提昇私校研發能量專案計畫-癌症的基礎及臨床研究-子計畫五:皮膚癌及肺癌細胞 Hedgehog 訊息傳遞以及趨化激素受體表現之關連性(II)?

CMUR > College of Medicine > School of Medicine > Research reports > Item 310903500/12942

Please use this identifier to cite or link to this item: http://ir.cmu.edu.tw/ir/handle/310903500/12942

Title:	提昇私校研發能量專案計畫-癌症的基礎及臨床研究-子計畫五:皮膚癌及肺癌細胞 Hedgehog 訊息傳遞以及趨化激素受體表現之關連性(II)?
Other Titles:	The Association of Hedgehog Signaling and Expression of Chemokine Receptor in Skin and Lung Cancers (II)
Authors:	吳孟澤(Wu,Meng-Tse)
Contributors:	醫學院醫學系學士班皮膚學科;中國附醫皮膚科
Date:	2006-07-31
Issue Date:	2009-09-01 16:11:06 (UTC+8)
Abstract:	趨化激素及其受體在調節細胞增殖, 凋亡,以及血管新生方面扮演了重要的角色, 因而可能增進腫瘤增生及轉移.在九十二年度的國科會計劃(92-2314-B-039-024)中,我們探討趨化激素及其受體在基底細胞癌腫瘤生長病程中所可能扮演的角色.我們發現趨化激素受體CXCR4 於培養基底細胞癌細胞中有高度之表現.為了進一步確定CXCR4 之表現是否在基底細胞癌腫瘤增生過程中扮演重要之角色, 我們利用retroviral transduction 技術將CXCR4cDNA 基因轉入基底細胞癌細胞, 而得到過度表現CXCR4 之基底細胞癌細胞株(CXCR4-BCC). 進一步研究發現CXCR4 之表現可增進細胞增生, 抵抗細胞凋亡, 以及促進血管新生. 這些結果顯示CXCR4 之表達對基底細胞癌之腫瘤增生可能扮演了重要的角色, 然而, 為何癌細胞於演化過程中會發展出CXCR4 表現之特性, 仍有待探索.“Hedgehog 訊息傳導路徑” 在脊椎動物胚胎發育過程中扮演了重要的角色. 近來研究也發現此一訊息傳導路徑之不正常活化對於某些特定腫瘤之發生扮演了重要的角色. 例如此路徑中的兩個關鍵基因PTCH 或是SMO 的錯亂,不論是PTCH 的去活化或是SMO 的活化, 都可能會導致易生皮膚基底細胞癌或神經管胚細之Gorlin 氏症候群, 或是單發性之基底細胞癌. 然而, 究竟hedgehog訊息傳導路徑如何藉由下遊之標的分子影響腫瘤發生仍然充滿疑問.於此我們假設hedgehog 訊息傳導路徑與趨化激素受體CXCR4 之表現在基底細胞癌腫瘤發生中有密切之相關. 此假設乃是基於以下過去研究所揭露之事實: (1) CXCR4 之表達對基底細胞癌之腫瘤增生可能扮演了重要的角色, (2) hedgehog 訊息傳導路徑訊息傳導路徑之不正常活化對於皮膚基底細胞癌之發生扮演了重要的角色, (3) 腫瘤抑制基因vonHipple-Lindau (VHL) 之不正常去活化可能導致腎臟癌(kidney clear cell carcinoma, RCC)CXCR4 之表達以及腫瘤發生, (4) 除了基底細胞癌之外, 小細胞肺癌(small cell lungcarcinoma, SCLC) 之腫瘤發生也同時受到hedgehog 訊息傳導路徑以及CXCR4 表達之調控. 我們因此提出此計畫以驗證以上之假設,此外, 我們也將嘗試探索Hedgehog 訊息傳導路徑藉由何種機轉影響腫瘤發生. 我們將嘗試利用現有的BCC-1/KMC 基底細胞癌細胞株:首先我們將檢驗此細胞株中hedgehog 訊息傳導路徑是否呈現不正常之活化, 並進一步確認此傳導路徑之活化是屬於PTCH 的不正常去活化或是SMO 的不正常活化. 接著再據此進一步改造BCC-1/KMC 基底細胞癌細胞株之基因. 若是屬於PTCH 的去活化, 我們將利用retroviral gene transfer 技術將將正常之PTCH 基因轉入; 若是屬於SMO 的不正常活化, 則利用RNA 干擾(RNA interference) 技術阻止SMO 之表達. 如此將hedgehog 訊息傳導路徑不正常之活化加以導正之後, 再進行一系列體外以及體內實驗比較基因改造前後之BCC-1/KMC 基底細胞癌細胞株, 以求証是否hedgehog 訊息傳導路徑之不正常之活化確實能影響CXCR4 之表現以及基底細胞癌細之腫瘤新生. 類似之研究模式亦將同時應用於探索小細胞肺癌中hedgehog signaling 與CXCR4 表達之關係.我們預期此計畫將會大幅提升我們對於hedgehog 訊息傳導路徑如何影響皮膚癌及肺癌腫瘤新生的了解; 更重要者, 以hedgehog訊息傳導路徑構成分子為標的之新治療策略將可因此得進一步的發展. Chemokines and their receptors play important roles in the regulation of cell proliferation, apoptosis, and angiogenesis, which may enhance tumor growth or metastasis. In our previous studies, we investigated the possible involvements of chemokine receptors in the pathogenesis of cutaneous basal cell carcinoma (BCC), the most common human cancer. We found high expression of chemokine receptor CXCR4 in a human BCC cell line and a subset of tissue samples from BCC lesions. Furthermore, by retroviral gene transduction, we have found expression of CXCR4 enhance BCC tumorigenesis by the up-regulation of cell proliferation, migration, apoptosis-resistance and angiogenesis. The results of our previous study clearly indicate that CXCR4 may play a critical role in BCC