【摘要】：背景和意義膀胱癌是全世界常見惡性腫瘤之一,居全球惡性腫瘤發(fā)病率第11位,約占全球腫瘤發(fā)病率的3%。2012年全球新增膀胱癌429800例,165100例患者死于膀胱癌。膀胱癌好發(fā)于男性,男性發(fā)病率大概是女性的3-4倍。膀胱癌發(fā)病率較高的是歐洲、北美、西亞以及東非,中非、西非以及東方國(guó)家及地區(qū)的發(fā)病率相對(duì)較低。在美國(guó),膀胱癌居男性惡性腫瘤發(fā)病率的第4位,據(jù)預(yù)測(cè)2015年美國(guó)將會(huì)新診斷74000例膀胱癌患者,而且將會(huì)有16000名患者因膀胱癌而死亡。全球男性膀胱癌死亡率最高的是土耳其,據(jù)估算,土耳其男性膀胱癌的死亡率(12.8/10萬(wàn))是美國(guó)的3倍,同時(shí)比歐洲最高死亡率的國(guó)家拉脫維亞(8.3/10萬(wàn))高出50%。在中國(guó)泌尿外科,膀胱癌是發(fā)病率最高的惡性腫瘤,2012年中國(guó)膀胱癌發(fā)病率在男性惡性腫瘤中居第6位,新增男性膀胱癌病人5.7萬(wàn)。1998至2008年中國(guó)膀胱癌發(fā)病率呈逐年增長(zhǎng)趨勢(shì),膀胱癌占中國(guó)腫瘤發(fā)病的構(gòu)成比例由1998年的2.21%增高至2008年的2.5%,居中國(guó)惡性腫瘤發(fā)病率第8位,占中國(guó)惡性腫瘤發(fā)病構(gòu)成的2.5%。膀胱癌分為非肌層浸潤(rùn)性膀胱癌(NMIBC)和肌層浸潤(rùn)性膀胱癌(MIBC)。據(jù)統(tǒng)計(jì),初診時(shí)70%-80%膀胱癌為分化良好或中等分化的NMIBC,首次經(jīng)尿道膀胱腫瘤切除(TURBT)術(shù)后,NMIBC第一年復(fù)發(fā)的幾率為15%-61%,五年內(nèi)復(fù)發(fā)率為31%-78%。其中約10%的患者最終進(jìn)展為肌層浸潤(rùn)性膀胱癌或者轉(zhuǎn)移性膀胱癌；尤其是高危非肌層浸潤(rùn)膀胱癌,行經(jīng)尿道膀胱腫瘤切除術(shù)后5年進(jìn)展的幾率達(dá)45%。侵襲和轉(zhuǎn)移是膀胱癌患者的首要死因,國(guó)內(nèi)一項(xiàng)研究顯示,各期膀胱癌患者5年生存率分別為：Ta-1期膀胱癌91.9%,T2期84.3%、T3期43.9%、T4期10.2%。國(guó)外研究報(bào)道,對(duì)于腫瘤局限膀胱內(nèi)并且無(wú)淋巴結(jié)轉(zhuǎn)移的非肌層浸潤(rùn)性膀胱癌5年和10年無(wú)復(fù)發(fā)生存比例分別為：P0期92%和86%,Pis期91%和89%,Pa期79%和74%,P1期83%和78%。對(duì)于肌層浸潤(rùn)性膀胱癌,若淋巴結(jié)陰性,5年無(wú)復(fù)發(fā)生存率和10年無(wú)復(fù)發(fā)生存率分別為：T2期：89%和87%,T3a期：78%和76%,T3b期：62%和61%,T4期：50%和45%。而淋巴結(jié)陽(yáng)性患者的5年和10年無(wú)復(fù)發(fā)生存率只有35%和34%。由于膀胱癌患者的生物行為存在明顯異質(zhì)性,所以現(xiàn)在治療指南推薦緊密的隨訪和有創(chuàng)的治療,造成患者大量的經(jīng)濟(jì)負(fù)擔(dān)。因此,準(zhǔn)確判斷出哪些腫瘤具有復(fù)發(fā)和進(jìn)展的潛能極其臨床意義。有一部分學(xué)者認(rèn)為對(duì)于反復(fù)復(fù)發(fā)和容易進(jìn)展的高危非肌層浸潤(rùn)性膀胱癌應(yīng)該盡早行根治性全膀胱切除以達(dá)到最好的腫瘤控制效果[9]。病理的分級(jí)、分期等曾是判斷腫瘤預(yù)后最好的臨床指標(biāo)之一,例如EORCT評(píng)分系統(tǒng),將其作為判斷術(shù)后NMIBC復(fù)發(fā)和進(jìn)展的幾率的重要風(fēng)險(xiǎn)因子；但是在指導(dǎo)個(gè)體化治療方面,其精確度欠佳。目前,在尋找預(yù)測(cè)膀胱癌進(jìn)展和復(fù)發(fā)的生物標(biāo)記物方面做了大量工作,但是仍然沒有較為理想的生物標(biāo)記物應(yīng)用臨床實(shí)踐中。據(jù)此,本項(xiàng)研究擬利用GEO數(shù)據(jù)庫(kù)下載的膀胱癌基因表達(dá)譜進(jìn)行深度挖掘,發(fā)現(xiàn)NMIBC和MIBC的差異表達(dá)基因,并且通過(guò)大樣本回顧性分析進(jìn)行驗(yàn)證,探討影響NMIBC術(shù)后復(fù)發(fā)進(jìn)展的關(guān)鍵調(diào)節(jié)基因。在初步研究中我們發(fā)現(xiàn)CDH11是促進(jìn)NMIBC進(jìn)展的關(guān)鍵因子之一,并初步探討其在膀胱癌的生物學(xué)功能,在臨床樣本中驗(yàn)證生物學(xué)信息的準(zhǔn)確性,并闡明其臨床意義。對(duì)深入研究NMIBC進(jìn)展的分子機(jī)制、指導(dǎo)NMIBC的精準(zhǔn)治療和改善NMIBC的預(yù)后具有重要的理論和臨床意義。材料和方法1.研究對(duì)象1.1膀胱癌組織標(biāo)本所有標(biāo)本收集于2007年1月-2014年5月,來(lái)自南方醫(yī)科大學(xué)第三附屬醫(yī)院和中山大學(xué)附屬腫瘤醫(yī)院泌尿外科。標(biāo)本分為三組：1.用于實(shí)時(shí)熒光定量PCR實(shí)驗(yàn)的59例冰凍膀胱癌組織和21例癌旁正常膀胱組織；2.用于Western Blot實(shí)驗(yàn)的10例冰凍膀胱癌組織和4例癌旁組織。3.用于免疫組化實(shí)驗(yàn)的209例石蠟膀胱癌組織以及12例癌旁組織。所有樣本經(jīng)南方醫(yī)科大學(xué)第三附屬醫(yī)院及中山大學(xué)附屬腫瘤醫(yī)院的病理科專家明確病理診斷。