MMP-9和TIMP-1在結(jié)直腸癌組織和血清中的表達(dá)及其臨床意義
發(fā)布時(shí)間：2019-07-05 21:28
【摘要】：背景:結(jié)直腸癌是臨床常見(jiàn)腫瘤之一。隨著人們生活水平改善,食物結(jié)構(gòu)的改變和生活壓力的增加,近年來(lái)我國(guó)結(jié)直腸癌發(fā)病率呈上升趨勢(shì)。結(jié)直腸癌發(fā)病隱匿,危險(xiǎn)性大,臨床癥狀出現(xiàn)已到中晚期,給結(jié)直腸癌診治帶來(lái)極大的困難。所以早期診斷對(duì)于結(jié)直腸癌患者尤為重要。侵襲和轉(zhuǎn)移是腫瘤兩個(gè)重要特征。MMPs(基質(zhì)金屬蛋白酶)能降解細(xì)胞外基質(zhì)(ECM),為腫瘤細(xì)胞的侵襲和遠(yuǎn)處轉(zhuǎn)移提供路徑。IV型膠原是ECM和基底膜(BM)重要成分。MMP-9作為MMPs中分子量最大的一種,能水解IV型膠原等成分,促進(jìn)腫瘤的侵襲和轉(zhuǎn)移。TIMP-1(基質(zhì)金屬蛋白酶抑制劑-1)能與MMP-9特異性地1:1比例結(jié)合,抑制MMP-9的蛋白水解作用。MMP-9和TIMP-1作為腫瘤標(biāo)志物已研究過(guò),但仍未應(yīng)用于臨床。一方面可能由于對(duì)于兩者在腫瘤中表達(dá)與患者的臨床病理特征的關(guān)系仍存在爭(zhēng)議,另一方面更關(guān)鍵的原因是由于兩者在腫瘤中的表達(dá)機(jī)制和作用仍不清楚。目的:論文旨在通過(guò)結(jié)直腸癌患者組織和血清中MMP-9和TIMP-1的表達(dá)情況,并分析它們與患者臨床病理特征以及與預(yù)后的關(guān)系,探索兩者作為腫瘤標(biāo)志物的可能性,進(jìn)而為結(jié)直腸癌的診治提供幫助。方法:(1)收集2015年3月到2016年3月在吉林大學(xué)第二醫(yī)院院手術(shù)切除的44例結(jié)直腸癌組織及癌旁正常組織,用免疫組化和Western blot研究MMP-9和TIMP-1在結(jié)直腸癌組織及癌旁正常組織的表達(dá),并分析兩者表達(dá)與臨床病理特征關(guān)系。采用SPSS20.0統(tǒng)計(jì)軟件包進(jìn)行統(tǒng)計(jì)學(xué)分析。(2)分別收集73例結(jié)直腸癌患者、24例結(jié)直腸腺瘤患者和24例健康對(duì)照的血清。其中結(jié)直腸癌患者和結(jié)直腸腺瘤患者均在2014年9月到2015年9月在吉林大學(xué)中日聯(lián)誼醫(yī)院經(jīng)結(jié)腸鏡或手術(shù)切除腫物,然后通過(guò)組織病理學(xué)確診。健康對(duì)照為經(jīng)該院體檢的健康個(gè)體。用Elisa方法檢測(cè)MMP-9和TIMP-1在不同標(biāo)本中的表達(dá),用電化學(xué)發(fā)光法檢測(cè)CEA和CA19-9在不同標(biāo)本中的表達(dá),并分析它們表達(dá)與臨床病理特征關(guān)系。采用ROC曲線分析血清中四種標(biāo)志物的診斷價(jià)值。采用Log Rank檢驗(yàn)分析患者的生存率,制作生存曲線,并比較它們的預(yù)后價(jià)值。采用SPSS20.0統(tǒng)計(jì)軟件包進(jìn)行統(tǒng)計(jì)學(xué)分析。結(jié)果:(1)結(jié)直腸癌組織中MMP-9和TIMP-1表達(dá)均高于其對(duì)應(yīng)的癌旁組織,兩者表達(dá)不相關(guān),并且MMP-9和TIMP-1在結(jié)直腸癌中的表達(dá)與結(jié)直腸癌患者年齡、性別、病理分型、腫瘤大小和部位無(wú)關(guān)(p0.05),而與結(jié)直腸癌分化程度和分期有關(guān)(p0.05)。MMP-9和TIMP-1在結(jié)直腸癌的陽(yáng)性表達(dá)率,在低分化中較高中分化高,III/VI期較I/II期高。(2)血清中MMP-9、TIMP-1、CEA和CA19-9在結(jié)直腸癌組、結(jié)直腸腺瘤組、正常對(duì)照組三組間差異均有統(tǒng)計(jì)學(xué)意義(p0.05),并依次減少;結(jié)直腸癌患者血清中四種標(biāo)志物在年齡、性別、部位上無(wú)統(tǒng)計(jì)學(xué)意義(p0.05),在腫瘤直徑、遠(yuǎn)處轉(zhuǎn)移、生存與否、Duke,s分期、腸壁浸潤(rùn)程度、淋巴結(jié)參與、分化程度有統(tǒng)計(jì)學(xué)意義(p0.05);ROC結(jié)果顯示:結(jié)直腸癌患者血清中MMP-9、TIMP-1、CEA和CA19-9的曲線下面積(AUC)依次為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無(wú)差異。結(jié)論:(1)本研究證實(shí)結(jié)直腸癌組織中MMP-9和TIMP-1較癌旁正常組織中表達(dá)增加,并且結(jié)直腸癌組織中MMP-9和TIMP-1表達(dá)與腫瘤分期分化程度密切相關(guān),提示MMP-9和TIMP-1可能參與結(jié)直腸癌的侵襲轉(zhuǎn)移過(guò)程。(2)本研究證實(shí)血清中MMP-9、TIMP-1、CEA和CA19-9在結(jié)直腸癌組、結(jié)直腸腺瘤組、正常對(duì)照組依次減少,結(jié)直腸癌血清中MMP-9、TIMP-1、CEA和CA19-9與腫瘤直徑、遠(yuǎn)處轉(zhuǎn)移、生存與否、Duke,s分期、腸壁浸潤(rùn)程度、淋巴結(jié)參與、分化程度有關(guān),說(shuō)明它們均可能參與結(jié)直腸癌的侵襲轉(zhuǎn)移過(guò)程。(3)本研究提示血清中MMP-9、TIMP-1對(duì)結(jié)直腸癌有一定的診斷預(yù)后價(jià)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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R735.34
本文編號(hào)：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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R735.34
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