牙龈卟啉单胞菌诱发炎症微环境促进食管鳞状细胞癌发生
目的:探讨牙龈卟啉单胞菌诱发食管炎症微环境在小鼠食管鳞状细胞癌发生过程中的作用。方法:采用数字表法随机将180只C57BL/6小鼠分为对照组、牙龈卟啉单胞菌组、4-硝基喹啉-1-氧化物（4NQO）组、4NQO+牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞菌+抗生素（甲硝唑、新霉素、氨苄青霉素和万古霉素，ABC）组，每组30只。给予ABC饮水2周，之后8周，对照组和牙龈卟啉单胞菌组小鼠饮用纯水，其余4组给予含30 μg/ml 4NQO的饮水。第11～12周，牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞...
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| Published in | 中华肿瘤杂志 Vol. 46; no. 8; pp. 746 - 754 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | Chinese |
| Published |
河南科技大学临床医学院 河南科技大学第一附属医院肿瘤医院，省部共建食管癌防治国家重点实验室，河南省微生态与食管癌防治重点实验室，河南省肿瘤表观遗传重点实验室，洛阳471003%许昌学院医学院细胞行为学重点实验室，许昌461000%洛阳理工学院数学与物理教学部，洛阳471023%洛阳市第一人民医院病理科，洛阳471000
23.08.2024
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0253-3766 |
| DOI | 10.3760/cma.j.cn112152-20231026-00259 |
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| Abstract | 目的:探讨牙龈卟啉单胞菌诱发食管炎症微环境在小鼠食管鳞状细胞癌发生过程中的作用。方法:采用数字表法随机将180只C57BL/6小鼠分为对照组、牙龈卟啉单胞菌组、4-硝基喹啉-1-氧化物（4NQO）组、4NQO+牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞菌+抗生素（甲硝唑、新霉素、氨苄青霉素和万古霉素，ABC）组，每组30只。给予ABC饮水2周，之后8周，对照组和牙龈卟啉单胞菌组小鼠饮用纯水，其余4组给予含30 μg/ml 4NQO的饮水。第11～12周，牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞菌+ABC组小鼠行上颌第2磨牙结扎；第11～34周，每周3次口腔感染牙龈卟啉单胞菌。第13～34周，4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞菌+ABC组小鼠分别接受塞来昔布和ABC处理。34周后处死小鼠，观察小鼠食管黏膜大体和形态学变化，采用实时荧光定量聚合酶链反应（RT-qPCR）和免疫组化检测小鼠食管组织中炎症和肿瘤相关分子表达。结果:34周时，4NQO单独处理未能显著增加小鼠食管黏膜乳头状增生病灶数、病变面积和食管壁厚度，单纯性增生病灶数（中位数为1.00个，
P＜0.05）和轻、中度不典型增生病灶数（中位数为2.00个，
P＜0.01）显著增加，小鼠食管组织中白细胞介素6（IL-6）、IL-1β、肿瘤坏死因子α（TNF-α）、c-myc mRNA的表达量［分别为8.35（3.45，8.99）、6.90（2.01，9.72）、12.04（3.31，14.08）、2.21（1.80，3.04），均
P＜0.05］和磷酸化信号转导和转录激活因子3（pSTAT3）、Ki-67、磷酸化组蛋白2A变异体（pH2AX）蛋白的表达明显高于对照组。4NQO+牙龈卟啉单胞菌组小鼠食管黏膜病变显著，乳头状增生病灶数（中位数为2.00个）、病变面积（中位数为2.51 mm
2）和食管壁厚度（中位数为172.52 μm）最大，且均与对照组差异有统计学意义（均
P＜0.01），单纯性增生病灶数（中位数为1.00个，
P＜0.05）和轻、中度不典型增生病灶数（中位数为1.00个，
P＜0.01）显著增加，小鼠食管组织中IL-6、IL-1β、TNF-α、γ-干扰素（IFN-γ）、c-myc、cyclin D1 mRNA的表达量［ |
|---|---|
| AbstractList | 目的:探讨牙龈卟啉单胞菌诱发食管炎症微环境在小鼠食管鳞状细胞癌发生过程中的作用。方法:采用数字表法随机将180只C57BL/6小鼠分为对照组、牙龈卟啉单胞菌组、4-硝基喹啉-1-氧化物（4NQO）组、4NQO+牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞菌+抗生素（甲硝唑、新霉素、氨苄青霉素和万古霉素，ABC）组，每组30只。给予ABC饮水2周，之后8周，对照组和牙龈卟啉单胞菌组小鼠饮用纯水，其余4组给予含30 μg/ml 4NQO的饮水。第11～12周，牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌组、4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞菌+ABC组小鼠行上颌第2磨牙结扎；第11～34周，每周3次口腔感染牙龈卟啉单胞菌。第13～34周，4NQO+牙龈卟啉单胞菌+塞来昔布组和4NQO+牙龈卟啉单胞菌+ABC组小鼠分别接受塞来昔布和ABC处理。34周后处死小鼠，观察小鼠食管黏膜大体和形态学变化，采用实时荧光定量聚合酶链反应（RT-qPCR）和免疫组化检测小鼠食管组织中炎症和肿瘤相关分子表达。结果:34周时，4NQO单独处理未能显著增加小鼠食管黏膜乳头状增生病灶数、病变面积和食管壁厚度，单纯性增生病灶数（中位数为1.00个，
P＜0.05）和轻、中度不典型增生病灶数（中位数为2.00个，
P＜0.01）显著增加，小鼠食管组织中白细胞介素6（IL-6）、IL-1β、肿瘤坏死因子α（TNF-α）、c-myc mRNA的表达量［分别为8.35（3.45，8.99）、6.90（2.01，9.72）、12.04（3.31，14.08）、2.21（1.80，3.04），均
P＜0.05］和磷酸化信号转导和转录激活因子3（pSTAT3）、Ki-67、磷酸化组蛋白2A变异体（pH2AX）蛋白的表达明显高于对照组。4NQO+牙龈卟啉单胞菌组小鼠食管黏膜病变显著，乳头状增生病灶数（中位数为2.00个）、病变面积（中位数为2.51 mm
2）和食管壁厚度（中位数为172.52 μm）最大，且均与对照组差异有统计学意义（均
P＜0.01），单纯性增生病灶数（中位数为1.00个，
P＜0.05）和轻、中度不典型增生病灶数（中位数为1.00个，
P＜0.01）显著增加，小鼠食管组织中IL-6、IL-1β、TNF-α、γ-干扰素（IFN-γ）、c-myc、cyclin D1 mRNA的表达量［ |