1.2膀胱癌基因表達(dá)譜數(shù)據(jù)從美國(guó)生物技術(shù)信息GEO數(shù)據(jù)庫(kù)(http://www.ncbi.nlm.nih.gov/gds/)下載4套基因表達(dá)譜,登錄號(hào)分別為GSE3167 GSE37317,GSE31684和GSE5287,篩選后將132例肌層浸潤(rùn)性膀胱癌和56例非肌層浸潤(rùn)性膀胱癌組織的基因芯片數(shù)據(jù)納入實(shí)驗(yàn)分析。2.研究方法2.1基因芯片數(shù)據(jù)分析使用R語(yǔ)言軟件,采用RMA方法和用Entrez基因?yàn)橹行牡腃DF文件代替原始的Affymetrix的CDF文件重新歸納基因表達(dá)譜數(shù)據(jù),以過(guò)濾GeneChips上的非特異探針,并且將代表同一Entrez基因的不同探針合并在一個(gè)探針集中。采用SAM方法分析MIBC和NMIBC組織之間的差異表達(dá)基因,篩選差異表達(dá)基因的標(biāo)準(zhǔn)：A=2.25,FDR=0.001。隨后采取GenCLiP軟件(網(wǎng)站：http://ci. smu.edu.cn)對(duì)差異表達(dá)基因進(jìn)行后續(xù)的Pathway和GO功能注釋。2.2實(shí)時(shí)熒光定量PCR分析采用實(shí)時(shí)熒光定量PCR方法檢測(cè)59例膀胱癌組織以及21例癌旁組織中CDH11mRNA的表達(dá)量。TBP作為內(nèi)參基因,采用2-△△Ct相對(duì)定量法來(lái)分析和反映樣本間CDH11基因的表達(dá)差異。2.3 Western Blot分析隨機(jī)挑選5例NMIBC、5例MIBC膀胱癌標(biāo)本和4例癌旁標(biāo)本,提取總蛋白進(jìn)行Western Blot實(shí)驗(yàn),用GAPDH作為內(nèi)參,進(jìn)行半定量分析。2.4免疫組化分析收集了209例膀胱癌石蠟組織(包括22例MIBC和187例NMIBC)以及12例正常膀胱組織。使用SP法免疫組化實(shí)驗(yàn)檢測(cè)CDH11蛋白在膀胱癌組織和正常膀胱組織中的表達(dá)情況。免疫組化實(shí)驗(yàn)評(píng)分判斷標(biāo)準(zhǔn)：每張玻片在高倍鏡下觀察5個(gè)視野。染色強(qiáng)度得分為：無(wú)(0分)、輕度(1分)、中度(2分)和重度(3分)；陽(yáng)性表達(dá)細(xì)胞占總腫瘤細(xì)胞的比例得分為：無(wú)(0分)、≤25%(1分)、≤50%(2分)、≤75%(3分)和75%(4分)�？偟梅�=染色強(qiáng)度得分+陽(yáng)性表達(dá)細(xì)胞占總腫瘤細(xì)胞的比例得分,總分范圍0-7分。陽(yáng)性定義：只要有細(xì)胞膜陽(yáng)性著色(總得分≥1)；陰性定義：細(xì)胞膜完全沒有陽(yáng)性著色(總得分=0)。2.5Transwell和Boyden實(shí)驗(yàn)使用Transwell和Boyden實(shí)驗(yàn)檢測(cè)CDH11對(duì)膀胱癌細(xì)胞株T24、BIU87、EJ和5637遷移侵襲能力的影響。2.6統(tǒng)計(jì)分析采用SPSS 20.0統(tǒng)計(jì)軟件分析實(shí)驗(yàn)數(shù)據(jù)。除特別說(shuō)明外,采用t檢驗(yàn)統(tǒng)計(jì)分析兩組間數(shù)據(jù)；使用卡方檢驗(yàn)分析CDH11與臨床指標(biāo)的關(guān)系,使用Kaplan-Meier and log-rank tests方法進(jìn)行生存分析以及單因數(shù)分析,多因素分析使用COX風(fēng)險(xiǎn)模型。P0.05有統(tǒng)計(jì)學(xué)意義。結(jié)果1.生物信息學(xué)分析結(jié)果提示：CDH11等基因介導(dǎo)的EMT現(xiàn)象與NMIBC術(shù)后進(jìn)展密切相關(guān)基因表達(dá)譜分析結(jié)果顯示：414個(gè)基因存在差異表達(dá),其中在肌層浸潤(rùn)性膀胱癌中表達(dá)上調(diào)的基因有185個(gè),表達(dá)下調(diào)的基因有229個(gè)。使用genclip軟件對(duì)差異表達(dá)基因進(jìn)行基因功能注解,GO分析發(fā)現(xiàn)這些差異表達(dá)基因與細(xì)胞粘附、細(xì)胞運(yùn)動(dòng)、細(xì)胞增殖、細(xì)胞凋亡等有關(guān),pathway分析發(fā)現(xiàn)差異表達(dá)基因主要與整合素信號(hào)通路、TGF-β信號(hào)通路和細(xì)胞外基質(zhì)等信號(hào)通路相關(guān)。此外,在414個(gè)差異表達(dá)基因中有164個(gè)基因與EMT相關(guān)；其中CDH11基因表達(dá)水平差異表達(dá)較大,達(dá)2.89倍,P0.0001。2.CDH11mRNA及蛋白在膀胱癌組織中表達(dá)上調(diào)實(shí)時(shí)熒光定量PCR和Western Blot實(shí)驗(yàn)分別檢測(cè)CDH11 mRNA和蛋白在膀胱癌組織中的表達(dá)水平。發(fā)現(xiàn)相對(duì)膀胱正常組織,膀胱癌中CDH11的mRNA和蛋白表達(dá)水平均升高,而且MIBC組織中CDH11的表達(dá)量高于NMIBC,差異具有統(tǒng)計(jì)學(xué)意義。免疫組化實(shí)驗(yàn)結(jié)果顯示：正常膀胱上皮組織不表達(dá)CDH11,CDH11表達(dá)于腫瘤細(xì)胞的細(xì)胞膜。NMIBC中CDH11表達(dá)陽(yáng)性率為30.5%(57/187),而MIBC中CDH11表達(dá)陽(yáng)性率為54.5%(12/22),差異表達(dá)具有統(tǒng)計(jì)學(xué)意義。3.CDH11促進(jìn)膀胱癌細(xì)胞遷移和侵襲。實(shí)時(shí)熒光定量PCR和Western Blot分析發(fā)現(xiàn)T24和BIU87細(xì)胞株中CDH11mRNA和蛋白表達(dá)水平相對(duì)較高,而5637和EJ細(xì)胞株中表達(dá)相對(duì)較低;Transwell和Boyden實(shí)驗(yàn)發(fā)現(xiàn)CDH11促進(jìn)膀胱癌細(xì)胞的遷移和侵襲能力。