本文選題：膀胱尿路上皮癌 + 谷胱甘肽��； 參考：《山東大學(xué)》2014年博士論文

【摘要】：背景 膀胱癌屬于泌尿系統(tǒng)中最常見(jiàn)的一種的惡性腫瘤,近年來(lái),膀胱尿路上皮癌的發(fā)病率和死亡率均有逐年增高的趨勢(shì),膀胱癌(bladder cancer)已成為危脅人類健康的世界性問(wèn)題,在全球惡性腫瘤的發(fā)病率中位列第九位[1]。2006年美國(guó)癌癥協(xié)會(huì)統(tǒng)計(jì)膀胱癌在男性中排名第四位,排在前列腺癌、肺癌和直腸癌之后。它是我國(guó)泌尿外科臨床上最常見(jiàn)的惡性疾病之一,是一種對(duì)患者生命安全造成直接威脅的疾病。國(guó)內(nèi)外學(xué)者對(duì)膀胱癌的危險(xiǎn)因素做了大量的研究,其具體的發(fā)生病因目前還不清楚,有機(jī)化學(xué)致癌物和人體色氨酸,代謝異常是目前公認(rèn)的常見(jiàn)原因。有研究發(fā)現(xiàn)膀胱長(zhǎng)期殘余尿、慢性膀胱炎、以及長(zhǎng)期的膀胱結(jié)石、導(dǎo)管刺激與膀胱癌的發(fā)生有著密切關(guān)系[2]。膀胱癌的病理類型包括尿路移行上皮細(xì)胞癌、鱗狀上皮細(xì)胞癌、腺細(xì)胞癌以及轉(zhuǎn)移癌、癌肉瘤等,而移性上皮細(xì)胞癌為膀胱癌中最常見(jiàn)的病理類型。非上皮性膀胱腫瘤來(lái)自于膀胱間葉組織,臨床上更為少見(jiàn)。膀胱癌的惡性程度以目前世界衛(wèi)生組織(World Health Organization,WHO)分級(jí)法表示,分級(jí)與腫瘤的惡性程度成正比,腫瘤分期分級(jí)愈高,數(shù)目越多,體積愈大,術(shù)后腫瘤浸潤(rùn)和復(fù)發(fā)的可能性愈大。膀胱癌的臨床分期是評(píng)判腫瘤預(yù)后最重要的參數(shù),它與腫瘤浸潤(rùn)深度和有無(wú)轉(zhuǎn)移密切相關(guān)。膀胱癌患者臨床上多表現(xiàn)為無(wú)痛性肉眼血尿,可間歇性出現(xiàn),如果伴有血塊可造成急性尿潴留。晚期膀胱癌患者由于腫瘤浸潤(rùn)、轉(zhuǎn)移可發(fā)生貧血、下腹部腫物、腰骶部疼痛、患肢水腫等臨床癥狀。非肌層浸潤(rùn)性膀胱癌可行經(jīng)尿道膀胱腫瘤切除術(shù),術(shù)后輔以局部膀胱灌洗化療。其發(fā)病機(jī)理還不完全明了。近年來(lái),已經(jīng)有大量的數(shù)據(jù)研究發(fā)現(xiàn),在機(jī)體細(xì)胞惡性增殖導(dǎo)致腫瘤產(chǎn)生的過(guò)程中,體內(nèi)的氧化還原系統(tǒng)較正常狀態(tài)下發(fā)生不同的改變,氧化還原狀態(tài)的失衡可能在腫瘤的病理進(jìn)展中非常重要,這與氧化應(yīng)激導(dǎo)致細(xì)胞中的大分子脫氧核糖核酸功能受損有一定的關(guān)系。各種氧化產(chǎn)物與惡性疾病的病情發(fā)展密切相關(guān),甚至,在癌癥發(fā)生以前就可能出現(xiàn)自由基和活性氧產(chǎn)物增多的現(xiàn)象。在各種不同的惡性組織細(xì)胞中,抗氧化能力的下降導(dǎo)致的后果是機(jī)體內(nèi)產(chǎn)生各種不同的大量的活性氧產(chǎn)物。在膀胱尿路上皮癌中,機(jī)體內(nèi)的的氧化應(yīng)激狀態(tài)發(fā)生了不同的改變[5]。在膀胱癌中,部分與氧化系統(tǒng)密切有關(guān)的物質(zhì)例如脂質(zhì)、蛋白及DNA等均產(chǎn)生不同程度的變化[6]。有學(xué)者研究認(rèn)為活性氧成分在黑色素瘤的疾病進(jìn)展過(guò)程中發(fā)揮十分顯著的作用,針對(duì)活性氧成分的治療措施能夠顯著的抑制癌細(xì)胞和抑制疾病的進(jìn)展。谷胱甘肽作為機(jī)體清除自由基的最重要的抗氧化成分之一在機(jī)體的各種防御系統(tǒng)中扮演著重要的角色,谷胱甘肽作為體內(nèi)相當(dāng)顯著的抗氧化成分,對(duì)保護(hù)機(jī)體各種組織細(xì)胞中的蛋白質(zhì)和酶類分子中的巰基發(fā)揮相當(dāng)重要的作用。谷氨酰半胱氨酸連接酶(GCL)是谷胱甘肽GSH在代謝中發(fā)揮重要作用的關(guān)鍵酶,其亞基在基因水平和蛋白水平及活性水平的改變能夠使惡性增殖細(xì)胞中的活性氧產(chǎn)物含量改變同時(shí)影響腫瘤細(xì)胞增殖的進(jìn)程。 目的 目前,谷氨酰半胱氨酸連接酶作為谷胱甘肽代謝過(guò)程中的關(guān)鍵酶在膀胱尿路上皮癌中尚無(wú)系統(tǒng)性的研究,我們希望通過(guò)對(duì)谷氨酰半胱氨酸連接酶在基因水平、蛋白水平和活性水平中較為系統(tǒng)的研究,探討其在膀胱尿路上皮癌中變化,為膀胱尿路上皮癌的診斷、治療和預(yù)后分析提供有效的數(shù)據(jù)基礎(chǔ)。 方法 對(duì)膀胱尿路上皮癌和正常對(duì)照人群的一般血液學(xué)指標(biāo)、臨床生化指標(biāo)和出凝血數(shù)據(jù)等實(shí)驗(yàn)室檢測(cè)項(xiàng)目進(jìn)行了系統(tǒng)的統(tǒng)計(jì)學(xué)處理；方法對(duì)46例膀胱尿路上皮癌組織和39例對(duì)照癌旁組織中的谷氨酰半胱氨酸連接酶的催化亞基(GCLC)和調(diào)節(jié)亞基(GCLM)信使核糖核酸(mRNA)的表達(dá)情況運(yùn)用實(shí)時(shí)熒光定量PCR(quantitative realtime-PCR)進(jìn)行實(shí)驗(yàn)分析；方法對(duì)膀胱尿路上皮癌組織和對(duì)照癌旁組織中的谷氨酰半胱氨酸連接催化亞基和調(diào)節(jié)亞基蛋白表達(dá)含量使用蛋白印跡(Western blotting)進(jìn)行實(shí)驗(yàn)分析；運(yùn)用酶的活性實(shí)驗(yàn)方法分析膀胱尿路上皮癌組織和對(duì)照癌旁組織中的谷氨酰半胱氨酸連接活性的改變。在實(shí)驗(yàn)過(guò)程中所收集的數(shù)據(jù)通過(guò)SPSS13.0統(tǒng)計(jì)學(xué)軟件進(jìn)行分析處理,采用Student's two-tailed t-tests方法進(jìn)行差異顯著性分析,p0.05為差異具有顯著性,統(tǒng)計(jì)數(shù)據(jù)均采用均數(shù)±標(biāo)準(zhǔn)誤(SEM)方式來(lái)表示。 