本文選題：B類Ⅰ型清道夫受體 + 結腸癌��； 參考：《山東大學》2017年碩士論文

【摘要】：研究背景結腸癌是臨床中發(fā)病率較高的疾病。近年來隨著人們生活水平的改善,結腸癌的發(fā)病率也在逐年的升高。在近年的調查中發(fā)現(xiàn)在所有癌癥患者中結腸癌的發(fā)病率居全世界第3位,并且女性患者普遍高于男性患者,平均每年有數(shù)十萬的結腸癌患者死亡,因此對于結腸癌的研究和治療具有重要的臨床意義。流行病學顯示,結腸癌的發(fā)生與高脂飲食,肥胖,飲酒,缺乏鍛煉密切相關。既往研究表明,結腸癌的進展與血脂水平異常,特別是血漿高密度脂蛋白(High-density lipoprotein,HDL)的水平下降相關。B 類 Ⅰ 型清道夫受體(scavenger receptor class B type Ⅰ,SR-BⅠ)是第一個在分子水平上得到確證的高密度脂蛋白受體,體內SR-BⅠ表達相對廣泛,主要表達于肝臟和腎上腺、卵巢、睪丸等固醇激素生成組織。SR-BⅠ是HDL中膽固醇及膽固醇酯轉運的重要受體,參與體內膽固醇逆向轉運過程。SR-BⅠ作為體內HDL的一種生理相關性受體,除了介導HDL抗炎、抗血栓、抗氧化等作用外,它還具有其它多種生物學作用,如在膿毒癥、丙型肝炎病毒入侵、炎癥、先天免疫、正常紅細胞成熟和雌性生育等方面都有重要的調節(jié)作用。隨后研究證實,SR-BⅠ在某些腫瘤細胞系中高表達,包括前列腺癌、肝癌、卵巢癌、乳腺癌、結腸癌、胰腺癌和鼻咽癌。然而,SR-BⅠ在結腸癌組織中的表達情況及其臨床意義尚沒有相關研究報道。在本課題中,我們首先應用生物信息學分析了脂質代謝相關基因在結腸癌患者與正常人之間的不同表達水平以及各基因與臨床病理變量的關系,證實了SCARB1是參與膽固醇內化的5個基因中唯一在結腸癌患者中上調的基因。其次,我們利用組織芯片免疫組織化學技術檢測了 SR-BI在90例結腸癌組織及其相應癌旁組織標本的表達情況,分析了 SR-BI的表達與患者各臨床病理變量、預后的關系,證實SR-BI的表達雖與各臨床病理變量無相關性,但是影響結腸癌預后的獨立危險因素。目的1.應用生物信息學分析脂質代謝相關基因在結腸癌患者與正常人之間的不同表達水平以及各基因與臨床病理變量的關系。2.采用含90例結腸癌組織及其相應癌旁組織標本的組織芯片檢測SR-BI蛋白的表達情況。3.分析SR-BI的表達與結腸癌患者各臨床病理變量之間的關系,并探討SR-BI的表達狀態(tài)與患者的預后關系,以期尋找新的結腸癌預后指標和潛在的治療靶點。方法1.以癌癥基因庫(The Cancer Genome Altas,TCGA)提供的245例結腸癌患者及21例正常人的17組與脂質代謝相關基因信息為研究對象,分析脂質代謝相關基因在結腸癌患者與正常人之間的不同表達水平以及各基因與臨床病理變量的關系。脂質代謝相關基因在結腸癌患者與正常人之間的不同表達水平采用T檢驗進行評估。各基因與臨床病理變量的關系采用單因素方差分析進行評價。2.采用免疫組織化學染色的方法對購自上海芯超生物科技有限公司的含90例結腸癌組織和相對應的癌旁組織的芯片進行SR-BI表達的檢測,并分析其與結腸癌癌的發(fā)生發(fā)展、臨床病理特征及患者預后的關系。免疫組織化學SR-BI染色的評分由兩個獨立的病理學家進行,屏蔽患者的臨床信息和預后情況。評分的方法應用改進的免疫反應評分法(immune response scoring method,IRS),主要評價染色細胞的百分比(無染色,0;10%,1;10-50%,2;51-80%,3;80%,4)和染色強度(無染色,0;弱,1;中度,2;強,3)。染色強度和染色陽性細胞數(shù)比例的乘積得分(范圍從0到12)作為每例患者的最終得分。在隨后的統(tǒng)計分析中應用兩級分層。腫瘤標本評分最后在0-4之間認為是SR-BI低表達,而≥6認為是高表達。SR-BI的表達與臨床病理特征之間的關系采用卡方檢驗或Fisher精確檢驗進行評估,取決于不同的臨床病理參數(shù)的數(shù)值性質和正態(tài)分布性。生存分析采用Kaplan-Meier生存分析進行評價,并用Log-rank檢驗各變量對生存時間(overall survival,OS)的影響。多因素分析采用Cox比例風險模型來計算,計算風險比(hazard ratio,HR)和95%可信區(qū)間(confidence interval,CI)。結果1.相比于正常人,5個基因在結腸癌患者中明顯上調,SCARB1(P = 0.000),金屬蛋白酶組織抑制物1(TIMP1,P = 0.000),基質金屬蛋白酶9(MMP-9,P = 0.000),固醇調節(jié)元件結合轉錄因子1(SREBF1,P = 0.028),脂肪酸合酶(FASN,P = 0.000)。9個基因在結腸癌患者中明顯下調,組織蛋白酶S(CTSS,P = 0.000),膽固醇脂化微囊蛋白1(CAV1,P = 0.001),極低密度脂蛋白受體相關蛋白(VLDLR,P = 0.000),ATP結合盒轉運子1(ABCA1,P = 0.000),乙酰輔酶A乙酰轉移酶1(ACAT1,P = 0.000),分化抗原簇36(CD36,P = 0.000),3-羥基-3-甲基-戊二酸-輔酶 A 還原酶(HMG-CoAR,P= 0.047),固醇調節(jié)元件結合轉錄因子2(SREBF2,=0.001),肝X受體激動劑 α(LXR-α,P = 0.000)。2.CD36(P = 0.002),CTSS(P = 0.028),VLDLR(P = 0.020)在結腸癌患者中的表達水平與淋巴結轉移的陽性率相關。CTSS(P = 0.025),ACAT1(P=0.006),MMP-9(P=0.003),HMG-CoAR(P = 0.005)與 T 分期相關。LDLRP(P = 0.041)和MMP-9(P = 0.047)與腫瘤分級相關。值得注意的是SCARB1的表達水平與各臨床病理變量無關。3.在90例結腸癌組織標本中,51例(56.7%)為SR-BⅠ高表達,39例(43.3%)為SR-BⅠ低表達。在90例相對應的癌旁組織中,48例(53.3%)為SR-BⅠ高表達,42例(46.7%)為SR-BⅠ低表達。SR-BⅠ在大多數(shù)結腸癌組織比相對應的癌旁組織表達高(P = 0.000)。4.與SCARB1的表達水平與各臨床病理變量無關的結果一致,SR-BⅠ的表達水平與性別、年齡、腫瘤pTNM分期、腫瘤大小、腫瘤分級、淋巴結總數(shù)、淋巴結轉移的陽性率、AJCC臨床分期無關。5.在結腸癌組織中,SR-BⅠ低表達的患者比SR-BⅠ高表達的患者總體生存率(OS)縮短(log-rank檢驗,P = 0.042)。Cox回歸多因素分析提示SR-BI的高表達是影響預后的獨立有利因素,HR為0.502(P = 0.039),除了 SR-BI之外,淋巴結轉移的陽性率也是結腸癌患者預后的獨立因素(P = 0.007)。結論1.基因SCARB1的表達水平在結腸癌患者中上調。2.結腸癌組織SR-BI表達水平比癌旁組織高。3.結腸癌組織中SR-BI的表達水平與結腸癌患者的生存相關。SR-BI表達水平越低,預后越差。4.結腸癌組織中SR-BI的表達水平是結腸癌患者的獨立預后因素。研究意義SR-BI的低表達狀態(tài)與結腸癌患者不良預后有關,SR-BI的表達可能被作為結腸癌的惡性指標之一而應用于臨床檢測中。
