NOD2和TLR9在大肠癌及结直肠腺瘤中的表达及临床意义
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摘要
目的探讨核苷酸结合寡聚化结构域(NOD2)和Toll样受体的膜结合受体家族(TLR9)在大肠癌及结直肠腺瘤中的表达及临床意义。方法选取2012年8月至2015年8月收治的30例大肠癌患者和30例结直肠腺瘤患者为研究对象,选用大肠癌患者距肿瘤10 cm以上的正常黏膜组织为对照组。用免疫组化方法检测大肠癌组,结直肠腺瘤组和正常组NOD2和TLR9蛋白表达,分析其在大肠癌中的表达与性别、年龄、病理分级、肿瘤淋巴结转移(TNM)分期等临床病理特征的关系。结果 NOD2和TLR9在结、直肠腺瘤和大肠癌均有表达,在大肠腺癌组中阳性表达率分别为66. 7%和60. 0%,显著高于其在结直肠腺瘤组中的阳性表达率(43. 3%和36. 7%),差异有统计学意义(P <0. 05)。且大肠癌组中的NOD2和TLR9蛋白表达的OD值显著高于结直肠腺瘤组,差异有统计学意义(P <0. 05)。NOD2和TLR9的阳性表达率与年龄、性别和淋巴结转移等临床病理特征无关,而与病理组织分级和TNM分期密切相关,随着组织学分级的升高和TNM分期的进展,NOD2和TLR9的阳性表达率显著升高(P <0. 05)。结论NOD2和TLR9在大肠癌组织中的阳性表达显著增强,提示二者参与了大肠癌的形成,且二者介导的自然免疫与大肠癌的发生和发展密切相关。
Objective To investigate the expression and clinical significance of NOD2 and TLR9 in colorectal carcinoma and colorectal adenoma. Methods A total of 30 patients with colorectal carcinoma and 30 patients with colorectal adenoma. Who were admitted and treated in our hospital from August 2012 to August 2015 were enrolled in the study,meanwhile,the other 30 healthy subjects were enrolled as control group. The expression levels of NOD2 and TLR9 were detected by immunohistochemistry. Moreover the correlation between their expressions and patient's sex and age,pathological grading,TNM staging was analyzed. Results The positive expression rates of NOD2 and TLR9 in colorectal carcinoma group were 66. 7% and 60. 0%,respectively,which were significantly higher than those( 43. 3% and 36. 7%) in colorectal adenoma group( P < 0. 05). Moreover the optical density values of NOD2 and TLR9 in colorectal carcinoma group were significantly higher than those in colorectal adenoma group( P < 0. 05). In addition the positive expression rates of NOD2 and TLR9 were not related to patient's age and sex,lymph node metastasis,however,which were closely related to the pathological grading and TNM staging. The positive expression rates of NOD2 and TLR9 were significantly increased with the increase of histological grade and TNM stage. Conclusion The positive expression rates of NOD2 and TLR9 are significantly increased in colorectal carcinoma tissues,which suggests that both of them are involved in the formation of colorectal cancer,and the natural immunity mediated by NOD2 and TLR9 is closely related to the pathogenesis and development of colorectal carcinoma.
Objective To investigate the expression and clinical significance of NOD2 and TLR9 in colorectal carcinoma and colorectal adenoma. Methods A total of 30 patients with colorectal carcinoma and 30 patients with colorectal adenoma. Who were admitted and treated in our hospital from August 2012 to August 2015 were enrolled in the study,meanwhile,the other 30 healthy subjects were enrolled as control group. The expression levels of NOD2 and TLR9 were detected by immunohistochemistry. Moreover the correlation between their expressions and patient's sex and age,pathological grading,TNM staging was analyzed. Results The positive expression rates of NOD2 and TLR9 in colorectal carcinoma group were 66. 7% and 60. 0%,respectively,which were significantly higher than those( 43. 3% and 36. 7%) in colorectal adenoma group( P < 0. 05). Moreover the optical density values of NOD2 and TLR9 in colorectal carcinoma group were significantly higher than those in colorectal adenoma group( P < 0. 05). In addition the positive expression rates of NOD2 and TLR9 were not related to patient's age and sex,lymph node metastasis,however,which were closely related to the pathological grading and TNM staging. The positive expression rates of NOD2 and TLR9 were significantly increased with the increase of histological grade and TNM stage. Conclusion The positive expression rates of NOD2 and TLR9 are significantly increased in colorectal carcinoma tissues,which suggests that both of them are involved in the formation of colorectal cancer,and the natural immunity mediated by NOD2 and TLR9 is closely related to the pathogenesis and development of colorectal carcinoma.
引文
1任建松,石菊芳,张洪召,等. 2012-2013年中国城市人群大肠癌筛查结果初步分析.中华预防医学杂志,2015:441-443.
