肠毒素脆弱拟杆菌与结直肠癌关系的研究
发布时间：2019-04-23 07:41
【摘要】：研究背景:人体肠道菌群可通过多种途径影响肠道稳态,导致结直肠癌以及炎症性肠病的发生。脆弱拟杆菌(Bacteroides fragilis,BF)为专性厌氧革兰阴性短杆菌,是人体肠道共生菌。肠毒素脆弱拟杆菌ETBF(Enterotoxin bacteroides fragilis)能合成分泌一种脆弱拟杆菌毒素BFT(Bacteroid fragilis toxin),BFT可通过诱导激活Stat-3信号通路,上调IL-17的表达,诱发肠上皮内瘤变的发生,从而促进结直肠癌的发生。研究发现ETBF在结直肠癌患者中的检出增多,而且其阳性率随着结直肠癌的肿瘤分期的增大而增加。但ETBF的致癌性仍缺乏足够的流行病学证据支持。材料与方法:收集南方医科大学南方医院的肠镜黏膜活检或手术切除结直肠肿瘤的石蜡组织242例,分为轻度炎症组50例、结直肠腺瘤组112例、结直肠癌组80例,收集临床资料并对结直肠癌患者进行为时一年的随访。提取各组石蜡组织DNA,PCR检测是否含有ETBF的特异性毒素基因bft,并分析ETBF与一些临床指标以及肿瘤预后指标之间的关系。最后进行Phospho-Stat3与IL-17免疫组织化学染色。本实验所用的统计学方法有:卡方检验、Mann-Whitney U检验、Kruska-Wallis H 检验。研究结果:结直肠腺瘤组与结直肠腺癌组的ETBF阳性率均明显高于轻度炎症组(p=0.008,p0.000),右半结肠的阳性率明显高于左半结肠(X2=14.13,p0.000),ETBF阳性结直肠癌患者的TNM肿瘤分期明显高于ETBF阴性患者(Z=-3.322,p=0.001)。ETBF阳性与阴性组之间的白细胞计数(WBC)、淋巴细胞计数(LYM)、中性粒细胞计数(NEU)、单核细胞计数(MO)均无明显差异(p0.05);ETBF阳性组CRP定量、CEA定量明显高于ETBF阴性组(p0.000,p=0.027)。ETBF阳性患者的淋巴结(Z=-2.892,p=0.004)与远处转移(Z=-2.881,p=0.004)均明显严重于阴性患者。ETBF是否阳性与肿瘤患者一年内是否复发或否死亡无明显差异(X2=3.878,p=0.078;x2 =3.374,p=0.151),而ETBF阳性组的化疗临床获益明显差于阴性组(X2=5.437,p=0.020);ETBF阳性组的无瘤生存率明显低于阴性组(X2 =12.836,p0.000)。轻度炎症组ETBF感染与Stat3磷酸化为中等程度相关联,其余两组无明显关联。结直肠腺瘤组中,ETBF阳性样本IL-17表达水平下降(p=0.011)。结论:1、结直肠肿瘤的ETBF阳性率明显升高,而且肿瘤TNM分期越靠近晚期,ETBF阳性率越高。2、ETBF阳性患者的肿瘤浸润深度与远处转移均明显严重于阴性患者;ETBF阳性组的化疗疗效明显差于阴性组;ETBF阳性组的无瘤生存率也更低。因此ETBF阳性的结直肠癌患者预后更差。3、在结直肠轻度炎症患者中,ETBF感染与Stat3磷酸化有一定关联,但在结直肠肿瘤患者中关联性不大。ETBF阳性的结直肠肿瘤中,Stat3磷酸化以及IL-17的表达并无明显升高,ETBF除了诱导Stat3磷酸化来促进TH17炎症反应之外可能还存在其他促癌机制。
[Abstract]:Background: human intestinal flora can affect intestinal homeostasis in many ways, leading to colorectal cancer and inflammatory bowel disease. Bacteroides fragilis (Bacteroides fragilis,BF) is a specific anaerobic gram-negative brevibacterium, which is a symbiotic bacteria in human intestinal tract. Enterotoxin ETBF (Enterotoxin bacteroides fragilis) can synthesize and secrete a fragile mycotoxin BFT (Bacteroid fragilis toxin), BFT, which can activate Stat-3 signaling pathway, up-regulate the expression of IL-17 and induce intestinal intraepithelial neoplasia. Thus promote the occurrence of colorectal cancer. It was found that ETBF was detected more frequently in colorectal cancer patients, and its positive rate increased with the increase of tumor stage. However, the carcinogenicity of ETBF is still not supported by enough epidemiological evidence. Materials and methods: a total of 242 paraffin-embedded tissues from Southern Hospital of Southern Medical University were divided into mild inflammation group (n = 50), colorectal adenomas group (n = 112) and colorectal cancer group (n = 80). The clinical data were collected and the patients with colorectal cancer were followed up for one year. DNA,PCR was extracted from paraffin-embedded tissues to detect the specific toxin gene bft, containing ETBF and the relationship between ETBF and some clinical indexes as well as tumor prognosis indexes was analyzed. Finally, immunohistochemical staining of Phospho-Stat3 and IL-17 was performed. The statistical methods used in this experiment are: Chi-square test, Mann-Whitney U test and Kruska-Wallis H test. Results: the positive rate of ETBF in colorectal adenomatosis and colorectal adenocarcinoma group was significantly higher than that in mild inflammatory group (p = 0.008, p0.000), and the positive rate in right colon was significantly higher than that in left colon (X2, 14.13, p0.000), and the positive rate in right colon was significantly higher than that in left colon (P < 0.001). The TNM staging in patients with ETBF positive colorectal cancer was significantly higher than that in patients with