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

Sang Hyun Lee, Jin Man Kim, Dong Gwang Lee, Jangwook Lee, Jong Gil Park, Tae Su Han, Hyun Soo Cho, Young Lai Cho, Kwang Hee Bae, Young Jun Park, Seon Jin Lee, Moo Seung Lee, Yong Min Huh, Deog Yeon Jo, Hwan Jung Yun, Heung Jin Jeon, Nayoung Kim, Mina Joo, Jang Seong Kim, Hyo Jin LeeJeong Ki Min

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6 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)968-984
Number of pages17
JournalCell Death and Differentiation
Issue number3
Publication statusPublished - 2021 Mar

Bibliographical note

Funding Information:
Acknowledgements This study was supported by a grant from the Korea Research Institute of Bioscience and Biotechnology and by grants from the National Research Foundation of Korea, which was funded by the Ministry of Science, Information & Communication Technology and Future Planning (NRF-2015M3A9D7029882, NRF-2013M3A9B6046566, NRF-2018R1A2B2006724, NRF-2017R1D1A 1B04034638, and NRF-2017R1A5A2015385)

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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