TM4SF5-mediated Resistance against EGFR Kinase Inhibitors Involves an IGF1R Cooperation.
TM4SF5와 인슐린유사성장인자1 수용체의 상호작용에 의한 상피세포성장인자 수용체 티로신 억제제 내성현상에 관한 연구

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자연과학대학 협동과정 유전공학전공
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학위논문 (석사)-- 서울대학교 대학원 : 협동과정 유전공학전공, 2015. 2. 이정원.
Transmembrane 4 L6 family member 5 (TM4SF5) is a membrane protein similar to the tetraspanins highly expressed in Hepatocellular carcinoma (HCC), and causes enhanced migration and invasion. TM4SF5 collaborates with other membrane proteins during its pro-tumorigenic roles, presumably at tetraspanin-enriched microdomain (TEM). Here, we explored the TM4SF5-mediated resistance against the clinically important EGFR kinase inhibitors, with regards to a cooperation with another membrane protein especially Insulin-like growth factor 1 receptor (IGF1R). In this study, therefore, I explored resistance against anti-tumor drugs using non-small cell lung carcinoma (NSCLC) cell lines that are ectopically overexpressing TM4SF5 or have suppressed IGF1R levels. When the NSCLC cells were tested with diverse anti-cancer drugs, TM4SF5-positive and/or IGF1R-positive cell lines showed more resistance against EGFR kinase inhibitors (TKIs), Erlotinib or Gefitinib, but not PDGFR/Raf kinase inhibitor, sorafenib. The levels of TM4SF5 and IGF1R modulated each other. Meanwhile, either suppression in EGFR TKI-resistant NCI-H1299 cells caused sensitizations to the EGFR kinase inhibitors, whereas expression of either of TM4SF5 and IGF1R caused activation of its downstream signaling molecules like ERKs, AKT, and S6K leading to resistance against the TKIs. Furthermore, TM4SF5 and IGF1R formed a complex each other, and even further, the complex included EGFR. The complex of EGFR, IGF1R, and TM4SF5 would be sustained in EGFR TKIs treated conditions. In addition to these 2 dimensional (2D) condition, the cells were examined for the drug resistancy when they were embedded in 3D collagen I gels. TM4SF5 and/or IGF1R expression in HCC827 and NCI-H1299 cell lines gave them compact spheroid formation ability in a less-adhesive aquaoues cell culture system. Further, the spheroids with high expression of TM4SF5 and IGF1R were resistant against EGFR TKIs, gefitinib and erlotinib. Thus, this study evidences that TM4SF5 and/or IGF1R appeared to collaborate to cause survival signaling, forming with a triple complex with EGFR, even with EGFR TK.
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College of Natural Sciences (자연과학대학)Program in Genetic Engineering (협동과정-유전공학전공)Theses (Master's Degree_협동과정-유전공학전공)
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