| Abstract_FL | Objective:To investigate the role of an inflammatory microenvironment induced by
Porphyromonasgingivalis (
P. gingivalis) in the occurrence of esophageal squamous cell carcinoma (ESCC) in mice.
Methods:A total of 180 C57BL/6 mice were randomly divided into 6 groups, i.e. control group,
P. gingivalis group, 4NQO group, 4NQO +
P. gingivalis group, 4NQO +
P. gingivalis + celecoxib group, and 4NQO +
P. gingivalis + antibiotic cocktail (ABC, including metronidazole, neomycin, ampicillin, and vancomycin) group, with 30 mice in each group, using the random number table. All mice were normalized by treatment with ABC in drinking water for 2 weeks. In the following 2 weeks, the mice in the control group and the
P. gingivalis group were given drinking water, while the other 4 groups were treated with 30 μg/ml 4NQO in the drinking water. In weeks 11-12, the mice in the
P. gingivalis group, the 4NQO +
P. gingivalis group, the 4NQO +
P. gingivalis + celecoxib group, and the 4NQO +
P. gingivalis + ABC group were subjected to ligation of the second molar in oral cavity followed by oral
P. gingivalis infection thrice weekly for 24 weeks in weeks 11-34. In weeks 13-34, the mice in 4NQO +
P. gingivalis+celecoxib group and 4NQO +
P. gingivalis + ABC group were administered with celecoxib and ABC for 22 weeks, respectively. At the end of 34 weeks, gross and microscopic alterations were examined followed by RT-qPCR and immunohistochemistry to examine the expression profiles of inflammatory- and tumor-molecules in esophagi of mice.
Results:At 34 weeks, 4NQO treatment alone did not affect the foci of papillary hyperproliferation, diseased area, and the thickness of the esophageal wall, but significantly enhanced the foci of hyperproliferation (median 1.00,
P＜0.05) and mild/moderate dysplasia (median 2.00,
P＜0.01). In addition, the expression levels of IL-6 [8.35(3.45,8.99)], IL-1β [6.90(2.01,9.72)], TNF-α [12.04(3.31,14.08)], c-myc [2.21(1.80,3.04)], pSTAT3, Ki-67, and pH2AX were higher than those in the control group. The pathological changes of the esophageal mucosa were significantly more overt in the 4NQO +
P. gingivalis group in terms of the foci of papillary hyperproliferation (median 2.00), diseased area (median 2.51 mm
2), the thickness of the esophageal wall (median 172.52 μm), the foci of hyperproliferation (median 1.00,
P＜0.05), and mild/moderate dysplasia (median 1.00,
P＜0.01). In mice of the 4NQO +
P. gingivalis group, the expression levels of IL-6 [12.27(5.35,22.08)], IL-1β [13.89(10.04,15.96)], TNF-α [19.56(6.07,20.36)], IFN-γ [11.37(8.23,20.07)], c-myc [2.62(1.51,4.25)], cyclin D1 [4.52(2.68,7.83)], nuclear pSTAT3, COX-2, Ki-67, and pH2AX were significantly increased compared with the mice in the control group. In mice of the 4NQO +
P. gingivalis group, the diseased area, invasive malignant foci as well as pSTAT3 and pH2AX expression were significantly blunted by celecoxib. Treatment with ABC markedly reduced the papillary hyperproliferative foci, invasive malignant foci, and pSTAT3 expression but not pH2AX.