[Abstract]:Background colon cancer is a disease with high incidence in clinic. In recent years, with the improvement of people's living standard, the incidence of colon cancer is also increasing year by year. In recent years, the incidence of colon cancer in all cancer patients is third in the world, and the female patients are generally higher than those of male patients. One hundred thousand of the colon cancer patients died, so the research and treatment of colon cancer has important clinical significance. Epidemiology shows that the occurrence of colon cancer is closely related to high fat diet, obesity, drinking and lack of exercise. Previous studies have shown that the progression of colon cancer and blood lipid levels are abnormal, especially the plasma high density lipoprotein (High-density lip). The level decline of oprotein, HDL) related.B class type I scavenger receptor (scavenger receptor class B type I, SR-B I) is the first high density lipoprotein receptor confirmed at the molecular level, and the expression of SR-B I in the body is relatively extensive, mainly expressed in the liver and adrenal, ovary, testis and other steroid hormone producing tissue.SR-B I is HDL .SR-B I, an important receptor for the transport of cholesterol and cholesteryl ester, is involved in the reverse transport of cholesterol in the body as a physiological receptor in the body of HDL. In addition to mediating the anti-inflammatory, antithrombotic and antioxidant functions of HDL, it also has many other biological effects, such as sepsis, hepatitis C virus invasion, inflammation, and innate immunity. SR-B I was highly expressed in some tumor cell lines, including prostate cancer, liver cancer, ovarian cancer, breast cancer, colon cancer, pancreatic cancer, and nasopharyngeal carcinoma. However, there is no correlation between the expression of SR-B I in colon cancer and its clinical significance. In this study, we first applied bioinformatics to analyze the different expression levels of lipid metabolism related genes in colon cancer patients and normal people, and the relationship between the genes and the clinicopathological variables, and confirmed that SCARB1 is the only gene for the 5 genes involved in cholesterol internalization in colon cancer patients. At the same time, we detected the expression of SR-BI in 90 cases of colon cancer tissue and its adjacent tissues by tissue microarray immunohistochemical technique, analyzed the relationship between the expression of SR-BI and the clinicopathological variables and the prognosis of the patients, and confirmed that the expression of SR-BI was not related to the clinicopathological variables, but it affected