COX-2、MMP-9在泪腺上皮性肿瘤中的表达及与预后的关系

发布时间：2018-04-25 12:40

本文选题：多形性腺瘤 + 腺样囊性癌　；参考：《郑州大学》2017年硕士论文

【摘要】：研究背景与目的泪腺肿瘤是临床上较常见的眼眶疾病之一,约占眼眶肿瘤的7%-13%,其中上皮性肿瘤约占泪腺肿瘤的70%。因具有眼突、眼球受压向内下方移位、上睑肿胀、部分患者可出现视物模糊和复视,恶性肿瘤患者更有持续性疼痛等临床表现,严重影响患者外观与日常生活。良性肿瘤易复发和恶变;恶性肿瘤易早期侵袭转移,10年生存率不足20%。所以近年来,随着分子生物学的发展,寻找新的影响泪腺上皮性肿瘤预后的分子生物学指标成为临床研究的重要课题之一,这对疾病预后的预测并给予针对性治疗,改善预后具有重要意义。环氧合酶(Cyclooxygenase,COX)是花生四烯酸转化为前列腺素过程的重要限速酶,分为两种亚型,即:COX-1,COX-2。COX-1在多数正常组织中表达,其m RNA及蛋白在人体组织中相对恒定,在维持组织和细胞的正常生理功能中发挥作用。COX-2在正常人体组织中极少表达或不表达,近些年来,研究发现COX-2在多数肿瘤中都具有高的阳性率,COX-2通路生成的前列腺素(prostaglandin,PG)在致癌过程中有重要作用。COX-2被认为可以通过影响肿瘤细胞的生长、增殖、侵袭、转移及血管生长而促进多种肿瘤的发生发展,这些肿瘤包括胃癌、结肠癌、肺癌、乳腺癌、涎腺肿瘤等,并影响着肿瘤的预后。基质金属蛋白酶-9(metalloproteninase-9)是MMPs家族成员之一,是一种钙锌依赖性蛋白。降解基底膜中的Ⅳ型胶原蛋白为其主要作用。肿瘤的侵袭和转移是多步骤的复杂过程,其中ECM的降解是其关键环节,基质金属蛋白酶家族(MMPs)是参与ECM降解的重要蛋白酶。由于Ⅳ型胶原是构成基底膜的重要组成部分,因此,MMP-9因为能降解基底膜的Ⅳ型胶原蛋白而被认为与肿瘤的浸润和转移有关。除此之外,在肿瘤侵袭转移过程中,MMP-9还可以促进新生血管形成。在大肠癌、胰腺癌研究中发现COX-2、MMP-9在通路上有着交互作用,共同参与肿瘤的发生、发展、侵袭转移,成为影响肿瘤预后的重要因素。但是二者在泪腺肿瘤中的表达在国内外文献中报道甚少。本研究采用免疫组织化学的方法检测了泪腺腺样囊性癌(adenoid cystic carcinoma,ACC)、多形性腺瘤(pleomorphic adenoma,PA)和瘤旁泪腺组织中COX-2、MMP-9的表达情况,观察其与泪腺上皮肿瘤临床预后的关系,为泪腺上皮肿瘤复发预测以及针对性治疗提供依据。1研究对象与方法1.1研究对象本研究收集2004年1月—2013年1月经郑州大学第一附属医院眼科手术治疗,病理科确诊且随访资料完整的泪腺上皮性肿瘤患者标本66例,其中泪腺多形性腺瘤37例,腺样囊性癌29例。另取8例瘤旁泪腺组织作为对照。泪腺多形性腺瘤组,男14例,女23例;年龄20-82岁,中位年龄45岁。泪腺腺样囊性癌组,男14例,女15例;年龄9-77岁,中位年龄47岁;其中腺样-管状型15例,实性型14例;所有肿瘤患者术前均未进行放、化疗。1.2研究方法采用免疫组织化学的方法检测了泪腺腺样囊性癌、多形性腺瘤和瘤旁泪腺组织中COX-2、MMP-9的表达情况。对所有患者均行电话随访或门诊复查,随访自手术之日作为起点,以肿瘤复发作为结局事件,记录随访结果。采用SPSS17.0统计软件对所得数据进行分析。临床标本COX-2、MMP-9表达的组间比较采用Mann-Whitney U秩和检验,两者之间相关性采用spearman等级相关分析,与复发的关系分析采用连续性校正χ2检验,以P0.05表示差异有统计学意义。2结果2.1 COX-2、MMP-9在瘤旁泪腺组织、多形性腺瘤、泪腺腺样囊性癌中的表达2.1.1 COX-2阳性表达主要位于肿瘤细胞的胞浆内,瘤旁泪腺组织中未见COX-2的阳性表达。COX-2在泪腺腺样囊性癌组及多形性腺瘤组中的阳性表达率分别为72.4%和32.4%,腺样囊性癌组阳性表达明显高于多形性腺瘤组,两组间差异具有统计学意义(Z=-3.671;P0.05)。2.1.2 MMP-9阳性表达定位于肿瘤细胞的胞浆或胞核。瘤旁泪腺组织中未见MMP-9的阳性表达。MMP-9在泪腺腺样囊性癌组及多形性腺瘤组中的表达阳性率分别为65.5%和21.6%,腺样囊性癌组阳性表达明显高于多形性腺瘤组,两组间差异具有统计学意义(Z=-4.136;P0.05)2.2 COX-2、MMP-9在泪腺上皮肿瘤中表达的相关性Spearman相关分析显示,在66例泪腺上皮肿瘤中,COX-2与MMP-9表达呈正相关(r=0.673;P0.01)2.3.COX-2、MMP-9与泪腺肿瘤患者复发关系随访结果发现66例泪腺上皮肿瘤患者中,腺样囊性癌组复发17例,多形性腺瘤组复发5例,共复发22例,经连续性校正χ2检验,COX-2、MMP-9阳性者泪腺上皮性肿瘤的复发风险显著大于阴性者(P0.05)。24例COX-2/MMP-9阳性者,复发17例,复发率达70.8%;30例COX-2/MMP-9阴性者有1例复发,复发率仅为3.3%。3结论(1)COX-2、MMP-9在瘤旁泪腺组织中均未见阳性表达,而在泪腺上皮性肿瘤中有较高表达,且腺样囊性癌组阳性表达明显高于多形性腺瘤组;(2)COX-2、MMP-9在泪腺上皮性肿瘤中的表达呈正相关。提示两者可能存在交互作用;(3)在泪腺上皮性肿瘤中,COX-2、MMP-9阳性表达患者复发风险显著大于阴性者,提示COX-2、MMP-9的表达与泪腺上皮性肿瘤的预后复发密切相关。
[Abstract]:Background and objective lacrimal gland tumor is one of the most common orbital diseases, which accounts for 7%-13% of the orbital tumor, in which the epithelial tumor accounts for the 70%. of the lacrimal gland tumor, which has an eye process, the pressure of the eyeball is moved downward, the upper eyelid is swollen, some patients can appear blurred visual substance and diplopia, and the patients with malignant tumor are more persistent pain and so on. The bed performance seriously affects the appearance and daily life of the patients. The benign tumor is prone to relapse and malignancy; the malignant tumor is prone to early invasion and metastasis, and the 10 year survival rate is less than 20%., so in recent years, with the development of molecular biology, it is one of the important topics in the clinical study to find new molecular biological indicators that affect the prognosis of lacrimal gland epithelial tumors. Cyclooxygenase (COX) is an important rate limiting