2 Udden SMN,Peng L,Gan JL,et al. NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways. Cell reports,2017,19:2756-2770.
3 中华人民共和国卫生和计划生育委员会医政医管局.中国结直肠癌诊疗规范(2015版).中华消化外科杂志,2015,14:783-799.
4 姚宏伟,刘荫华.结直肠癌TNM分期(2010)更新内容解读.中华外科杂志,2010,48:1601-1604.
5 饶振华,谢小梅. NODs蛋白及其与TLRs相互调控在机体抗病原真菌感染中的作用.中华微生物学和免疫学杂志,2012,32:281-285.
6 Keestragounder AM,Byndloss MX,Seyffert N,et al. NOD1/NOD2signaling links ER stress with inflammation. Nature,2016,532:394-397.
7 Basu M,Paichha M,Swain B,et al. Modulation of TLR2,TLR4,TLR5,NOD1 and NOD2 receptor gene expressions and their downstream signaling molecules following thermal stress in the Indian major carp catla(Catla catla). Biotech,2015,5:1-10.
8 Zheng S,Hedl M,Abraham C. Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators. Journal of Immunology,2015,195:217-226.
9 Correa RG,Milutinovic S,Reed JC. Roles of NOD1(NLRC1)and NOD2(NLRC2)in innate immunity and inflammatory diseases. Bioscience Reports,2012,32:597-608.
10 魏柏,朱尤庆,汤晓燕,等.胃癌及癌前病变组织中幽门螺杆菌感染与NOD2和TLR9蛋白表达的相关性.中华普通外科杂志,2008,23:866-868.
11 Lu CC,Kuo HC,Wang FS,et al. Upregulation of TLRs and IL-6 as a marker in human colorectal cancer. Nternational Journal of Molecular Sciences,2015,16:159-177.
12 Lan F,Yue X,Ren G,et al. miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-κB signaling pathway. International Journal of Radiation Oncology Biology Physics,2015,91:73-81.
13 Seya T,Shime H,Takeda Y,et al. Adjuvant for vaccine immunotherapy of cancer-focusing on TLR2 and TLR3 agonists for safely enhancing antitumor immunity. Cancer Science,2015,106:1659-1668.
14 罗斌,王世夫,应香岚,等. NOD2和TRAF2在结直肠癌中的表达.中国中西医结合外科杂志,2012,18:30-33.
2 Udden SMN,Peng L,Gan JL,et al. NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways. Cell reports,2017,19:2756-2770.
3 中华人民共和国卫生和计划生育委员会医政医管局.中国结直肠癌诊疗规范(2015版).中华消化外科杂志,2015,14:783-799.
4 姚宏伟,刘荫华.结直肠癌TNM分期(2010)更新内容解读.中华外科杂志,2010,48:1601-1604.
5 饶振华,谢小梅. NODs蛋白及其与TLRs相互调控在机体抗病原真菌感染中的作用.中华微生物学和免疫学杂志,2012,32:281-285.
6 Keestragounder AM,Byndloss MX,Seyffert N,et al. NOD1/NOD2signaling links ER stress with inflammation. Nature,2016,532:394-397.
7 Basu M,Paichha M,Swain B,et al. Modulation of TLR2,TLR4,TLR5,NOD1 and NOD2 receptor gene expressions and their downstream signaling molecules following thermal stress in the Indian major carp catla(Catla catla). Biotech,2015,5:1-10.
8 Zheng S,Hedl M,Abraham C. Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators. Journal of Immunology,2015,195:217-226.
9 Correa RG,Milutinovic S,Reed JC. Roles of NOD1(NLRC1)and NOD2(NLRC2)in innate immunity and inflammatory diseases. Bioscience Reports,2012,32:597-608.
10 魏柏,朱尤庆,汤晓燕,等.胃癌及癌前病变组织中幽门螺杆菌感染与NOD2和TLR9蛋白表达的相关性.中华普通外科杂志,2008,23:866-868.
11 Lu CC,Kuo HC,Wang FS,et al. Upregulation of TLRs and IL-6 as a marker in human colorectal cancer. Nternational Journal of Molecular Sciences,2015,16:159-177.
12 Lan F,Yue X,Ren G,et al. miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-κB signaling pathway. International Journal of Radiation Oncology Biology Physics,2015,91:73-81.
13 Seya T,Shime H,Takeda Y,et al. Adjuvant for vaccine immunotherapy of cancer-focusing on TLR2 and TLR3 agonists for safely enhancing antitumor immunity. Cancer Science,2015,106:1659-1668.
14 罗斌,王世夫,应香岚,等. NOD2和TRAF2在结直肠癌中的表达.中国中西医结合外科杂志,2012,18:30-33.