結(jié)果 熒光定量PCR的實(shí)驗(yàn)結(jié)果分析顯示,與癌旁組織的對(duì)照組相比較,膀胱尿路上皮癌組織中谷氨酰半胱氨酸連接酶的催化亞基GCLc和調(diào)節(jié)亞基GCLm基因表達(dá)出現(xiàn)顯著降低的變化,兩者之間具有顯著的統(tǒng)計(jì)學(xué)差異(GCLc基因：BUC組1±0.028,對(duì)照組3.74±0.545;p0.01)(GCLm基因：BUC組1±0.05,對(duì)照組3.07±0.571；p0.01)。根據(jù)蛋白印跡的的實(shí)驗(yàn)結(jié)果分析顯示,與癌旁組織的對(duì)照組相比較,在膀胱尿路上皮癌組織中谷氨酰半胱氨酸連接酶的催化亞基和調(diào)節(jié)亞基的蛋白表達(dá)顯示顯著下降的變化,兩者之間具有顯著的統(tǒng)計(jì)學(xué)差異(GCLc基因：BUC組0.983±0.022,對(duì)照組1.248±0.076;p0.05)(GCLm基因：BUC組1.103±0.014,對(duì)照組1.306±0.033；p0.05)。根據(jù)酶活性的實(shí)驗(yàn)結(jié)果分析顯示,與癌旁組織的對(duì)照組相比較,谷氨酰半胱氨酸連接酶的活性在膀胱尿路上皮癌組織中的活性亦出現(xiàn)顯著下降的趨勢(shì)(p0.01)。膀胱尿路上皮癌中GCL的平均酶活為98+21mmol/分鐘/mg蛋白而對(duì)照組織中的GCL平均酶活為。342±85mmol/分鐘/mg蛋白。 結(jié)論 在膀胱尿路上皮癌中,谷氨酰半胱氨酸連接酶催化亞基及調(diào)節(jié)亞基無(wú)論在基因表達(dá)還是蛋白含量均明顯降低,提示在膀胱尿路上皮癌中可能通過(guò)谷氨酰半胱氨酸連接酶基因表達(dá)和蛋白含量的變化進(jìn)而調(diào)節(jié)谷胱甘肽在腫瘤細(xì)胞中的表達(dá),從而對(duì)腫瘤細(xì)胞的氧化狀態(tài)造成影響,進(jìn)而影響腫瘤細(xì)胞的增殖和分化；膀胱尿路上皮癌中GCL酶活性顯著升高,提示在腫瘤細(xì)胞中,可能因?yàn)槊负康淖兓枰叩拿富钚詠?lái)調(diào)節(jié)細(xì)胞的氧化平衡狀態(tài)。本研究結(jié)果顯示谷胱甘肽代謝過(guò)程中的限速酶谷氨酰半胱氨酸連接酶可能作為治療膀胱尿路上皮癌及判斷膀胱尿路上皮癌患者預(yù)后的一個(gè)有效的靶點(diǎn)。
[Abstract]:background
Bladder cancer is one of the most common malignant tumors in the urinary system. In recent years, the incidence and mortality of bladder urothelial carcinoma have been increasing year by year. Bladder cancer (bladder cancer) has become a worldwide problem threatening human health. It is the ninth American Cancer Association in [1].2006 years in the incidence of global malignant tumor. Statistical bladder cancer ranked fourth in the male, after prostate cancer, lung cancer and rectal cancer. It is one of the most common malignant diseases in the Department of Urology in our country. It is a direct threat to the life safety of the patients. The domestic and foreign scholars have done a lot of research on the risk factors of bladder cancer, and the specific cause of the disease. It is not clear that organic chemical carcinogens and human tryptophan and metabolic abnormalities are commonly recognized causes. Studies have found long-term residual urinary bladder, chronic cystitis, and long-term bladder stones. Catheter stimulation is closely related to the occurrence of bladder cancer, which is closely related to the pathological types of [2]. bladder cancer, including urinary transitional epithelial cell carcinoma, scales. Epithelial cell carcinoma, adenocarcinoma, metastatic carcinoma and carcinosarcoma are the most common pathological types of bladder cancer. Non epithelial bladder tumor is from the intravesical leaf tissue and is more rare in clinic. The malignancy of bladder cancer is expressed by the current WHO (World Health Organization, WHO) classification