Conclusions:P. gingivalis promotes the occurrence of esophageal squamous cell carcinoma in mice by inducing an inflammatory microenvironment primed with 4NQO induced DNA damage. Clearance of
P. gingivalis with ABC or anti-inflammatory intervention holds promise for prevention of esophageal squamous cell malignant pathogenesis via blockage of IL-6/STAT3 signaling and amelioration of inflammation. |
| Author | 阮豪杰 焦叶林 许海军 高社干 伍当柔 陈攀 李孟祥 齐义军 刘其伟 李智涛 |
| AuthorAffiliation | 河南科技大学临床医学院 河南科技大学第一附属医院肿瘤医院，省部共建食管癌防治国家重点实验室，河南省微生态与食管癌防治重点实验室，河南省肿瘤表观遗传重点实验室，洛阳471003%许昌学院医学院细胞行为学重点实验室，许昌461000%洛阳理工学院数学与物理教学部，洛阳471023%洛阳市第一人民医院病理科，洛阳471000 |
| AuthorAffiliation_xml | – name: 河南科技大学临床医学院 河南科技大学第一附属医院肿瘤医院，省部共建食管癌防治国家重点实验室，河南省微生态与食管癌防治重点实验室，河南省肿瘤表观遗传重点实验室，洛阳471003%许昌学院医学院细胞行为学重点实验室，许昌461000%洛阳理工学院数学与物理教学部，洛阳471023%洛阳市第一人民医院病理科，洛阳471000 |
| Author_FL | Jiao Yelin Ruan Haojie Li Mengxiang Chen Pan Li Zhitao Xu Haijun Qi Yijun Liu Qiwei Wu Dangrou Gao Shegan |
| Author_FL_xml | – sequence: 1 fullname: Xu Haijun – sequence: 2 fullname: Qi Yijun – sequence: 3 fullname: Wu Dangrou – sequence: 4 fullname: Liu Qiwei – sequence: 5 fullname: Chen Pan – sequence: 6 fullname: Li Mengxiang – sequence: 7 fullname: Jiao Yelin – sequence: 8 fullname: Ruan Haojie – sequence: 9 fullname: Li Zhitao – sequence: 10 fullname: Gao Shegan |
| Author_xml | – sequence: 1 fullname: 许海军 – sequence: 2 fullname: 齐义军 – sequence: 3 fullname: 伍当柔 – sequence: 4 fullname: 刘其伟 – sequence: 5 fullname: 陈攀 – sequence: 6 fullname: 李孟祥 – sequence: 7 fullname: 焦叶林 – sequence: 8 fullname: 阮豪杰 – sequence: 9 fullname: 李智涛 – sequence: 10 fullname: 高社干 |
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| DocumentTitle_FL | Porphyromonas gingivalis promotes the occurrence of esophageal squamous cell carcinoma via an inflammatory microenvironment |
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| Keywords | Porphyromonas gingivalis Inflammatory microenvironment 白细胞介素6 环氧合酶2 Interleukin-6 炎症微环境 信号转导和转录激活因子3 4-nitroquinoline-1-oxide 食管鳞状细胞癌 Signal transducer and 牙龈卟啉单胞菌 4-硝基喹啉-1-氧化物 组蛋白2A变异体 Esophageal squamous cell carcinoma |
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| PublicationTitle | 中华肿瘤杂志 |
| PublicationTitle_FL | Chinese Journal of Oncology |
| PublicationYear | 2024 |
| Publisher | 河南科技大学临床医学院 河南科技大学第一附属医院肿瘤医院，省部共建食管癌防治国家重点实验室，河南省微生态与食管癌防治重点实验室，河南省肿瘤表观遗传重点实验室，洛阳471003%许昌学院医学院细胞行为学重点实验室，许昌461000%洛阳理工学院数学与物理教学部，洛阳471023%洛阳市第一人民医院病理科，洛阳471000 |
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