条件性敲除TGF-β信号途径对小鼠诱导膀胱癌的发展和侵袭影响机制研究

发布时间：2018-04-25 22:35

本文选题：膀胱癌 + TGF-β　；参考：《安徽医科大学》2017年硕士论文

【摘要】：膀胱癌(Bladder Cancer,BCa)是我国泌尿系统中最常见的恶性肿瘤,严重危害人民的健康,近年来我国膀胱癌发病率和死亡人数均呈显著增高趋势。大多数的膀胱癌是尿路上皮癌,其复发率非常高。虽然目前对膀胱癌的研究持续深入,但膀胱癌的发生、发展及复发机制尚不明确。研究发现转化生长因子TGF-β(transforming growth factorbeta)在调节细胞生长和分化中起着至关重要的作用,它是一种多功能的多肽类细胞因子,TGF-β信号通路的激活能够促进肿瘤生成、浸润、迁移和抑制免疫等作用。上皮-间质转化(Epithelial-mesenchymal transition,EMT)是指上皮细胞因失去极性,而导致其迁移能力增强,能够在细胞外基质间自由迁移运动,并呈现间质细胞表型的转化过程。肿瘤细胞EMT的发生和肿瘤的转移密切相关,EMT发生后可以导致单个肿瘤细胞离开肿瘤起始病灶并向其它地方转移,EMT的细胞可以通过促进细胞外基质的降解而促进EMT和非EMT细胞进入血液。TGF-β被认为是众所周知的促进癌症发展、侵袭和转移及诱导上皮细胞发生间质转化(EMT)的关键因子,TGF-β能诱导肿瘤细胞的EMT,增加肿瘤细胞的转移潜能。尽管TGF-β信号通路相对较简单,但其调节机制却十分复杂。目前,TGF-β信号通路的调控及其与其他信号通路的关系已成为一个新的研究热点。然而,关于TGF-β信号在体内对于肿瘤特别是膀胱癌的发生发展的影响存有极大争议。在膀胱癌中,TGF-β信号已经被证实参与肿瘤发生促进EMT,但目前并没有体内实验的数据表明其在膀胱癌发生和发展过程中的作用和机制。在本研究中,我们在小鼠中利用N-butyl-N-4-hydroxybutyl Nitrosamine(BBN)诱导膀胱癌发生,并使用KRT5-Cre条件性敲除TGF-β2,以及使用TGF-1受体特异性抑制剂LY364947,证明在体内抑制下调TGF-β信号通路可以抑制肿瘤膀胱癌的发展,浸润以及EMT。这一结果表明利用TGF-β信号拮抗剂作为单剂或联合制剂,可以针对性治疗膀胱癌或是其它依赖TGF-β信号通路的实体肿瘤,并为进一步的临床研究提供理论基础。
[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.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.14

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