ETBF negative (Z = 3.322, p < 0.001). White blood cell count (WBC), lymphocyte count (LYM), neutrophil count (NEU), between positive and negative patients with ETBF was found to be significant higher than that in ETBF negative patients (P < 0.01). There was no significant difference in monocyte count (MO) (p0.05). The quantity of CRP and CEA in the ETBF positive group was significantly higher than that in the ETBF negative group (p0.000, p = 0.027). The lymph nodes and distant metastasis of the patients with positive ETBF were significantly higher than those in the ETBF negative group (P < 0.001, p = 0.004) and distant metastasis (P < 0.01, P < 0.01). There was no significant difference between the positive rate of ETBF and the recurrence or death of the tumor patients within one year (X2 / 3.878, p = 0.078). X2 = 3.374, p = 0.151), but the tumor-free survival rate of ETBF positive group was significantly lower than that of negative group (X2 = 12.836, p0.000), but the tumor-free survival rate of positive group was significantly lower than that of negative group (X2 = 5.437, p0.020); ETBF positive group). ETBF infection was associated with moderate phosphorylation of Stat3 in mild inflammatory group, but no significant correlation was found between the other two groups. In colorectal adenomas group, the expression level of IL-17 in ETBF positive samples was decreased (p < 0. 011). Conclusion: 1. The positive rate of ETBF in colorectal carcinoma was significantly higher, and the closer to the late stage of TNM stage, the higher the positive rate of ETBF. 2. The depth of invasion and distant metastasis in patients with positive tumor were more serious than those in patients with negative tumor. The chemotherapy efficacy of ETBF positive group was significantly lower than that of negative group, and the tumor-free survival rate of ETBF positive group was also lower. Therefore, the prognosis of patients with ETBF positive colorectal cancer is worse. 3. In patients with mild colorectal inflammation, ETBF infection is associated with phosphorylation of Stat3, but not in patients with colorectal cancer. The phosphorylation of Stat3 and the expression of IL-17 did not increase significantly. Besides inducing Stat3 phosphorylation to promote the inflammatory response of TH17, ETBF may also have other carcinogenic mechanisms.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.34
本文编号：2463259
[Abstract]:Background: human intestinal flora can affect intestinal homeostasis in many ways, leading to colorectal cancer and inflammatory bowel disease. Bacteroides fragilis (Bacteroides fragilis,BF) is a specific anaerobic gram-negative brevibacterium, which is a symbiotic bacteria in human intestinal tract. Enterotoxin ETBF (Enterotoxin bacteroides fragilis) can synthesize and secrete a fragile mycotoxin BFT (Bacteroid fragilis toxin), BFT, which can activate Stat-3 signaling pathway, up-regulate the expression of IL-17 and induce intestinal intraepithelial neoplasia. Thus promote the occurrence of colorectal cancer. It was found that ETBF was detected more frequently in colorectal cancer patients, and its positive rate increased with the increase of tumor stage. However, the carcinogenicity of ETBF is still not supported by enough epidemiological evidence. Materials and methods: a total of 242 paraffin-embedded tissues from Southern Hospital of Southern Medical University were divided into mild inflammation group (n = 50), colorectal adenomas group (n = 112) and colorectal cancer group (n = 80). The clinical