enzyme for the transformation of Arachis four eNIC acid into prostaglandin process, which is divided into two subtypes, namely, COX-1, COX-2.COX-1 in most normal tissues, and m RNA and protein are relatively constant in human tissues. To maintain the normal physiological functions of tissues and cells,.COX-2 is rarely expressed or expressed in normal human tissues. In recent years, studies have found that COX-2 has a high positive rate in most tumors. The prostaglandin (prostaglandin, PG) generated by the COX-2 pathway plays an important role in the carcinogenesis, and.COX-2 is considered to be able to pass through the shadow. The growth, proliferation, invasion, metastasis and vascular growth of tumor cells promote the development of a variety of tumors. These tumors include gastric cancer, colon cancer, lung cancer, breast cancer, salivary gland tumor and so on, and affect the prognosis of the tumor. Matrix metalloproteinase -9 (metalloproteninase-9) is one of the members of the MMPs family, a calcium zinc dependent protein. The main role of collagen type IV collagen in the basement membrane is to affect the invasion and metastasis of the tumor. The degradation of ECM is the key link, and the matrix metalloproteinase family (MMPs) is an important protease involved in the degradation of ECM. As type IV collagen is an important component of the basement membrane, MMP-9 is degraded because of its degradation. Type IV collagen in the basement membrane is considered to be associated with tumor invasion and metastasis. In addition, MMP-9 can also promote neovascularization during the invasion and metastasis of the tumor. In the study of colorectal cancer, the study of pancreatic cancer found that COX-2 and MMP-9 have interaction on the pathway, and participate in the occurrence, development, invasion and metastasis of the tumor. But the expression of the two in lacrimal gland tumor is rarely reported in the domestic and foreign literature. The present study used immunohistochemical method to detect the expression of adenoid cystic carcinoma (ACC), pleomorphic adenoma (PA) and the expression of COX-2 in the lacrimal gland tissue adjacent to the tumor. The relationship between the clinical prognosis and the prognosis of lacrimal gland epithelial tumors was investigated to provide a basis for.1 research and method 1.1 research objects and methods for the treatment of lacrimal gland epithelial tumor. The study collected the eye surgery of the First Affiliated Hospital of Zhengzhou University from January 2004 to 2013, and the pathology department confirmed and followed up the complete lacrimal gland epithelium. There were 66 cases of tumor patients, including 37 cases of pleomorphic adenoma of lacrimal gland, 29 cases of adenoid cystic carcinoma and 8 cases of lacrimal gland tissue adjacent to the lacrimal gland as control. The lacrimal gland pleomorphic adenoma group, 14 male, 23 case; age 20-82, age 45. The lacrimal gland adenoid cystic carcinoma group, 14 men, 15 cases; age 9-77 years, middle age 47 years; adenoid tubular 15, 15 cases, 14 cases of solid type; all tumor patients were not placed before operation. The.1.2 method of chemotherapy was used to detect the expression of COX-2 and MMP-9 in lacrimal gland adenoid cystic carcinoma, pleomorphic adenoma and lacrimal gland tissue adjacent to the tumor. SPSS17.0 