Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

Cited 2 time in scopus
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Title
Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation
Author(s)
Sang-Hyun Lee; J M Kim; Dong Gwang LeeJangwook LeeJong Gil ParkTae-Su HanHyun-Soo ChoYoung Lai ChoKwang-Hee BaeYoung-Jun ParkSeon-Jin LeeMoo-Seung Lee; Y M Huh; D Y Jo; H J Yun; H J Jeong; N Kim; M Joo; Jang Seong Kim; H J Lee; Jeong Ki Min
Bibliographic Citation
Cell Death and Differentiation, vol. 20, pp. 628-4
Publication Year
2021
Abstract
Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.
ISSN
1350-9047
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41418-020-00628-4
Type
Article
Appears in Collections:
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
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