data were collected and the patients with colorectal cancer were followed up for one year. DNA,PCR was extracted from paraffin-embedded tissues to detect the specific toxin gene bft, containing ETBF and the relationship between ETBF and some clinical indexes as well as tumor prognosis indexes was analyzed. Finally, immunohistochemical staining of Phospho-Stat3 and IL-17 was performed. The statistical methods used in this experiment are: Chi-square test, Mann-Whitney U test and Kruska-Wallis H test. Results: the positive rate of ETBF in colorectal adenomatosis and colorectal adenocarcinoma group was significantly higher than that in mild inflammatory group (p = 0.008, p0.000), and the positive rate in right colon was significantly higher than that in left colon (X2, 14.13, p0.000), and the positive rate in right colon was significantly higher than that in left colon (P < 0.001). The TNM staging in patients with ETBF positive colorectal cancer was significantly higher than that in patients with ETBF negative (Z = 3.322, p < 0.001). White blood cell count (WBC), lymphocyte count (LYM), neutrophil count (NEU), between positive and negative patients with ETBF was found to be significant higher than that in ETBF negative patients (P < 0.01). There was no significant difference in monocyte count (MO) (p0.05). The quantity of CRP and CEA in the ETBF positive group was significantly higher than that in the ETBF negative group (p0.000, p = 0.027). The lymph nodes and distant metastasis of the patients with positive ETBF were significantly higher than those in the ETBF negative group (P < 0.001, p = 0.004) and distant metastasis (P < 0.01, P < 0.01). There was no significant difference between the positive rate of ETBF and the recurrence or death of the tumor patients within one year (X2 / 3.878, p = 0.078). X2 = 3.374, p = 0.151), but the tumor-free survival rate of ETBF positive group was significantly lower than that of negative group (X2 = 12.836, p0.000), but the tumor-free survival rate of positive group was significantly lower than that of negative group (X2 = 5.437, p0.020); ETBF positive group). ETBF infection was associated with moderate phosphorylation of Stat3 in mild inflammatory group, but no significant correlation was found between the other two groups. In colorectal adenomas group, the expression level of IL-17 in ETBF positive samples was decreased (p < 0. 011). Conclusion: 1. The positive rate of ETBF in colorectal carcinoma was significantly higher, and the closer to the late stage of TNM stage, the higher the positive rate of ETBF. 2. The depth of invasion and distant metastasis in patients with positive tumor were more serious than those in patients with negative tumor. The chemotherapy efficacy of ETBF positive group was significantly lower than that of negative group, and the tumor-free survival rate of ETBF positive group was also lower. Therefore, the prognosis of patients with ETBF positive colorectal cancer is worse. 3. In patients with mild colorectal inflammation, ETBF infection is associated with phosphorylation of Stat3, but not in patients with colorectal cancer. The phosphorylation of Stat3 and the expression of IL-17 did not increase significantly. Besides inducing Stat3 phosphorylation to promote the inflammatory response of TH17, ETBF may also have other carcinogenic mechanisms.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.34
【参考文献】
中国期刊全文数据库 前1条
1 王建成;许淑珍;;产肠毒素脆弱类杆菌聚合酶链反应检测[J];胃肠病学;2007年03期
，本文编号：2463259
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