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Title: | 探討Wnt5a在肺癌細胞的功能與EGFR-TKI抗藥性的關聯 Investigation of the Wnt5a function in lung cancer and the correlation between Wnt5a and TKI-resistance |
Authors: | Jheng-Cheng Huang 黃正誠 |
Advisor: | 張逸良,施金元 |
Keyword: | 肺癌,EGFR-TKI,抗藥性,Wnt5a, Lung cancer,EGFR-TKI,Resistance,Wnt5a, |
Publication Year : | 2015 |
Degree: | 碩士 |
Abstract: | 肺癌是癌症死亡排行榜的首位。研究報告顯示表皮生長因子受體 (epidermal growth factor receptor, EGFR) 的突變在東方人的肺癌細胞有較高比例。EGFR是一個酪胺酸激酶受體 (receptor tyrosine kinase),與肺癌細胞的分化、增生、轉移及存活有關。目前國內的肺癌病患若是檢測出具有EGFR mutations (exon 19 deletion or/and L858R),將以表皮生長因子受體激酶抑制劑 (EGFR-TKI) 作為標靶治療的藥物。目前可以使用的EGFR-TKI包括有 Gefitinib (Iressa) 與 Erlotinib (Tarceva) 以及 Afatinib (Gilotrif)。然而EGFR突變的病患平均在標靶治療後的8到12個月就會出現抗藥性,因此仍須尋找EGFR-TKI產生抗藥性的相關基因。目前此實驗初步的研究結果顯示在gefitinib-resistant cell line (PC9/gef) and sensitive cell line (PC9) 透過cDNA microarray分析中找到與EGFR-TKI抗藥性相關的Wnt5a基因。Wnt5a是Wnt家族19個成員的其中之一,Wnt配體由高保守性的醣蛋白組成,能夠調節各種細胞功能,包括增殖、存活以及遷移。有研究報告指出Wnt5a與癌症病患的預後不佳有關係。根據本研究結果表示相較於EGFR-TKI-sensitive PC9 細胞株,Wnt5a在EGFR-TKI-resistant PC9/gef的細胞株表現有明顯的上升。當我們在PC9/gef細胞株抑制了Wnt5a的表現時將可以觀察到細胞對於EGFR-TKI的抗藥性、細胞生長、遷移以及入侵能力受到抑制。這可能暗示著Wnt5a在肺癌細胞的功能與EGFR-TKI抗藥性過程中扮演重要的角色。 Lung cancer is the leading cause of cancer death. Some studies indicate that epidermal growth factor receptor (EGFR) mutation in Asian lung cancer cell of a substantial percentage. EGFR is a receptor tyrosine kinase that correlates with cell proliferation, growth, metastasis and survival in lung cancer. Currently, EGFR-TKI target therapy is specific for patients with exon 19 deletion or/and L858R mutations. EGFR-TKIs include the drugs Gefitinib (Iressa), Erlotinib (Tarceva) and Afatinib (Gilotrif). Gefitinib and Erlotinib are the first-generation reversible EGFR TKIs. Afatinib is the second-generation irreversible EGFR TKI. Despite of high response rate in these patients, the resistance to EGFR-TKIs occurs on average between 8-12 months. Therefore, we tried to find genes capable of conferring EGFR-TKI resistance. In our studies, we performed cDNA microarrays comparing gefitinib-resistant cell line (PC9/gef) and parental sensitive cell line (PC9) to identify the resistance-related genes, which may be involved in the EGFR-TKI resistance. The candidate gene Wnt5a (Wingless-type MMTV integration site family, member 5A) is a component of Wnt signaling, and we are interested in studying the role of Wnt5a in EGFR-TKI resistance. Wnt ligands consist of 19 highly conserved secreted glycoproteins that regulate various of cell functions including proliferation, survival, and migration. Although some studies indicate that Wnt5a correlates with poor overall survival in patients with lung cancer, the role of Wnt5a in relation to EGFR-TKIs resistance remains unclear. In our results, significant up-regulation of Wnt5a mRNA and protein in EGFR-TKI resistant PC9/gef as compared to its expression in EGFR-TKI sensitive PC9 cell line. We found that EGFR-TKI resistance decreased by the knockdown of Wnt5a in EGFR-TKI resistant cells. At the same time we also found that cell proliferation, migration and invasion ability were decreased by the knockdown of Wnt5a in EGFR-TKI resistant cells. These results implied that Wnt5a played a critical role in EGFR-TKI resistance and the functions of lung cancer. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52748 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 病理學科所 |
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ntu-104-1.pdf Restricted Access | 1.96 MB | Adobe PDF |
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