4.CDH11在膀胱癌中的臨床意義臨床病理資料分析發(fā)現(xiàn)CDH11陽(yáng)性表達(dá)與膀胱癌的腫瘤分級(jí)、分期、復(fù)發(fā)、進(jìn)展等臨床指標(biāo)呈正性相關(guān);陽(yáng)性表達(dá)CDH11的患者更容易復(fù)發(fā)和進(jìn)展。單因素分析和多因素分析發(fā)現(xiàn)CDH11陽(yáng)性表達(dá)是影響NMIBC患者的無(wú)復(fù)發(fā)和無(wú)進(jìn)展生存時(shí)間的獨(dú)立危險(xiǎn)因素。結(jié)論：1.通過(guò)基因芯片以及生物信息學(xué)技術(shù)篩選出與膀胱癌進(jìn)展相關(guān)的大量差異表達(dá)基因,分析發(fā)現(xiàn)這些基因主要涉及整合素信號(hào)通路、TGF-P信號(hào)通路和細(xì)胞外基質(zhì)等信號(hào)通路；且與細(xì)胞粘附、細(xì)胞運(yùn)動(dòng)、細(xì)胞增殖、細(xì)胞凋亡等有關(guān)；而且這些差異表達(dá)基因主要與EMT現(xiàn)象相關(guān)。2.CDH11 mRNA和蛋白在膀胱癌組織中表達(dá)上調(diào),而且肌層浸潤(rùn)性膀胱癌中的表達(dá)水平高于非肌層浸潤(rùn)性膀胱癌。3.CDH11在T24和BIU87細(xì)胞株中相對(duì)高表達(dá),在EJ和5637細(xì)胞株中相對(duì)低表達(dá),具有促進(jìn)膀胱癌細(xì)胞遷移和侵襲的能力。4.CDH11與膀胱癌分級(jí)、分期、復(fù)發(fā)、進(jìn)展等臨床指標(biāo)呈正相關(guān),CDH11陽(yáng)性表達(dá)提示患者預(yù)后不良。CDH11也許可以作為預(yù)測(cè)膀胱癌預(yù)后的生物標(biāo)記物。
[Abstract]:BACKGROUND AND SIGNIFICANCE Bladder cancer is one of the most common malignant tumors in the world, ranking 11th in the incidence of malignant tumors worldwide, accounting for about 3% of the global cancer incidence. In 2012, 429 800 new bladder cancer cases, 165,100 patients died of bladder cancer. Bladder cancer is predominant in men, and the incidence of male is about 3-4 times higher than that of female. Bladder cancer is the fourth most common malignancy in men in the United States. It is estimated that 74,000 new bladder cancer cases will be diagnosed in the United States in 2015 and 16,000 deaths from bladder cancer will occur worldwide. Turkey has the highest rate of bladder cancer. It is estimated that the mortality rate of male bladder cancer in Turkey (128/100,000) is three times higher than that in the United States and 50% higher than that in Latvia (8.3/100,000), the European country with the highest mortality rate. From 1998 to 2008, the incidence of bladder cancer in China increased from 2.21% in 1998 to 2.5% in 2008, ranking eighth in the incidence of malignant tumors in China, accounting for 2.5% in the incidence of malignant tumors in China. Bladder cancer (NMIBC) and myometrial invasive bladder cancer (MIBC). According to statistics, 70% to 80% of bladder cancer at first diagnosis is well-differentiated or moderately differentiated NMIBC. After the first transurethral resection of bladder tumor (TURBT), the recurrence rate of NMIBC in the first year is 15% - 61%, and the recurrence rate is 31% - 78% within five years. Invasion and metastasis are the leading causes of death in patients with bladder cancer. According to a domestic study, the 5-year survival rates of patients with various stages of bladder cancer are 91.9% for Ta-1, 84.3% for T2, 43.9% for T3, and 43.9% for T4, respectively. The 5-year and 10-year survival