the prognosis of colon cancer. Independent risk factors. Objective 1. application of bioinformatics to analyze the different expression levels of lipid metabolism related genes in patients with colon cancer and normal people and the relationship between the genes and the clinicopathological variables.2. use the tissue core of 90 cases of colon cancer tissue and its corresponding paracancerous tissue samples to detect the expression of SR-BI protein.3. analysis S The relationship between the expression of R-BI and the clinicopathological variables of colon cancer patients, and the relationship between the expression of SR-BI and the prognosis of the patients, in order to find a new prognostic indicator and potential therapeutic targets for colon cancer. Method 1. the 17 groups of colon cancer patients and 21 normal persons were provided with the The Cancer Genome Altas (TCGA). The different expression levels of lipid metabolism related genes in colon cancer patients and normal people and the relationship between genes and clinicopathological variables are analyzed with lipid metabolism related gene information. The different expression levels of lipid metabolism related genes in colon cancer patients and normal people are evaluated by T test. The relationship with the clinicopathological variables was evaluated by single factor ANOVA..2. was used to detect the expression of SR-BI in 90 cases of colon cancer tissue and corresponding para cancerous tissues purchased from Shanghai core superbiological science and Technology Co., Ltd., and analyzed the occurrence and development of carcinoma of colon and clinical disease. The relationship between physical characteristics and patient prognosis. The score of immunohistochemical SR-BI staining was carried out by two independent pathologists to shield the patient's clinical information and prognosis. The scoring method was used to evaluate the percentage of dyed cells (no staining, 0; 10%, 1; 10-5) by the improved immune response score (Immune response scoring method, IRS). 0%, 2; 51-80%, 3; 80%, 4) and the intensity of dyed (no dyeing, 0; weak, 1; moderate, 2; 3). The product score (range from 0 to 12) was the final score of each patient (range from 0 to 12). The relationship between the expression of high expression of.SR-BI and the clinicopathological features was evaluated by chi square test or Fisher accurate test, depending on the numerical and normal distribution of different clinicopathological parameters. The survival analysis was evaluated by Kaplan-Meier survival analysis, and the Log-rank test was used to test the survival time (overall surviv). The effect of Al, OS). The multifactor analysis uses the Cox proportional hazard model to calculate the risk ratio (hazard ratio, HR) and the 95% confidence interval (confidence interval, CI). Results 1. compared to normal people, 5 genes were significantly up-regulated in colon