食管组织中IL-17、IL-23、IL-1β、CXCL1、CXCL2、S100A8、S100A9、MMP-9和MMP-13 mRNA的表达水平升高(P <0. 05)。4-NQO组小鼠食管组织中IL-23、CXCL1、CXCL2、S100A8、S100A9、MMP-9和MMP-13 mRNA与IL-17 mRNA的表达水平呈正相关(r=0. 918、0. 909、0. 725、0. 924、0. 941、0. 940和0. 943,P均<0. 05)。结论:IL-17可能通过促进CXCL1、CXCL2、S100A8、S100A9、MMP-9和MMP-13等相关基因的表达,参与食管癌的发生发展。
Aim: To investigate the changes of IL-17 signaling pathway-related gene expression in tumor microenvironment during esophageal carcinogenesis. Methods: The mouse esophageal cancer model was induced by treating adult male C57 BL/6 J mice with the carcinogen 4-nitroquinoline-1-oxide( 4-NQO) by drinking water( n = 8),and 5 mice drinking normal water were used as control. Body weight of the mice were monitored. After 28 weeks,the mice were killed and the esophagus was taken for histopathological examination. The mRNA expression levels of IL-17,IL-1β,IL-23,CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13 in mouse esophageal tissue were detected by qRT-PCR. Results: The weight of mice in the 4-NQO group was significantly lower than that in the control group( P < 0. 05). Pathological changes such as hyperplasia,inflammation and heteromorphism in the esophagus of the 4-NQO group were observed. Compared with the control group,the expression levels of IL-17,IL-23,IL-1β,CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13 mRNA were significantly up-regulated in the 4-NQO group( P < 0. 05). The expressions of IL-23,CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13 mRNA were significantly positively correlated with the expression level of IL-17 mRNA( r =0. 918,0. 909,0. 725,0. 924,0. 941,0. 940 and 0. 943,P < 0. 05). Conclusion: IL-17 may be involved in the development of esophageal cancer by promoting the expressions of CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13.
Aim: To investigate the changes of IL-17 signaling pathway-related gene expression in tumor microenvironment during esophageal carcinogenesis. Methods: The mouse esophageal cancer model was induced by treating adult male C57 BL/6 J mice with the carcinogen 4-nitroquinoline-1-oxide( 4-NQO) by drinking water( n = 8),and 5 mice drinking normal water were used as control. Body weight of the mice were monitored. After 28 weeks,the mice were killed and the esophagus was taken for histopathological examination. The mRNA expression levels of IL-17,IL-1β,IL-23,CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13 in mouse esophageal tissue were detected by qRT-PCR. Results: The weight of mice in the 4-NQO group was significantly lower than that in the control group( P < 0. 05). Pathological changes such as hyperplasia,inflammation and heteromorphism in the esophagus of the 4-NQO group were observed. Compared with the control group,the expression levels of IL-17,IL-23,IL-1β,CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13 mRNA were significantly up-regulated in the 4-NQO group( P < 0. 05). The expressions of IL-23,CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13 mRNA were significantly positively correlated with the expression level of IL-17 mRNA( r =0. 918,0. 909,0. 725,0. 924,0. 941,0. 940 and 0. 943,P < 0. 05). Conclusion: IL-17 may be involved in the development of esophageal cancer by promoting the expressions of CXCL1,CXCL2,S100 A8,S100 A9,MMP-9 and MMP-13.