method. The higher the malignancy of the tumor, the higher the stage of the tumor, the more the number, the larger the volume, the greater the possibility of the invasion and recurrence of the tumor. The clinical stage of bladder cancer is the most important parameter to judge the prognosis of the tumor. It is closely related to the depth of invasion and the metastasis of the tumor. Ocular hematuria, which may occur intermittently, can cause acute urinary retention if accompanied by blood clot. Patients with advanced bladder cancer may have clinical symptoms such as anemia, abdominal mass, lumbosacral pain, and limb edema due to tumor infiltration. Non muscular invasive bladder cancer can be excised by urethral bladder tumor and adjuvant chemotherapy after local bladder irrigation. The pathogenesis is not completely clear. In recent years, a large number of data have been found that the redox system in the body is different from the normal state in the process of the malignant proliferation of the body, and the imbalance of redox state may be very important in the pathological progress of the tumor, which is related to the oxidative stress. There is a certain relationship between the damage to the function of the large molecular deoxyribonucleic acid in the cells. Various oxidation products are closely related to the development of the disease. Even the phenomenon of the increase of free radicals and reactive oxygen species may occur before the occurrence of cancer. The consequences of the decline in antioxidant capacity in various malignant tissue cells A variety of active oxygen products are produced in the body. In bladder urothelial carcinoma, the oxidative stress in the body has different changes in the state of [5]. in bladder cancer. Some substances such as lipid, protein, and DNA, which are closely related to the oxidation system, have varying degrees of change. [6]. has been studied for reactive oxygen species. Ingredients play a significant role in the progression of melanoma, and the treatment of reactive oxygen species can significantly inhibit the progression of cancer cells and inhibition of disease. Glutathione, as one of the most important antioxidant components in the body, plays an important role in the various defense systems of the body, Glutathione, a very significant antioxidant in the body, plays an important role in protecting the sulfhydryl groups of proteins and enzymes in various tissues and cells. GCL is a key enzyme that plays an important role in the metabolism of glutathione GSH. Its subunits are at gene level, protein level and activity. The change of sex level can change the content of reactive oxygen species in malignant proliferative cells and influence the process of tumor cell proliferation.