cancer patients, SCARB1 (P = 0), metalloproteinase tissue inhibitor 1 (TIMP1, 0), and matrix metalloproteinases. Enzyme 9 (MMP-9, P = 0), sterol regulatory element combined with transcription factor 1 (SREBF1, P = 0.028), fatty acid synthase (FASN, P = 0).9 genes were significantly down regulated in colon cancer patients, cathepsin S (CTSS, P = 0), cholesterol lipoprotein microcystin 1 (CAV1, P = 0.001), extremely low density lipoprotein receptor related protein (0 = 0), binding Box transporter 1 (ABCA1, P = 0), acetyl coenzyme A acetyltransferase 1 (ACAT1, P = 0), differentiated antigen cluster 36 (CD36, P = 0), 3- hydroxyl -3- methyl - glutaric acid - coenzyme A reductase (HMG-CoAR, P= 0.047), sterol regulator element binding transcription factor 2. 0.028), the expression level of VLDLR (P = 0.020) in colon cancer patients was related to the positive rate of lymph node metastasis (.CTSS (P = 0.025), ACAT1 (P=0.006), MMP-9 (P=0.003), HMG-CoAR (P = 0.005) and T staging related.LDLRP (0.041) and P = 0.047). Of the 90 cases of colon cancer, 51 cases (56.7%) were high expression of SR-B I, 39 (43.3%) was SR-B I low expression. In the corresponding para cancerous tissues of 90 cases, 48 cases (53.3%) were high expression of SR-B I, 42 (46.7%) was SR-B I low expression.SR-B I expressed high (P = 0).4. and SCA in most colon cancer tissues than corresponding cancerous tissues. The expression level of RB1 was consistent with that of various clinicopathological variables. The expression level of SR-B I was not related to sex, age, tumor pTNM staging, tumor size, tumor classification, lymph node number, positive rate of lymph node metastasis, and.5. in colon cancer tissue, and the patients with low expression of SR-B I were higher than those with high expression of SR-B I. The survival rate (OS) shortening (log-rank test, P = 0.042).Cox regression multivariate analysis suggested that the high expression of SR-BI was an independent factor affecting the prognosis, HR was 0.502 (P = 0.039). Besides SR-BI, the positive rate of lymph node metastasis was also an independent factor (P = 0.007) for the prognosis of colon cancer patients. Conclusion the expression level of the 1. gene SCARB1 is in colon cancer patients. The expression level of SR-BI in the.2. colon cancer tissue is higher than that of the high.3. colon cancer tissue of the paracancerous tissue. The lower the expression level of SR-BI in the colon cancer patients, the lower the.SR-BI expression level, the worse the prognosis in.4. colon cancer tissue, the expression level of SR-BI is the independent preconditioning factor of colon cancer patients. The poor prognosis of patients with colorectal cancer is related. The expression of SR-BI may be used as a malignant marker of colon cancer and used in clinical detection.

【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R735.35

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