探討CXCR7在人類肺腺癌發展進程中的影響

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题名:	探討CXCR7在人類肺腺癌發展進程中的影響 Investigation of the Impact of CXCR7 in Human Lung Adenocarcinoma Progression
作者:	洪珮珊;Pei-Shan Hung
贡献者:	醫學院基礎醫學研究所
关键词:	CXCR7;CXCR4;肺腺癌;CXCR7;CXCR4;adenocarcinoma
日期:	2010
上传时间:	2010-09-29 12:13:22 (UTC+8)
摘要:	CXCR7 (RDC1)，是近來才被定義出來的G蛋白耦合性受體(G protein-coupled receptors, GPCRs)。G蛋白耦合性受體會在發炎反應的情況下，與趨化素(chemokine) 結合並且回歸(homing) 驅化素CXCL11/ITAC 和CXCL12/SDF-1。近來許多相關研究指出，在免疫缺乏的小鼠試驗中， CXCR7會提高肺癌及乳癌腫瘤生長與肺癌轉移。然而，在一個分析CL1-0及CL1-5，這兩種具有不同侵犯能力與轉移能力的肺腺癌細胞株DNA晶片中，發現CXCR7在較低侵犯能力與轉移能力的肺癌細胞株CL1-0表現量較高。此結果異於之前相關文獻的發現。因此，CXCR7在人類肺腺癌發展進程中的假說仍然是非常分歧。此篇研究，主要探討CXCR7在人類肺腺癌發展進程中的影響。首先，我們利用反轉錄RT-PCR (reverse transcription-polymerase chain reaction) 與西方墨點法(Western blotting assays)，測定細胞株的內生性的CXCR7。實驗結果中，CXCR7的表現量會依細胞株的侵襲能力增加而下降。進一步地，我們利用慢病毒載體系統(lentivirus system)，將專一針對CXCR7的shRNA及持續表現CXCR7的質體，分別送入CL1-0與CL1-5細胞株內。我們發現當改變CXCR7在細胞株的表現時，亦會影響CXCR4的表現。並且，在細胞增生、細胞移動能力與細胞侵犯實驗中，當CL1-0細胞株被轉染(tranfect) 專一針對CXCR7的shRNA 降低 (knockdown) CXCR7表現時，會提升細胞增生、移動能力與侵犯的能力；反之，當CL1-5細胞株被轉染(tranfect) 持續表現CXCR7的質體時，則會減少這些能力。目前，我們所發現到的結果，與先前相關研究是截然不同的。我們認為，CXCR7在肺腺癌的發展進程中扮演著關鍵的角色，並且可以減少CXCR4的表現與下游的訊息表現。 CXCR7, formerly called RDC1 is a recently deorphanized G-protein coupled receptor which binds with high affinity the inflammatory and homing chemokines CXCL11/ITAC and CXCL12/SDF-1. Several reports have recently documented that CXCR7 promotes growth of tumors formed from breast and lung cancer cells and enhances experimental lung metastases in immunodeficient as well as immunocompetent mouse models of cancer. These effects did not depend on expression of the related receptor CXCR4. However, a new interesting finding from earlier microarray data of selection of invasive and metastatic expression patterns from two human lung adenocarcinoma cell lines, CL1-0 and CL1-5, indicated that up-regulation of CXCR7 appeared in low invasive and metastatic cells (CL1-0) but not in high invasive and metastatic cells (CL1-5). Therefore, it has the potential puzzle for the role of CXCR7 in human lung cancer progression. The purpose of this study is to investigate the impact of CXCR7 in human lung cancer progression. Our results from RT-PCR (reverse transcription-polymerase chain reaction) and western blotting assays confirmed that the levels of CXCR7 expression decreased as the tumors become more aggressive. The human lung adenocarcinoma cell line with high invasiveness and metastasis, CL1-5, had lower expression of CXCR7 than the CL1-0 cells, which is the low invasive and metastatic subpopulation. To investigate the role of CXCR7 in lung cancer progression, we used lentiviral vectors to stably and specifically knock down CXCR7 in CL1-0 cells and over-express CXCR7 in CL1-5 cells. Knockdown and over-expression of CXCR7 induced inverse expression of CXCR4 in protein levels. In vitro proliferation assay, migration assay and invasion assay showed that knock down of CXCR7 expression in CL1-0 cells promoted their proliferation, migration and invasion activities but over-expression of CXCR7 expression in CL1-5 cells suppressed these activities. These results differ from those in a previous report on murine lung cancer cells. Our data suggest that the CXCR7 plays a potential tumor suppresser in human lung adenocarcinoma cells and its mechanism may inhibit CXCR4 expression and its downstream signaling.
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