rates of non-myometrial invasive bladder cancer with localized bladder tumor and no lymph node metastasis were 92% and 86%, 91% and 89% in Pis stage, 79% and 74% in Pa stage, 83% and 78% in P1 stage, respectively. Recurrence survival rates were 89% and 87% in stage T2, 78% and 76% in stage T3a, 62% and 61% in stage T3b, 50% and 45% in stage T4, respectively. In lymph node-positive patients, 5-year and 10-year recurrence-free survival rates were only 35% and 34% respectively. Some scholars believe that radical cystectomy should be performed as soon as possible for high-risk non-myometrial invasive bladder cancer with recurrence and easy progression to achieve the best tumor control effect [9]. The EORCT scoring system, for example, has been used as an important risk factor for the recurrence and progression of NMIBC after surgery, but its accuracy in guiding individualized treatment is poor. A great deal of work has been done, but there is still no ideal clinical application of biomarkers. Therefore, this study intends to use the gene expression profiles downloaded from GEO database to dig in depth and find the differentially expressed genes between NMIBC and MIBC, and verify them by a large sample retrospective analysis to explore the impact of NMIBC recurrence after surgery. In the preliminary study, we found that CDH11 is one of the key factors to promote the progress of NMIBC, and preliminarily explore its biological function in bladder cancer, verify the accuracy of biological information in clinical samples, and clarify its clinical significance. Materials and Methods 1.1 All specimens of bladder cancer tissue were collected from January 2007 to May 2014 from the Third Affiliated Hospital of Southern Medical University and the Urology Department of the Cancer Hospital of Sun Yat-sen University. The specimens were divided into three groups: 1. Real-time fluorescence quantitative PCR 59 cases of frozen bladder cancer tissue and 21 cases of normal bladder tissue adjacent to cancer; 2. 10 cases of frozen bladder cancer tissue and 4 cases of adjacent bladder tissue used in the Western Blot experiment. 3. 209 cases of paraffin bladder cancer tissue and 12 cases of adjacent tissues used in immunohistochemistry. All samples were obtained from the Third Affiliated Hospital of Southern Medical University and the Oncologist Affiliated to Zhongshan University. Pathological specialists in the hospital confirmed the pathological diagnosis. 