本文選題：膀胱癌 + TGF-β��； 參考：《安徽醫(yī)科大學(xué)》2017年碩士論文

【摘要】：膀胱癌(Bladder Cancer,BCa)是我國泌尿系統(tǒng)中最常見的惡性腫瘤,嚴(yán)重危害人民的健康,近年來我國膀胱癌發(fā)病率和死亡人數(shù)均呈顯著增高趨勢。大多數(shù)的膀胱癌是尿路上皮癌,其復(fù)發(fā)率非常高。雖然目前對膀胱癌的研究持續(xù)深入,但膀胱癌的發(fā)生、發(fā)展及復(fù)發(fā)機制尚不明確。研究發(fā)現(xiàn)轉(zhuǎn)化生長因子TGF-β(transforming growth factorbeta)在調(diào)節(jié)細胞生長和分化中起著至關(guān)重要的作用,它是一種多功能的多肽類細胞因子,TGF-β信號通路的激活能夠促進腫瘤生成、浸潤、遷移和抑制免疫等作用。上皮-間質(zhì)轉(zhuǎn)化(Epithelial-mesenchymal transition,EMT)是指上皮細胞因失去極性,而導(dǎo)致其遷移能力增強,能夠在細胞外基質(zhì)間自由遷移運動,并呈現(xiàn)間質(zhì)細胞表型的轉(zhuǎn)化過程。腫瘤細胞EMT的發(fā)生和腫瘤的轉(zhuǎn)移密切相關(guān),EMT發(fā)生后可以導(dǎo)致單個腫瘤細胞離開腫瘤起始病灶并向其它地方轉(zhuǎn)移,EMT的細胞可以通過促進細胞外基質(zhì)的降解而促進EMT和非EMT細胞進入血液。TGF-β被認為是眾所周知的促進癌癥發(fā)展、侵襲和轉(zhuǎn)移及誘導(dǎo)上皮細胞發(fā)生間質(zhì)轉(zhuǎn)化(EMT)的關(guān)鍵因子,TGF-β能誘導(dǎo)腫瘤細胞的EMT,增加腫瘤細胞的轉(zhuǎn)移潛能。盡管TGF-β信號通路相對較簡單,但其調(diào)節(jié)機制卻十分復(fù)雜。目前,TGF-β信號通路的調(diào)控及其與其他信號通路的關(guān)系已成為一個新的研究熱點。然而,關(guān)于TGF-β信號在體內(nèi)對于腫瘤特別是膀胱癌的發(fā)生發(fā)展的影響存有極大爭議。在膀胱癌中,TGF-β信號已經(jīng)被證實參與腫瘤發(fā)生促進EMT,但目前并沒有體內(nèi)實驗的數(shù)據(jù)表明其在膀胱癌發(fā)生和發(fā)展過程中的作用和機制。在本研究中,我們在小鼠中利用N-butyl-N-4-hydroxybutyl Nitrosamine(BBN)誘導(dǎo)膀胱癌發(fā)生,并使用KRT5-Cre條件性敲除TGF-β2,以及使用TGF-1受體特異性抑制劑LY364947,證明在體內(nèi)抑制下調(diào)TGF-β信號通路可以抑制腫瘤膀胱癌的發(fā)展,浸潤以及EMT。這一結(jié)果表明利用TGF-β信號拮抗劑作為單劑或聯(lián)合制劑,可以針對性治療膀胱癌或是其它依賴TGF-β信號通路的實體腫瘤,并為進一步的臨床研究提供理論基礎(chǔ)。
[Abstract]:Bladder carcinoma (BCA) is the most common malignant tumor in the urinary system in China, which seriously endangers the health of the people. In recent years, the incidence of bladder cancer and the number of deaths have increased significantly in China. Most bladder cancer is urothelial cancer, its recurrence rate is very high. Although the current research on bladder cancer continues to deepen, the mechanism of occurrence, development and recurrence of bladder cancer is unclear. It has been found that TGF- 尾 growth factorbeta plays an important role in regulating cell growth and differentiation. TGF- 尾 is a multifunctional polypeptide cytokine that activates TGF- 尾 signaling pathway and promotes tumor formation and infiltration. Migration and immunosuppression. Epithelial-mesenchymal transition (EMTT) is the process of phenotype transformation of epithelial cells due to their loss of polarity and their ability to migrate freely between extracellular matrices. The occurrence of EMT in tumor cells is closely related to the metastasis of tumor cells. After the occurrence of EMTs, single tumor cells can leave the initial focus of the tumor and metastasize to other places. These cells can promote EMT by promoting the degradation of extracellular matrix (ECM). And non-EMT cells entering the blood. TGF- 尾 is known to promote cancer development, TGF- 尾, a key factor of invasion and metastasis and induction of mesenchymal transformation of epithelial cells, can induce EMT- 尾 of tumor cells and increase the metastatic potential of tumor cells. Although TGF- 尾 signaling pathway is relatively simple, its regulation mechanism is very complex. At present, the regulation of TGF- 尾 signaling pathway and its relationship with other signal pathways have become a new research hotspot. However, the influence of TGF- 尾 signal on the development of tumor, especially bladder cancer, is controversial. TGF- 尾 signal has been proved to be involved in carcinogenesis and promoting EMTs in bladder cancer, but there is no experimental data in vivo to demonstrate its role and mechanism in the carcinogenesis and development of bladder cancer. In this study, we used N-butyl-N-4-hydroxybutyl Nitrosamine (BBN) to induce bladder cancer in mice, and used KRT5-Cre conditional knockout TGF- 尾 2 and TGF-1 receptor specific inhibitor LY364947 to prove that inhibition of down-regulation of TGF- 尾 signaling pathway in vivo can inhibit the development of bladder cancer. Infiltration and EMT. These results suggest that TGF- 尾 signal antagonists can be used as a single or combined agent to treat bladder cancer or other solid tumors dependent on TGF- 尾 signaling pathway, and provide a theoretical basis for further clinical research.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R737.14

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