引文
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[19]黄岚,张毅.肿瘤微环境中T细胞功能障碍及其逆转策略[J].中国肿瘤生物治疗杂志,2017,24(11):1247
[20]李静,欧周罗,邵志敏.微环境中间质细胞通过趋化因子对乳腺癌生长和转移的影响[J].中国肿瘤生物治疗杂志,2008,15(5):494
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[22]陈小梦,闫昊,左子欣,等.癌组织中MMP-9的表达对食管癌诊断价值的meta分析[J].郑州大学学报(医学版),2018,53(5):642
[2] CHEN W,ZHENG R,BAADE PD,et al. Cancer statistics in China,2015[J]. CA Cancer J Clin,2016,66(2):115
[3] HANAHAN D,WEINBERG RA. Hallmarks of cancer:the next generation[J]. Cell,2011,144(5):646
[4] NAGARSHETH N,WICHA MS,ZOU W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy[J]. Nat Rev Immunol,2017,17(9):559
[5] LIN EW,KARAKASHEVA TA,HICKS PD,et al. The tumor microenvironment in esophageal cancer[J]. Oncogene,2016,35(41):5337
[6] CHEN CL,WANG Y,HUANG CY,et al. IL-17 induces antitumor immunity by promoting beneficial neutrophil recruitment and activation in esophageal squamous cell carcinoma[J]. Oncoimmunology,2018,7(1):e1373234
[7] KORN T,BETTELLI E,OUKKA M,et al. IL-17 and Th17cells[J]. Annu Rev Immunol,2009,27:485
[8] HIROTA K,AHLFORS H,DUARTE JH,et al. Regulation and function of innate and adaptive interleukin-17-producing cells[J]. EMBO Rep,2012,13(2):113
[9] WANG B,LI L,LIAO Y,et al. Mast cells expressing interleukin 17 in the muscularis propria predict a favorable prognosis in esophageal squamous cell carcinoma[J].Cancer Immunol Immunother,2013,62(10):1575
[10]陈慧,高鑫,李刚,等. 4NQO诱发C57BL/6小鼠舌癌及食管鳞状细胞癌模型的建立[J].苏州大学学报(医学版),2010,30(5):972
[11]WANG R,YANG L,ZHANG C,et al. Th17 cell-derived IL-17A promoted tumor progression via STAT3/NF-kappa B/Notch1 signaling in non-small cell lung cancer[J]. Oncoimmunology,2018,7(11):e1461303
[12]MURUGAIYAN G,SAHA B. Protumor vs antitumor functions of IL-17[J]. J Immunol,2009,183(7):4169
[13]DOWELL AC,COBBY E,WEN K,et al. Interleukin-17-positive mast cells influence outcomes from BCG for patients with CIS:data from a comprehensive characterisation of the immune microenvironment of urothelial bladder cancer[J]. PLo S One,2017,12(9):e0184841
[14]王平,武传星,吕凌,等. IL-17在原发性肝癌组织中的表达及其临床意义[J].中国肿瘤生物治疗杂志,2011,18(2):216
[15]HURTADO CG,WAN FY,HOUSSEAU F,et al. Roles for interleukin 17 and adaptive immunity in pathogenesis of colorectal cancer[J]. Gastroenterology,2018,155(6):1706
[16]MCGEACHY MJ,CUA DJ,GAFFEN SL. The IL-17 family of cytokines in health and disease[J]. Immunity,2019,50(4):892
[17]LOWES MA,RUSSELL CB,MARTIN DA,et al. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses[J]. Trends Immunol,2013,34(4):174
[18]MIOSSEC P,KOLLS JK. Targeting IL-17 and TH17 cells in chronic inflammation[J]. Nat Rev Drug Discov,2012,11(10):763
[19]黄岚,张毅.肿瘤微环境中T细胞功能障碍及其逆转策略[J].中国肿瘤生物治疗杂志,2017,24(11):1247
[20]李静,欧周罗,邵志敏.微环境中间质细胞通过趋化因子对乳腺癌生长和转移的影响[J].中国肿瘤生物治疗杂志,2008,15(5):494
[21]LUKANIDIN E,SLEEMAN JP. Building the niche:the role of the S100 proteins in metastatic growth[J]. Semin Cancer Biol,2012,22(3):216
[22]陈小梦,闫昊,左子欣,等.癌组织中MMP-9的表达对食管癌诊断价值的meta分析[J].郑州大学学报(医学版),2018,53(5):642