The study of N-methyl-N-nitrosourea combined with Helicobacter pylori infection inducing gastric inflammation-cancer transformation process in mice
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摘要: 目的 探讨N-甲基-N-亚硝基脲(MNU)联合幽门螺杆菌(Hp)在C57BL/6J小鼠胃黏膜“炎-癌”转化进程中的作用。方法 将112只C57BL/6J小鼠分为对照组(3、6、9、12个月，n=8)和模型组(3、6、9、12个月，n=20)，模型组小鼠使用MNU灌胃联合Hp感染法造模，2组小鼠分别在3、6、9、12个月时进行取材，观察胃黏膜的肿瘤成瘤情况及该造模方式对胃炎症因子转录水平的影响。结果 MNU联合Hp造模9个月组和12个月组的成瘤率分别约为30%和40%，在造模后的9个月和12个月，胃黏膜可见大量炎性细胞浸润，主要为淋巴细胞和嗜酸粒细胞，并伴有胃黏膜异型增生改变。肿瘤坏死因子(TNF-α)mRNA水平在感染后6、9、12个月均显著上调。白介素-1β(IL-1β)mRNA在造模后3、6个月均显著上调，并在12个月出现显著下调。此外，IL-33的mRNA水平上调不明显，在12个月模型组中IL-33水平显著下调。结论 MNU联合Hp造模显示出明显的炎症浸润表现，在9个月组和12个月组的成瘤率分别约为30%和40%。联合造模可加速C57BL/6J小鼠胃黏膜慢性胃炎至异型增生的病理改变的进程。
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关键词:
- 幽门螺杆菌 /
- N-甲基-N-亚硝基脲 /
- “炎-癌”转化 /
- 解痉多肽表达化生 /
- 异型增生
Abstract: Objective To investigate the role of N-methyl-N-nitrosourea (MNU) combined with Helicobacter pylori (Hp) in the "inflammation-cancer" transformation process of gastric mucosa in C57BL/6J mice.Methods A total of 112 C57BL/6J mice were divided into a control group (3, 6, 9, 12 months, n=8) and a model group (3, 6, 9, 12 months, n=20). Mice in the model group were molded by MNU combined with Hp infection. Tissues were collected from the mice in the modeling group at 3, 6, 9, and 12 months respectively, to observe tumor formation in gastric mucosa and the impact of this modeling method on the transcription levels of gastric inflammation factors.Results The tumor formation rates in the 9-month and 12-month groups of MNU combined with Hp modeling were approximately 30% and 40%, respectively. After modeling for 9 and 12 months, extensive infiltration of inflammatory cells, mainly lymphocytes and eosinophils, was observed in the gastric mucosa, accompanied by dysplastic changes. The mRNA levels of TNF-α showed a significant upregulation in the 6, 9, and 12-month groups after infection. IL-1β was significantly upregulated in the 3, and 6-month groups and declined in the 12-month group. The expression of IL-33, associated with precancerous lesions of gastric cancer, did not show significant upregulation in this study but was significantly downregulated in the 12-month model group.Conclusion MNU combined with Hp modeling showed significant manifestations of inflammation infiltration, with tumor formation rates of approximately 30% and 40% in the 9-month and 12-month groups, respectively. This combined modeling can accelerate the pathological changes from chronic gastritis to dysplasia in C57BL/6J mouse gastric mucosa. -
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[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] 严鑫鑫, 曹毛毛, 滕熠, 等. 中国与全球胃癌负担及归因于人口老龄化的比例及趋势分析[J]. 中华肿瘤防治杂志, 2024, 31(4): 196-204. https://www.cnki.com.cn/Article/CJFDTOTAL-QLZL202404003.htm
[3] 王文帆, 王汉, 程义涛, 等. 中医药治疗胃癌前病变研究进展[J]. 亚太传统医药, 2024, 20(1): 239-242. https://www.cnki.com.cn/Article/CJFDTOTAL-YTCT202401050.htm
[4] He Y, Wang Y, Luan F, et al. Chinese and global burdens of gastric cancer from 1990 to 2019[J]. Cancer Med, 2021, 10(10): 3461-3473. doi: 10.1002/cam4.3892
[5] Correa P. A human model of gastric carcinogenesis[J]. Cancer Res, 1988, 48(13): 3554-2560.
