MMP-9和TIMP-1在结直肠癌组织和血清中的表达及其临床意义
发布时间：2019-07-05 21:28
【摘要】：背景:结直肠癌是临床常见肿瘤之一。随着人们生活水平改善,食物结构的改变和生活压力的增加,近年来我国结直肠癌发病率呈上升趋势。结直肠癌发病隐匿,危险性大,临床症状出现已到中晚期,给结直肠癌诊治带来极大的困难。所以早期诊断对于结直肠癌患者尤为重要。侵袭和转移是肿瘤两个重要特征。MMPs(基质金属蛋白酶)能降解细胞外基质(ECM),为肿瘤细胞的侵袭和远处转移提供路径。IV型胶原是ECM和基底膜(BM)重要成分。MMP-9作为MMPs中分子量最大的一种,能水解IV型胶原等成分,促进肿瘤的侵袭和转移。TIMP-1(基质金属蛋白酶抑制剂-1)能与MMP-9特异性地1:1比例结合,抑制MMP-9的蛋白水解作用。MMP-9和TIMP-1作为肿瘤标志物已研究过,但仍未应用于临床。一方面可能由于对于两者在肿瘤中表达与患者的临床病理特征的关系仍存在争议,另一方面更关键的原因是由于两者在肿瘤中的表达机制和作用仍不清楚。目的:论文旨在通过结直肠癌患者组织和血清中MMP-9和TIMP-1的表达情况,并分析它们与患者临床病理特征以及与预后的关系,探索两者作为肿瘤标志物的可能性,进而为结直肠癌的诊治提供帮助。方法:(1)收集2015年3月到2016年3月在吉林大学第二医院院手术切除的44例结直肠癌组织及癌旁正常组织,用免疫组化和Western blot研究MMP-9和TIMP-1在结直肠癌组织及癌旁正常组织的表达,并分析两者表达与临床病理特征关系。采用SPSS20.0统计软件包进行统计学分析。(2)分别收集73例结直肠癌患者、24例结直肠腺瘤患者和24例健康对照的血清。其中结直肠癌患者和结直肠腺瘤患者均在2014年9月到2015年9月在吉林大学中日联谊医院经结肠镜或手术切除肿物,然后通过组织病理学确诊。健康对照为经该院体检的健康个体。用Elisa方法检测MMP-9和TIMP-1在不同标本中的表达,用电化学发光法检测CEA和CA19-9在不同标本中的表达,并分析它们表达与临床病理特征关系。采用ROC曲线分析血清中四种标志物的诊断价值。采用Log Rank检验分析患者的生存率,制作生存曲线,并比较它们的预后价值。采用SPSS20.0统计软件包进行统计学分析。结果:(1)结直肠癌组织中MMP-9和TIMP-1表达均高于其对应的癌旁组织,两者表达不相关,并且MMP-9和TIMP-1在结直肠癌中的表达与结直肠癌患者年龄、性别、病理分型、肿瘤大小和部位无关(p0.05),而与结直肠癌分化程度和分期有关(p0.05)。MMP-9和TIMP-1在结直肠癌的阳性表达率,在低分化中较高中分化高,III/VI期较I/II期高。(2)血清中MMP-9、TIMP-1、CEA和CA19-9在结直肠癌组、结直肠腺瘤组、正常对照组三组间差异均有统计学意义(p0.05),并依次减少;结直肠癌患者血清中四种标志物在年龄、性别、部位上无统计学意义(p0.05),在肿瘤直径、远处转移、生存与否、Duke,s分期、肠壁浸润程度、淋巴结参与、分化程度有统计学意义(p0.05);ROC结果显示:结直肠癌患者血清中MMP-9、TIMP-1、CEA和CA19-9的曲线下面积(AUC)依次为0.768、0.854、0.663和0.616。血清MMP-9和TIMP-1低值患者生存率高于血清MMP-9和TIMP-1高值患者,但血清CEA和CA19-9高值和低值患者生存率无差异。结论:(1)本研究证实结直肠癌组织中MMP-9和TIMP-1较癌旁正常组织中表达增加,并且结直肠癌组织中MMP-9和TIMP-1表达与肿瘤分期分化程度密切相关,提示MMP-9和TIMP-1可能参与结直肠癌的侵袭转移过程。(2)本研究证实血清中MMP-9、TIMP-1、CEA和CA19-9在结直肠癌组、结直肠腺瘤组、正常对照组依次减少,结直肠癌血清中MMP-9、TIMP-1、CEA和CA19-9与肿瘤直径、远处转移、生存与否、Duke,s分期、肠壁浸润程度、淋巴结参与、分化程度有关,说明它们均可能参与结直肠癌的侵袭转移过程。(3)本研究提示血清中MMP-9、TIMP-1对结直肠癌有一定的诊断预后价值。
[Abstract]:BACKGROUND: Colorectal cancer is one of the most common tumors in the world. With the improvement of people's living standard, the change of food structure and the increase of living pressure, the incidence of colorectal cancer in our country has been on the rise in recent years. The occurrence of colorectal cancer is hidden, the risk is high, and the clinical symptoms are in the middle and late stage, which brings great difficulty to the diagnosis and treatment of colorectal cancer. Early diagnosis is particularly important for patients with colorectal cancer. The invasion and metastasis are two important features of the tumor. MMPs (matrix metalloproteinases) can degrade the extracellular matrix (ECM) and provide a pathway for the invasion and distant metastasis of tumor cells. Type IV collagen is an important component of the ECM and the basement membrane (BM). MMP-9, as one of the largest molecular weights in MMPs, can hydrolyze the components such as type IV collagen and promote the invasion and metastasis of the tumor. TIMP-1 (matrix metalloproteinase inhibitor-1) can be combined with MMP-9 in 1:1 ratio to inhibit the protein hydrolysis of MMP-9. MMP-9 and TIMP-1 have been studied as tumor markers, but are not yet applied to clinical use. On the one hand, there is a dispute over the relationship between the expression of both in the tumor and the clinical pathology of the patient, and, on the other hand, more critical because the mechanism and role of the expression of both in the tumor remains unclear. Objective: To study the expression of MMP-9 and TIMP-1 in the tissues and serum of patients with colorectal cancer, and to analyze their relationship with the clinicopathological features of the patients and their prognosis, and to explore the possibility of both as tumor markers and to help the diagnosis and treatment of colorectal cancer. Methods: (1) The expression of MMP-9 and TIMP-1 in the normal tissues of colorectal cancer and adjacent to the cancer was studied by immunohistochemistry and Western blot. And the relationship between the expression of the two and the clinical pathological characteristics is analyzed. Statistical analysis was performed using the SPSS10.0 statistical software package. (2) The serum of 73 patients with colorectal cancer,24 patients with colorectal adenoma and 24 healthy controls were collected. In the patients with colorectal cancer and colorectal adenoma, patients with colorectal cancer and colorectal adenoma were treated with colonoscopy or surgical resection at