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Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

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dc.contributor.authorKim, H-P-
dc.contributor.authorHan, S-W-
dc.contributor.authorSong, S-H-
dc.contributor.authorJeong, E-G-
dc.contributor.authorLee, M-Y-
dc.contributor.authorHwang, D.-
dc.contributor.authorIm, S-A-
dc.contributor.authorBang, Yung-Jue-
dc.contributor.authorKim, T-Y-
dc.date.accessioned2021-01-31T12:01:03Z-
dc.date.available2021-01-31T12:01:03Z-
dc.date.issued2014-06-
dc.identifier.citationOncogene, Vol.33 No.25, pp.3334-3341-
dc.identifier.issn0950-9232-
dc.identifier.other111364-
dc.identifier.urihttps://hdl.handle.net/10371/173209-
dc.description.abstractHuman epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited beta-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.-
dc.subjectTestican-1-
dc.subjectepithelial-mesenchymal transition-
dc.subjectlapatinib resistance-
dc.subjectbeta-catenin-
dc.subjectXAV939-
dc.subjectHER2-positive gastric cancer-
dc.titleTestican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer-
dc.typeArticle-
dc.contributor.AlternativeAuthor방영주-
dc.identifier.doi10.1038/onc.2013.285-
dc.citation.journaltitleOncogene-
dc.identifier.scopusid2-s2.0-84908037648-
dc.citation.endpage3341-
dc.citation.number25-
dc.citation.startpage3334-
dc.citation.volume33-
dc.identifier.rimsid111364-
dc.identifier.sci000338443400013-
dc.contributor.affiliatedAuthorBang, Yung-Jue-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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