[6] Thrift AP, El-Serag HB. Burden of Gastric Cancer[J]. Clin Gastroenterol Hepatol, 2020, 18(3): 534-542. doi: 10.1016/j.cgh.2019.07.045
[7] 李远盛. 中日胃癌发病趋势比较及中国胃癌发病率的空间自相关分析[D]. 泸州: 西南医科大学, 2023.
[8] 宋聪华. 幽门螺杆菌与Correa's Cascade关系及ERM家族在其中的机制探究[D]. 南昌: 南昌大学, 2021.
[9] Kuo HY, Chang WL, Yeh YC, et al. Spasmolytic polypeptide-expressing metaplasia associated with higher expressions of miR-21, 155, and 223 can be regressed by Helicobacter pylori eradication in the gastric cancer familial relatives[J]. Helicobacter, 2019, 24(3): e12578. doi: 10.1111/hel.12578
[10] Jeong H, Lee B, Kim KH, et al. WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury[J]. Gastroenterology, 2021, 161(3): 953-967.e15. doi: 10.1053/j.gastro.2021.05.058
[11] Lian DW, Xu YF, Ren WK, et al. Unraveling the Novel Protective Effect of Patchouli Alcohol Against Helicobacter pylori-Induced Gastritis: Insights Into the Molecular Mechanism in vitro and in vivo[J]. Front Pharmacol, 2018, 9: 1347. doi: 10.3389/fphar.2018.01347
[12] Xu YF, Lian DW, Chen YQ, et al. In Vitro and In Vivo Antibacterial Activities of Patchouli Alcohol, a Naturally Occurring Tricyclic Sesquiterpene, against Helicobacter pylori Infection[J]. Antimicrob Agents Chemother, 2017, 61(6): e00122-17.
[13] Hong X, Li H, Lin Y, et al. Efficacy and potential therapeutic mechanism of Weiwei decoction on Spasmolytic polypeptide-expressing metaplasia in Helicobacter pylori-infected and Atp4a-knockout mice[J]. J Ethnopharmacol, 2024, 319(Pt1): 117062.
[14] 高远飞, 魏秋亚, 张栋岩, 等. 基因多态性与饮食在胃癌中的作用研究进展[J]. 现代医学, 2023, 51(7): 1012-1018. doi: 10.3969/j.issn.1671-7562.2023.07.022
[15] 陈涛, 薛春丽, 张菡, 等. 中医药治疗幽门螺杆菌感染性慢性胃炎研究进展[J]. 河南中医, 2024, 44(2): 311-316. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZY202402031.htm
[16] 李慧敏, 高锦明. NF-κB在幽门螺杆菌诱导胃癌发展及治疗中的作用研究进展[J]. 现代肿瘤医学, 2023, 31(23): 4476-4480. doi: 10.3969/j.issn.1672-4992.2023.23.035
[17] 齐乐, 唐敏, 汪文生, 等. 慢性萎缩性胃炎患者幽门螺旋杆菌感染情况调查及其耐药性分析[J]. 中国病原生物学杂志, 2021, 16(10): 1216-1219. https://www.cnki.com.cn/Article/CJFDTOTAL-ZISC202110021.htm
[18] 孙振灿, 张晓彤, 王军, 等. 幽门螺杆菌毒力因子及其诱发胃癌作用机制研究进展[J]. 山东医药, 2024, 64(2): 104-107. https://www.cnki.com.cn/Article/CJFDTOTAL-SDYY202402026.htm
[19] Zhou XZ, Lyu NH, Zhu HY, et al. Large-scale, national, family-based epidemiological study on Helicobacter pylori infection in China: the time to change practice for related disease prevention[J]. Gut, 2023, 72(5): 855-869. doi: 10.1136/gutjnl-2022-328965
[20] Loogna P, Franzén L, Sipponen P, et al. Effects of Helicobacter pylori and bile on N-methyl-N'-nitro-N'-nitrosoguanidine exposed antral mucosa of C57BU6 mice[J]. Virchows Arch, 2001, 439(5): 661-667. doi: 10.1007/s004280100456
[21] Pritchard DM, Przemeck SM. Review article: How useful are the rodent animal models of gastric adenocarcinoma?[J]. Aliment Pharmacol Ther, 2004, 19(8): 841-859. doi: 10.1111/j.1365-2036.2004.01911.x
[22] 张水莲. 组蛋白修饰参与化学致癌剂MNNG和MNU诱发人胃粘膜上皮细胞恶性转化的机制研[D]. 杭州: 浙江大学, 2016.