objective
At present, there is no systematic study of the glutamine cysteine ligase as a key enzyme in the metabolic process of glutathione. We hope to explore the changes in the bladder urothelial carcinoma by systematic study of the glutamine cysteine ligase at the level of gene, protein and activity. The diagnosis, treatment and prognosis analysis of bladder urothelial carcinoma provide an effective data base.
Method
The general hematological indexes, clinical biochemical indexes and blood coagulation data in normal controls were systematically treated. The catalytic subunit (GCLC) and regulation of glutamyl cysteinic ligase (GCLC) in 39 cases of bladder urothelial carcinoma and 39 control para cancerous tissues were treated. The expression of GCLM messenger RNA (mRNA) was analyzed by real time fluorescence quantitative PCR (quantitative realtime-PCR). The expression of glutamyl cysteine linked catalytic subunit and regulatory subunit protein in the bladder urothelial carcinoma tissue and the control para cancerous tissue was used to use Western blot (Western blotting). The changes in the activity of glutamyl cysteine connection in the bladder urothelial carcinoma and the control of the para cancerous tissue were analyzed by the enzyme activity test. The data collected during the experiment were analyzed by the SPSS13.0 statistical software, and the difference was statistically significant by the Student's two-tailed t-tests method. Analysis shows that P0.05 is significant for difference, and statistical data are expressed by means of mean + standard error (SEM).
Result
The results of the fluorescence quantitative PCR analysis showed that the catalytic subunit GCLc and the regulatory subunit GCLm gene expression in the bladder urothelial carcinoma were significantly lower than those in the control group of the para cancerous tissue, and there were significant differences between the two groups (GCLc gene: the BUC group was 1 + 0.028, and the control group was 3. .74 + 0.545; P0.01) (GCLm gene: BUC group 1 + 0.05, control group 3.07 + 0.571; P0.01). According to the experimental results of Western blot analysis, the expression of the protein expression of the catalytic subunit and the regulatory subunit of the glutamyl cysteine ligase in the bladder urothelial carcinoma tissue was significantly decreased. There were significant statistical differences between the two (GCLc gene: group BUC 0.983 + 0.022, control group 1.248 + 0.076; P0.05) (GCLm gene: BUC group 1.103 + 0.014, control group 1.306 + 0.033; P0.05). According to experimental results of enzyme activity, the activity of glutamyl cysteine ligase in bladder urine was compared with the control group of paracancerous tissue. The activity in the skin carcinoma of the road was also significantly decreased (P0.01). The average enzyme activity of GCL in bladder urothelial carcinoma was 98+21mmol/ min /mg protein, while the average GCL enzyme activity in the control tissue was.342 + 85mmol/ minutes /mg protein.
conclusion
In bladder urothelial carcinoma, the glutamyl cysteine ligase catalyzed subunit and the regulatory subunit decreased significantly in gene expression and protein content, suggesting that the expression of glutamyl cysteine ligase gene and protein content may be regulated in bladder urothelial carcinoma to regulate the table of glutathione in tumor cells. It has an effect on the oxidation state of tumor cells, and then affects the proliferation and differentiation of tumor cells. The activity of GCL enzyme in bladder urothelial carcinoma increases significantly. It suggests that in the tumor cells, higher enzyme activity may be needed to regulate the state of oxygen balance in the tumor cells. The results of this study show that the glutathione generation is glutathione. The speed limiting enzyme glutamyl cysteine ligase in Xie Guocheng may be an effective target for the treatment of bladder urothelial carcinoma and the prognosis of bladder urothelial carcinoma.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R737.14

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