statistical software was used to analyze the results of the recurrence as an outcome event. The SPSS17.0 statistical software was used to analyze the data. The comparison of the expression of COX-2 and MMP-9 was compared with the Mann-Whitney U rank and test. The correlation between the two groups was analyzed by Spearman grade correlation analysis. The relationship analysis with the recurrence was analyzed by the continuity correction chi 2 test, and expressed in P0.05. The difference was statistically significant.2 results 2.1 COX-2, MMP-9 in the lacrimal gland tissue, pleomorphic adenoma, and adenoid cystic carcinoma of lacrimal gland, the expression of 2.1.1 COX-2 was mainly located in the cytoplasm of the tumor cells. There was no positive expression of COX-2 in the lacrimal gland tissue beside the tumor, and the positive expression of.COX-2 in the lacrimal gland adenoid cystic carcinoma group and the pleomorphic adenoma group was expressed. The positive expression of the adenoid cystic carcinoma group was significantly higher than that of the pleomorphic adenoma group. The difference between the two groups was statistically significant (Z=-3.671; P0.05), the positive expression of.2.1.2 MMP-9 was located in the cytoplasm or nucleus of the tumor cells. There was no MMP-9 positive expression of MMP-9 in the lacrimal gland tissue beside the tumor, and in the lacrimal gland adenoid cystic carcinoma group and the polygonous gland The positive rates of expression in the tumor group were 65.5% and 21.6% respectively. The positive expression of the adenoid cystic carcinoma group was significantly higher than that of the pleomorphic adenoma group. The difference between the two groups was statistically significant (Z=-4.136; P0.05) 2.2 COX-2. The correlation of MMP-9 expression in the lacrimal gland epithelial tumor was revealed by Spearman correlation analysis. In 66 cases of lacrimal gland epithelial tumors, the expression of COX-2 and MMP-9 was expressed. The follow-up results of positive correlation (r=0.673; P0.01) 2.3.COX-2, MMP-9 and lacrimal gland tumor recurrence found that in 66 cases of lacrimal gland epithelial tumor, there were 17 cases of adenoid cystic carcinoma, 5 recurrences in the pleomorphic adenoma group, 22 cases with a total recurrence. The recurrence rate of COX-2 and MMP-9 positive patients was significantly greater than that of negative carcinoma with COX-2 and MMP-9 positive. There were 17 cases of COX-2/MMP-9 positive in.24 (P0.05), recurrence rate of 70.8%, 30 cases of COX-2/MMP-9 negative, recurrence rate of only 3.3%.3 conclusion (1) COX-2, MMP-9 in lacrimal gland tissue near the tumor, but high expression in lacrimal gland epithelial tumor, and the positive expression of adenoid cystic carcinoma group was significantly higher than that of pleomorphic adenoma (2) the expression of COX-2 and MMP-9 in lacrimal gland epithelial tumor is positively correlated. It suggests that there may be interaction between them. (3) in lacrimal gland epithelial tumors, the recurrence risk of COX-2 and MMP-9 positive patients is significantly greater than that of negative ones, suggesting that the expression of COX-2, MMP-9 is closely related to the recurrence of lacrimal gland epithelial tumor.

【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R739.7

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