Investigation of the Wnt5a function in lung cancer and the correlation between Wnt5a and TKI-resistance

• Main Authors: Jheng-Cheng Huang, 黃正誠
• Other Authors: 張逸良
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/58314758765001959546

碩士 === 國立臺灣大學 === 病理學研究所 === 103 === 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.