[23] Han SU, Kim YB, Joo HJ, et al. Helicobacter pylori infection promotes gastric carcinogenesis in a mice model[J]. J Gastroenterol Hepatol, 2002, 17(3): 253-261. doi: 10.1046/j.1440-1746.2002.02684.x
[24] Kim DH, Kim SW, Song YJ, et al. Long-term evaluation of mice model infected with Helicobacter pylori: focus on gastric pathology including gastric cancer[J]. Aliment Pharmacol Ther, 2003, 18 Suppl 1: 14-23.
[25] Kang S, Park M, Cho JY, et al. Tumorigenic mechanisms of estrogen and Helicobacter pylori cytotoxin-associated gene A in estrogen receptor α-positive diffuse-type gastric adenocarcinoma[J]. Gastric Cancer, 2022, 25(4): 678-696. doi: 10.1007/s10120-022-01290-0
[26] Lee A, O'Rourke J, De Ungria MC, et al. A standardized mouse model of Helicobacter pylori infection: introducing the Sydney strain[J]. Gastroenterology, 1997, 112(4): 1386-1397. doi: 10.1016/S0016-5085(97)70155-0
[27] 王剑, 王吉耀, 沈锡中, 等. 幽门螺杆菌感染Balb/c小鼠模型的建立及对N-甲基-N-亚硝基脲诱发胃癌的影响[J]. 中华消化杂志, 2005, 25(3): 146-149. https://www.cnki.com.cn/Article/CJFDTOTAL-ZHHX200503006.htm
[28] 钟婵, 张涛, 黄李冰雪, 等. 清热化湿方对MNU联合幽门螺杆菌感染小鼠胃组织中TNF-α、IL-8及TLR-4水平的影响[J]. 中成药, 2020, 42(5): 1339-1343. https://www.cnki.com.cn/Article/CJFDTOTAL-ZCYA202005046.htm
[29] 刘雨溪, 王璐, 龙凯花, 等. 慢性萎缩性胃炎及癌前病变复合造模法评价[J]. 山西医科大学学报, 2024, 55(2): 170-174. https://www.cnki.com.cn/Article/CJFDTOTAL-SXYX202402006.htm
[30] 王睿斌, 赵艳杰, 乔士峰. 幽门螺杆菌感染与胃癌前病变及胃癌形成关系的动物试验研究[J]. 临床医学, 2005, 25(10): 19-21. https://www.cnki.com.cn/Article/CJFDTOTAL-EBED200510011.htm
[31] Dincǎ AL, Meliţ LE, Mǎrginean CO. Old and New Aspects of H. pylori-Associated Inflammation and Gastric Cancer[J]. Children (Basel), 2022, 9(7): 1083.
[32] Morningstar-Wright L, Czinn SJ, Piazuelo MB, et al. The TNF-Alpha Inducing Protein is Associated With Gastric Inflammation and Hyperplasia in a Murine Model of Helicobacter pylori Infection[J]. Front Pharmacol, 2022, 13: 817237.
[33] Shigematsu Y, Niwa T, Rehnberg E, et al. Interleukin-1β induced by Helicobacter pylori infection enhances mouse gastric carcinogenesis[J]. Cancer Lett, 2013, 340(1): 141-147.
[34] Han Y, Zhang YY, Pan YQ, et al. IL-1β-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance[J]. Mol Cell, 2023, 83(11): 1887-1902.e8.
[35] Li ML, Hong XX, Zhang WJ, et al. Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia[J]. World J Clin Cases, 2023, 11(16): 3714-3724.
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