CDX2及COX2的表达与结直肠癌预后的相关性研究

发布时间：2018-02-21 11:33

本文关键词： 结直肠癌尾型同源盒转录因子2 环氧合酶2 预后免疫组织化学　出处：《大连医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:在我国,近30年结直肠癌的发病率和死亡率均呈上升趋势,而且多数患者发现时已属于中晚期。近年来越来越多的研究发现尾型同源盒转录因子2(caudal-related homeobox transcription factor 2,CDX2)及环氧合酶2(cyclooxygenase2,COX2)共同参与结直肠癌的形成、侵袭、转移过程,而且CDX2可通过多条信号转导途径调控COX2的转录和表达,两者之间关系密切。本实验通过研究CDX2及COX2在结直肠癌组织中蛋白的表达情况,探讨二者的表达与结直肠癌各项临床病理因素之间的相关性,二者之间表达的相关性以及二者的表达与结直肠癌患者的预后的相关性,为结直肠癌的早期诊断和预后评估提供理论依据。方法:收集大连医科大学附属第一医院2009年6月-2011年6月经手术后病理证实的结直肠腺癌患者的术后结直肠癌组织石蜡包埋标本44例。所有患者均行结直肠癌根治术治疗,术前均未接受放疗和化疗,临床及病理资料完整。术后采用电话方式进行随访,起点为手术之日,终点为患者出现死亡、失访或至截止时间(2016年6月3日)。随访结束时,获得完整随访资料40例,随访率为90.9%,15例结直肠癌患者死亡。同时选取距肿瘤大于3cm的切缘正常组织作为对照组。采用免疫组化染色法检测44例结直肠腺癌及其对应癌旁正常结直肠黏膜组织标本的CDX2及COX2的蛋白表达水平。统计学分析:(1)运用χ2检验及Fisher确切概率法分析肿瘤组织CDX2及COX2的表达与临床病理因素的关系;(2)运用Spearman秩和检验分析CDX2和COX2在结直肠癌中表达水平的相关性;(3)运用Kaplan-Melen法、Log-rank检验分析肿瘤组织CDX2及COX2的表达与患者总生存期(OS)、无病生存期(DFS)、术后生存时间、5年生存率的关系。结果:1.CDX2在结直肠癌组织与癌旁正常组织中呈现不同程度表达,在结直肠癌组织中阳性表达为65.9%(29/44),而在癌旁正常结直肠黏膜组织中阳性表达为93.2%(41/44),两组间差异存在统计学意义,χ2=10.057,P=0.003。COX2在结直肠癌组织与癌旁正常组织中呈现不同程度表达,在结直肠癌组织中阳性表达为72.7%(32/44),而在癌旁正常结直肠黏膜组织中阳性表达为25.0%(11/44),两组间差异存在统计学意义,χ2=20.056,P0.001。2.CDX2的表达水平与性别(P=0.431)、年龄(P=0.294)、TNM分期(P=0.184)、侵润深度(P=0.135)、远处转移(P=0.07)无显著相关性,而与分化程度(P=0.049)、左右半结肠部位(P=0.034)、淋巴结转移(P=0.034)、5年生存率(P=0.048)显著相关。COX2的表达水平与性别(P=0.658)、年龄(P=0.873)、TNM分期(P=0.75)、侵润深度(P=0.333)、远处转移(P=0.53)、分化程度(P=0.826)、左右半结肠部位(P=0.388)、淋巴结转移(0.622)均无显著相关性,P值均0.05,均无统计学意义。3.CDX2和COX2在结直肠癌肿瘤组织中表达的相关性,用Spearman秩和检验相关性分析来分析发现两者在结直肠癌组织中的表达呈明显负相关,且具有统计学意义(r=-0.339,P=0.0240.05)。4.用Kaplan-Meier方法和Log-rank检验进行生存分析,CDX2阴性组患者中位OS为39.86个月,明显低于CDX2阳性组的62.09个月,χ2=6.844,P=0.009,有统计学意义。CDX2阴性组患者中位DFS为26.79个月,明显低于CDX2阳性组的51.65个月,χ2=7.246,P=0.007,也具有统计学意义。COX2阴性组患者中位OS为55.23个月,中位DFS为44.86个月,COX2阳性组中位OS为54.70个月,中位DFS为43.02个月。生存分析两组OS之间差异没有统计学意义,χ2=0.901,P=0.342;两组DFS之间差异同样没有统计学意义,χ2=0.940,P=0.332。5.在有淋巴结转移的亚组中,CDX2阴性组的术后生存时间明显短于CDX2阳性组,且差异有统计学意义,P=0.001;而在无淋巴结转移的亚组中,CDX2阴性组的术后生存时间与CDX2阳性组之间差异无统计学意义,P=0.617。结论:1.CDX2在结直肠癌组织中的表达水平明显低于正常结直肠组织,其表达与结直肠癌分化程度、左右半结肠部位、淋巴结转移相关,与5年生存率、OS、DFS、术后生存时间相关。其表达缺失或下调提示不良预后,尤其是对于淋巴结阳性的患者。CDX2可能成为预测结直肠癌预后的生物标志物。2.COX2在结直肠癌组织中的表达水平明显高于正常结直肠组织。但其表达与各项临床病理因素及患者OS及DFS均无相关性,不能作为结直肠癌的预后指标。3.CDX2和COX2在结直肠癌中的表达呈负相关,表明CDX2在结直肠癌中的缺失可能诱导激活COX2的表达,两者可能均参与了结直肠癌的发生发展,为肿瘤精准治疗提供了新的潜在靶点。
[Abstract]:Objective: in China, nearly 30 years the incidence and mortality of colorectal cancer showed an upward trend, and most patients were found in the late fall. In recent years, more and more studies have found caudal type homeobox transcription factor 2 (caudal-related homeobox transcription factor 2, CDX2) and cyclooxygenase 2 (cyclooxygenase2, COX2) to participate in the formation of colorectal cancer, invasion, metastasis, and CDX2 transcription through multiple signal transduction pathways and the regulation of COX2 expression, the close relationship between the two. The expression of fabric in protein in colorectal cancer group through the study of CDX2 and COX2, the correlation between the expression and clinicopathological factors in colorectal cancer two the correlation between the expression of the correlation between the two and two expression in patients with colorectal carcinoma and the prognosis, and provide a theoretical basis for early diagnosis and prognosis of colorectal cancer. Methods: the First Affiliated Hospital of Dalian Medical University from June 2009 6 menstrual surgery after -2011 years of pathology in patients with colorectal adenocarcinoma after resection of colorectal cancer paraffin embedded specimens from 44 cases. All patients underwent radical resection of colorectal cancer treatment, were not receiving preoperative radiotherapy and chemotherapy, complete clinical and pathological data after surgery by telephone. Follow up, the starting point for the date of surgery, end point for patients died or lost to the deadline (June 3, 2016). At the end of the follow-up, 40 cases received complete follow-up, follow-up rate was 90.9%, 15 cases of colorectal cancer patients died. At the same time selected from a tumor more than 3cm margin normal tissues as control group. The expression of CDX2 and COX2 detected by immunohistochemical method in 44 cases of colorectal adenocarcinoma and adjacent normal colorectal mucosa tissue protein. Statistical analysis: (1) using the 2 test and Fis Analysis of the relationship between the expression of CDX2 and COX2 in tumor tissues and the clinicopathological factors of her exact probability