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Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer.

Authors
  • Tomasich, Erwin1
  • Topakian, Thais1
  • Heller, Gerwin1
  • Udovica, Simon2
  • Krainer, Michael1
  • Marhold, Maximilian3
  • 1 Division of Oncology, Department for Medicine I, Medical University of Vienna, Vienna, Austria. , (Austria)
  • 2 Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria. , (Austria)
  • 3 Division of Oncology, Department for Medicine I, Medical University of Vienna, Vienna, Austria. Electronic address: [email protected] , (Austria)
Type
Published Article
Journal
Translational research : the journal of laboratory and clinical medicine
Publication Date
Apr 01, 2021
Volume
230
Pages
21–33
Identifiers
DOI: 10.1016/j.trsl.2020.11.005
PMID: 33197651
Source
Medline
Language
English
License
Unknown

Abstract

Loss of hepatocellular carcinoma-related protein 1 (HCRP1) (alias VPS37A) plays a role in endocytosis of receptor tyrosine kinases as a member of the ESCRT complex and has been linked to poor patient outcome in various types of epithelial cancer. To this date, the molecular and biological mechanisms explaining how its absence would contribute to tumor progression remain unknown. Using genomic editing with CRISPR-Cas9, we generated ovarian and breast cancer cell lines with loss-of-function mutations of HCRP1. We hypothesized that pathways downstream of receptor tyrosine kinases such as epidermal growth factor receptor are affected by HCRP1 loss and looked for deregulated signaling using immunoblotting and classical cancer biology assays. In our study, we show that endogenous deletion of HCRP1 leads to elevated phosphorylation of the transcription factor Signal transducer and activator of transcription 3 (STAT3) and induces upregulation of PD-L1, an important regulator of immune checkpoint inhibition. HCRP1 loss further leads to a mesenchymal phenotype switch in cancer cells, leading to increased proliferation and migration. Concludingly, our data emphasize the role of the tumor microenvironment in tumors with low or absent HCRP1 expression and suggest HCRP1 loss as a potential marker for metastatic potential and immunogenicity of epidermal growth factor receptor-driven cancer. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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