the University of Jilin University from September 2014 to September 2015, and then confirmed by histopathology. The health control is a healthy individual for the physical examination of the hospital. The expression of MMP-9 and TIMP-1 in different specimens was detected by Elisa method, and the expression of CEA and CA19-9 in different specimens was detected by using the chemiluminescence method, and the relationship between the expression of MMP-9 and TIMP-1 in different specimens was analyzed. The diagnostic value of four markers in serum was analyzed by ROC curve. The survival rate of patients was analyzed by Log Rank test, survival curves were made, and their prognostic value was compared. Statistical analysis was performed using the SPSS10.0 statistical software package. Results: (1) The expression of MMP-9 and TIMP-1 in colorectal cancer tissues was higher than that of the corresponding adjacent tissues, and the expression of MMP-9 and TIMP-1 in colorectal cancer was not related to the age, sex, pathological type, tumor size and location of colorectal cancer (p0.05). The positive rate of expression of MMP-9 and TIMP-1 in colorectal cancer was higher in low-differentiation and high in stage III/ VI than in stage I/ II. (2) The difference of MMP-9, TIMP-1, CEA and CA19-9 in the serum of colorectal cancer group, colorectal adenoma group and normal control group was statistically significant (p0.05) and decreased in turn; the four markers in serum of patients with colorectal cancer had no statistical significance in age, sex and location (p0.05). The results showed that the area under the curve of MMP-9, TIMP-1, CEA and CA19-9 in the serum of patients with colorectal cancer was 0.768, 0.854, 0.663 and 0.616. The survival rate of serum MMP-9 and TIMP-1 was higher in patients with high value of MMP-9 and TIMP-1 in serum, but there was no difference in the survival rate of serum CEA and CA19-9 and low-value patients. Conclusion: (1) In this study, the expression of MMP-9 and TIMP-1 in the tissue of colorectal cancer is increased, and the expression of MMP-9 and TIMP-1 in colorectal cancer is closely related to the degree of differentiation of the tumor, and it is suggested that MMP-9 and TIMP-1 may be involved in the invasion and metastasis of colorectal cancer. (2) In this study, the levels of MMP-9, TIMP-1, CEA and CA19-9 in the serum of the colorectal cancer group, the colorectal adenoma group and the normal control group were decreased, and the MMP-9, TIMP-1, CEA and CA19-9 in the serum of the colorectal cancer were compared with the tumor diameter, distant metastasis, survival or not, Duke, s stage, and the degree of intestinal wall infiltration. The degree of lymph node involvement and degree of differentiation suggests that they may be involved in the invasion and metastasis of colorectal cancer. (3) In this study, the expression of MMP-9 and TIMP-1 in the serum is valuable for the diagnosis of colorectal cancer.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.34
本文编号：2510823
[Abstract]:BACKGROUND: Colorectal cancer is one of the most common tumors in the world. With the improvement of people's living standard, the change of food structure and the increase of living pressure, the incidence of colorectal cancer in our country has been on the rise in recent years. The occurrence of colorectal cancer is hidden, the risk is high, and the clinical symptoms are in the middle and late stage, which brings great difficulty to the diagnosis and treatment of colorectal cancer. Early diagnosis is particularly important for patients with colorectal cancer. The invasion and metastasis are two important features of the tumor. MMPs (matrix metalloproteinases) can degrade the extracellular matrix (ECM) and provide a pathway for the invasion and distant metastasis of tumor cells. Type IV collagen is an important component of the ECM and the basement membrane (BM). MMP-9, as one of the largest molecular weights in MMPs, can hydrolyze the components such as type IV collagen and promote the invasion and metastasis of the tumor. TIMP-1 (matrix metalloproteinase inhibitor-1) can be combined with MMP-9 in 1:1 ratio to inhibit the protein hydrolysis of MMP-9. MMP-9 and TIMP-1 have been studied as tumor markers, but are not yet applied to clinical use. On the one hand, there