tumorigenesis, but the question remains about how an evolving tumor cell is 3 re-engineered to express CXCR4. The hedgehog signaling pathway plays an essential role in embryonic development and patterning of diverse vertebrate structures. The role of the hedgehog pathway in tumorigenesis was based on the finding that the gene aberration of either one of two key members of hedgehog signaling (either inactivating mutations in the PTCH gene or the activating mutations in SMO gene) is responsible for the inherited disorder known as Gorlin syndrome, which is predisposed to develop BCC, medulloblastoma and other tumors, as well as sporadic BCC. However, it is still unclear, by what mechanisms, hedgehog signaling may lead to the tumorigenesis of BCC. Herein we propose to test our hypothesis that hedgehog signaling pathway and CXCR4/CXCL12 axis may be closely related in the BCC tumorigenesis. This hypothesis is based on the following facts: (1) CXCR4 expression enhances BCC tumorigenesis, (2) Hedgehog signaling pathway activation (either inactivation of tumor-suppressor PTCH gene or activation of tumor-enhancer SMO) may lead to BCC tumorigenesis, (3) Inactivation of tumor-suppressor VHL gene mediates CXCR4 expression and tumorigenesis of RCC cells, (4) small cell lung carcinoma (SCLC) is another example whose tumorigenesis is controlled by hedgehog pathway and CXCR4 expression. Furthermore, we seek to address the mechanisms utilized by hedgehog signaling to enhance BCC tumorigenesis. In order to test our hypothesis, herein we propose to take advantage of the human BCC cell line, BCC-1/KMC. We will firstly examine whether BCC-1/KMC cells possess an active hedgehog signaling pathway. We will try to delineate the nature of hedgehog activation, which may either attribute to the inactivation of PTCH or activation of SMO genes. Depending on the nature of hedgehog signaling in BCC-1/KMC cells, gene modification will be employed either using gene transfer to enhance the PTCH gene or gene knockdown to silence the SMO gene, in order to inactivate the inherent hedgehog signaling in BCC cells. The hedgehog-gene-modified BCC cells will then be subject to a series of in vitro and in vivo test to determine whether the inactivation of hedgehog signaling will eventually affect the expression of CXCR4, and the tumorigenesis of BCC. This model will also be used to explore whether hedgehog signaling pathway and CXCR4 expression may also cooperate in the tumorigenesis of SCLC. We envision this work may contribute greatly to the further understanding of how hedgehog signaling pathway may be involved in the evolution of skin and lung cancer cells, and new therapeutic strategies targeting certain component genes in hedgehog pathway may thus be developed.
Appears in Collections:	[School of Medicine] Research reports

Files in This Item:

File	Description	Size	Format
94-2745-B039-001-URD.pdf		262Kb	Adobe PDF	227	View/Open

Loading...