1.2 Bladder oncogene expression profiles were downloaded from the US Biotechnology Information GEO database (http://www.ncbi.nlm.nih.gov/gds/) and registered at GSE3167 GSE37317, GSE31684 and GSE5287, respectively. After screening, 132 cases of myometrial invasive bladder cancer and 56 cases of non-myometrial invasive bladder cancer were selected. Methods 2.1 Gene chip data analysis used R language software, RMA method and CFD file with Entrez gene as the center were used to replace the original CFD file of Affymetrix to re-summarize gene expression profile data to filter non-specific probes on GeneChips and represent the same. Different probes of Entrez gene were merged into one probe set. SAM method was used to analyze the differentially expressed genes between MIBC and NMIBC tissues, and the criteria of differentially expressed genes were screened: A = 2.25, FDR = 0.001. GenCLiP software (website: http://ci.smu.edu.cn) was then used to annotate the differentially expressed genes in Pathway and GO function.2.2. The expression of CDH11 mRNA in 59 bladder cancer tissues and 21 adjacent bladder cancer tissues was detected by real-time fluorescence quantitative PCR. TBP was used as an internal reference gene. The expression of CDH11 gene was analyzed and reflected by 2-delta CT relative quantitative method. 2.3 Western Blot analysis randomly selected 5 cases of NMIBC and 5 cases of MIBC bladder cancer. Total protein was extracted from specimens and 4 adjacent specimens for Western Blot assay. GAPDH was used as internal reference for semi-quantitative analysis. 2.4 Immunohistochemistry was used to collect paraffin tissues from 209 cases of bladder cancer (including 22 cases of MIBC and 187 cases of NMIBC) and 12 cases of normal bladder tissues. Normal expression of bladder tissue. Immunohistochemical test score criteria: each slide was observed under high power microscope 5 visual fields. The staining intensity scores were: no (0 points), mild (1 point), moderate (2 points) and severe (3 points); the proportion of positive cells in total tumor cells was: no (0 points), < 25% (1 point), < 50% (2 points), < 75% (3 points). Positive definitions: as long as there is positive staining of the cell membrane (total score (> 1); negative definitions: there is no positive staining of the cell membrane (total score = 0). 2.5 Transwell and Boyden experiments used Transwell and Boyden tests. The effects of CDH11 on the migration and invasion of bladder cancer cell lines T24, BIU87, EJ and 5637 were measured. 2.6 The experimental data were analyzed by SPSS 20.0 statistical software. Survival analysis and single factor analysis showed that COX risk model was used for multivariate analysis. P 0.05 had statistical significance. Results 1. Bioinformatics analysis showed that CDH11 and other gene-mediated EMT phenomena were closely related to the progress of NMIBC after operation. Gene expression profiles showed that 414 genes were differentially