method; (2) using the Spearman rank sum test and analysis of CDX2 and COX2 in colorectal cancer the expression level of correlation; (3) using Kaplan-Melen method, Log-rank test analysis of the expression of CDX2 and COX2 in tumor tissue and overall survival (OS), disease free survival (DFS), postoperative survival time, the relationship between the survival rate of 5 years. Results: 1.CDX2 showed different degrees in colorectal cancer tissue and adjacent normal tissue expression in colorectal cancer tissues the positive expression was 65.9% (29/44), while the positive expression in adjacent normal colorectal mucosa tissues 93.2% (41/44), statistically significant differences between the two groups of X 2=10.057, P=0.003.COX2 showed different degrees in colorectal cancer tissue and adjacent normal tissue expression in colorectal cancer tissues the positive expression was 72.7% (32/44), and in adjacent normal The positive expression in colorectal tissues was 25% (11/44), statistically significant differences between the two groups of X 2=20.056, the expression level of P0.001.2.CDX2 and gender (P=0.431), age (P=0.294), TNM stage (P=0.184), the depth of invasion (P=0.135), distant metastasis (P= 0.07) had no significant correlation with differentiation, and degree (P=0.049), left and right half colon (P=0.034), lymph node metastasis (P=0.034), the 5 year survival rate (P=0.048) expression level and gender were significantly related to.COX2 (P=0.658), age (P=0.873), TNM stage (P=0.75), the depth of invasion (P=0.333), distant metastasis (P=0.53), differentiation degree (P=0.826), left and right half colon (P=0.388), lymph node metastasis (0.622) had no significant correlation, P value was 0.05, there was no statistically significant correlation between the expression of.3.CDX2 and COX2 in colorectal carcinoma, was analyzed by Spearman rank sum test correlation analysis found both in colorectal cancer group There was a negative correlation in the expression of the fabric, and have statistical significance (r=-0.339, P=0.0240.05).4. survival was analyzed by Kaplan-Meier method and Log-rank test, the CDX2 negative patients the median OS was 39.86 months, significantly less than 62.09 months, CDX2 positive group were 2=6.844, P=0.009, was statistically significant in patients with.CDX2 negative the median DFS was 26.79 months, significantly less than 51.65 months, CDX2 positive group was 2=7.246, P=0.007 was also statistically significant in patients with.COX2 negative OS was 55.23 months, median DFS was 44.86 months in COX2 positive group, the median OS was 54.70 months, median DFS was 43.02 months the difference between the two groups. The survival analysis of OS was not statistically significant, X 2=0.901, P=0.342; the difference between the two groups was not statistically significant DFS the same, X 2=0.940, P=0.332.5. in lymph node metastasis group, CDX2 negative group the postoperative survival time was significantly shorter in the CDX2 positive group, and A statistically significant difference in P=0.001; and without lymph node metastasis subgroup, CDX2 negative group the postoperative survival time and the difference between the CDX2 positive group was not statistically significant. Conclusion: the P=0.617. expression of 1.CDX2 in colorectal cancer tissues was significantly lower than that in normal colorectal tissues, its expression and degree of differentiation of colorectal cancer, about half the colon, lymph node metastasis, and 5 year survival rate, OS, DFS, postoperative survival time. Its expression is down regulated or absent prognostic factors, especially for patients with positive lymph nodes may become.CDX2 expression level of predictive biomarkers of.2.COX2 colorectal cancer prognosis in colorectal cancer tissues was significantly higher than normal colorectal tissue. But its expression had no correlation with the clinical and pathological factors of patients with OS and DFS, the expression can not be used as colorectal cancer prognostic indicators of.3.CDX2 and COX2 in colorectal cancer A negative correlation indicates that the loss of CDX2 in colorectal cancer may induce the activation of COX2 expression. Both of them may participate in the occurrence and development of colorectal cancer, and provide new potential targets for precise treatment of tumors.

【学位授予单位】：大连医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.34

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