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研究生:黃彥達
研究生(外文):Yen Ta Huang
論文名稱:腦源滋養因子促進膀胱癌於嚴重免疫不全鼠體內之生長
論文名稱(外文):Brain-derived Neurotrophic Factor Promotes Bladder Cancer Growth in SCID Mice
指導教授:邱鐵雄邱鐵雄引用關係
指導教授(外文):Ted H. Chiu
學位類別:碩士
校院名稱:慈濟大學
系所名稱:藥理暨毒理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
畢業學年度:94
語文別:英文
論文頁數:47
中文關鍵詞:膀胱癌腦源滋養因子
外文關鍵詞:Bladder cancerTrkBBDNF
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腦源滋養因子(BDNF)主要之功能,在於使神經元細胞存活及分化。BDNF、其受體TrkB與癌症的關係,最早之研究為神經母細胞瘤,學者發現化療抗藥性的媒介,是透過TrkB受體的表達。近年來的研究指出,許多腫瘤諸如胰管腺癌和攝護腺癌等均表達BDNF及TrkB受體,然而探討兩者對於腫瘤生長影響的研究卻不多。到目前為止,尚無研究發現膀胱癌表達BDNF及TrkB受體。

本研究發現人類膀胱癌中之第三級移型細胞癌細胞株BFTC905,利用免疫細胞染色有表達BDNF及其受體TrkB;以西方點墨法同樣證實膀胱癌細胞株有表達TrkB受體,而反轉錄酶-聚合酶鏈反應與酵素免疫偵測則有BDNF之表達。將BFTC905細胞注入免疫不全鼠之腹股溝觀察腫瘤成長,同時於生長過程中於腫瘤處每週注射100 ng BDNF,可見腫瘤成長較控制組快速,並於28天起達到統計學有意義上之差異。然而於細胞培養時外加BDNF則並不會對細胞增生有所影響。另外分別每週注射100 ng BDNF、100 ng VEGF以及合併兩者注射,可見腫瘤成長由大至小依序為:BDNF+VEGF>BDNF>VEGF。將腫瘤取下,以石蠟包埋、切片後利用免疫組織染色證實腫瘤表達BDNF及TrkB受體,接著同樣以免疫組織染色分析三位膀胱癌病患組織切片檢體,亦證明有BDNF及TrkB之表達。TrkB抑制劑K252a在500 nM的濃度下,可以於BFTC905細胞培養時有效抑制其增生;另外每週三次注射1 μg之K252a至腫瘤處,則可以延緩腫瘤之成長。以BDNF之短鏈雙股核糖核酸(siRNA)每週注射兩次0.4 nmole於腫瘤處,無抑制腫瘤成長之效果。

根據這些實驗結果可知,BDNF與TrkB於膀胱癌成長中扮演重大角色。抑制BDNF與TrkB之表達,可做為未來膀胱癌治療之新方向。
Brain-derived neurotrophic factor (BDNF) is essential for the growth of several types of neurons in the central nervous system. Recently, BDNF and/or its receptor TrkB were also found in solid tumors such as pancreatic ductal adenocarcinoma and prostate cancer. BDNF acting on the TrkB receptor has been reported to promote the growth of neuroblastoma and hepatocellular carcinoma in vitro. However, the role of BDNF in the bladder cancer growth has not been investigated.
In this study, expression of TrkB was observed in BFTC905 cells (a grade III bladder papillary transitional cell carcinoma) and xenograft tumors of bladder cancer by Western blot. Expression of BDNF was demonstrated by ELISA and RT-PCR. Immunocytochemistry and immuohistochemistry staining of both BDNF and TrkB were found in BFTC905 cells, xenograft tumors and human bladder cancer specimens. Weekly subcutaneous injection of BDNF (100 ng/50 μl) significantly promoted xenograft tumor growth compared to control 28 days after cancer cell injected into the inguinal area of SCID (severe combined immunodeficiency) mice. However, exogenous BDNF did not promote proliferation of BFTC905 cells in vitro. Besides, weekly injection of 100 ng each of BDNF, VEGF or combination of BDNF plus VEGF into the cancer cell loading site during a course of 6 weeks accelerated the growth rate of tumor with the degree of effect: BDNF+VEGF> BDNF> VEGF. BDNF and TrkB were also expressed in the control and drug treated tumors by immunohistochemistry one week after the last treatment. Delayed xenograft tumor growth was observed with injection of 1μg of K252a (TrkB inhibitor) into the tumor 3 times a week, and 500 nM K252a inhibited BFTC905 cells growth in vitro. Administration of BDNF siRNA (0.4 nmole/ 50 μl twice weekly) into the tumor did not reduce the growth rate of xenograft tumors.
These results indicate that BDNF and TrkB receptor play important roles in regulating the growth of BFTC905 bladder cancer. siRNA or drugs aimed at BDNF or TrkB may provide a new approach toward the treatment of bladder cancer.
中文摘要…………………………………………………………………………………………….2
Abstract..…………………………………………………………………………………………….3
Abbreviation………………………………………………………………………………………...4
Introduction
Bladder cancer………………………………………………………………………..………..5
Brain-derived neurotrphic factor (BDNF)…………………………………………..……….7
Small interfering ribonucleic acid (siRNA).………………………………………..…...……9
Materials and methods
Cell and cell culture…………………………………………………………………………..11
Patients’ specimens…………………………………………………………………………...11
siRNA preparation……………………………………………………………………………12
Mouse xenograft model…………………………………………………………………...….12
Immunocytochemistry and immunohistochemistry…………………………………..……13
Western blot…………………………………………………………………………………..14
Cell growth assay……………………………………………………………………………..15
Enzyme-linked immunosorbent assay (ELISA)…..………………………………………..15
Reverse transcription-polymerase chain reaction (RT-PCR)............................................16
Results………………………………………………………………………………………………18
Discussion…………………………………………………………………………………………..21
References…………………………………………………………………………………………..25
Appendix
Table1………………………………………………………………………………………….31
Table2………………………………………………………………………………………….31
Figure1………………………………………………………………………………………...32
Figure2………………………………………………………………………………………...33
Figure3………………………………………………………………………………………...34
Figure4………………………………………………………………………………………...35
Figure5………………………………………………………………………………………...36
Figure6………………………………………………………………………………………...37
Figure7………………………………………………………………………………………...39
Figure8………………………………………………………………………………………...41
Figure9………………………………………………………………………………………...43
Figure10……………………………………………………………………………………….44
Figure11……………………………………………………………………………………….45
Figure12……………………………………………………………………………………….46
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