expressed, including infiltration in muscular layer. There were 185 up-regulated genes and 229 down-regulated genes in bladder cancer. Genclip software was used to annotate the function of differentially expressed genes. GO analysis showed that these differentially expressed genes were related to cell adhesion, cell movement, cell proliferation and cell apoptosis. Path analysis showed that differentially expressed genes were mainly related to integrin signaling. In addition, 164 of 414 differentially expressed genes were associated with EMT, and the expression level of CDH11 gene was 2.89 times, P 0.0001.2. The expression of CDH11 mRNA and protein was up-regulated by real-time quantitative PCR and Western Blot assay in bladder cancer tissues. The expression levels of CDH11 mRNA and protein in bladder cancer tissues were detected respectively. It was found that the expression levels of CDH11 mRNA and protein in bladder cancer tissues were higher than those in normal bladder tissues, and the expression level of CDH11 in MIBC tissues was higher than that in NMIBC tissues. The positive rate of CDH11 expression in NMIBC was 30.5% (57/187), while that in MIBC was 54.5% (12/22). The difference was statistically significant. 3. CDH11 promoted the migration and invasion of bladder cancer cells. Real-time fluorescence quantitative PCR and Western Blot analysis showed that CDH11 mRNA and eggs were found in T24 and BIU87 cell lines. The expression level of CDH11 in bladder cancer was relatively high, while that in 5637 and EJ cells was relatively low. Transwell and Boyden experiments showed that CDH11 promoted the migration and invasion of bladder cancer cells. The positive expression of CDH11 was found to be an independent risk factor for recurrence-free and progression-free survival in patients with NMIBC by univariate and multivariate analysis. Differentially expressed genes were mainly involved in integrin signaling pathway, TGF-P signaling pathway and extracellular matrix signaling pathway, and were related to cell adhesion, cell movement, cell proliferation, cell apoptosis, etc. These differentially expressed genes were mainly related to EMT phenomena. 2. CDH11 mRNA and protein in bladder cancer tissue surface. CDH11 was relatively high in T24 and BIU87 cell lines, but relatively low in EJ and 5637 cell lines. It has the ability to promote the migration and invasion of bladder cancer cells. 4. CDH11 and bladder cancer classification, stage, recurrence, progression and other clinical indicators were presented. CDH11 may be a biomarker for predicting the prognosis of bladder cancer.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R737.14

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