is a dispute over the relationship between the expression of both in the tumor and the clinical pathology of the patient, and, on the other hand, more critical because the mechanism and role of the expression of both in the tumor remains unclear. Objective: To study the expression of MMP-9 and TIMP-1 in the tissues and serum of patients with colorectal cancer, and to analyze their relationship with the clinicopathological features of the patients and their prognosis, and to explore the possibility of both as tumor markers and to help the diagnosis and treatment of colorectal cancer. Methods: (1) The expression of MMP-9 and TIMP-1 in the normal tissues of colorectal cancer and adjacent to the cancer was studied by immunohistochemistry and Western blot. And the relationship between the expression of the two and the clinical pathological characteristics is analyzed. Statistical analysis was performed using the SPSS10.0 statistical software package. (2) The serum of 73 patients with colorectal cancer,24 patients with colorectal adenoma and 24 healthy controls were collected. In the patients with colorectal cancer and colorectal adenoma, patients with colorectal cancer and colorectal adenoma were treated with colonoscopy or surgical resection at the University of Jilin University from September 2014 to September 2015, and then confirmed by histopathology. The health control is a healthy individual for the physical examination of the hospital. The expression of MMP-9 and TIMP-1 in different specimens was detected by Elisa method, and the expression of CEA and CA19-9 in different specimens was detected by using the chemiluminescence method, and the relationship between the expression of MMP-9 and TIMP-1 in different specimens was analyzed. The diagnostic value of four markers in serum was analyzed by ROC curve. The survival rate of patients was analyzed by Log Rank test, survival curves were made, and their prognostic value was compared. Statistical analysis was performed using the SPSS10.0 statistical software package. Results: (1) The expression of MMP-9 and TIMP-1 in colorectal cancer tissues was higher than that of the corresponding adjacent tissues, and the expression of MMP-9 and TIMP-1 in colorectal cancer was not related to the age, sex, pathological type, tumor size and location of colorectal cancer (p0.05). The positive rate of expression of MMP-9 and TIMP-1 in colorectal cancer was higher in low-differentiation and high in stage III/ VI than in stage I/ II. (2) The difference of MMP-9, TIMP-1, CEA and CA19-9 in the serum of colorectal cancer group, colorectal adenoma group and normal control group was statistically significant (p0.05) and decreased in turn; the four markers in serum of patients with colorectal cancer had no statistical significance in age, sex and location (p0.05). The results showed that the area under the curve of MMP-9, TIMP-1, CEA and CA19-9 in the serum of patients with colorectal cancer was 0.768, 0.854, 0.663 and 0.616. The survival rate of serum MMP-9 and TIMP-1 was higher in patients with high value of MMP-9 and TIMP-1 in serum, but there was no difference in the survival rate of serum CEA and CA19-9 and low-value patients. Conclusion: (1) In this study, the expression of MMP-9 and TIMP-1 in the tissue of colorectal cancer is increased, and the expression of MMP-9 and TIMP-1 in colorectal cancer is closely related to the degree of differentiation of the tumor, and it is suggested that MMP-9 and TIMP-1 may be involved in the invasion and metastasis of colorectal cancer. (2) In this study, the levels of MMP-9, TIMP-1, CEA and CA19-9 in the serum of the colorectal cancer group, the colorectal adenoma group and the normal control group were decreased, and the MMP-9, TIMP-1, CEA and CA19-9 in the serum of the colorectal cancer were compared with the tumor diameter, distant metastasis, survival or not, Duke, s stage, and the degree of intestinal wall infiltration. The degree of lymph node involvement and degree of differentiation suggests that they may be involved in the invasion and metastasis of colorectal cancer. (3) In this study, the expression of MMP-9 and TIMP-1 in the serum is valuable for the diagnosis of colorectal cancer.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.34
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