The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion

Nat Commun. 2017 May 25:8:15129. doi: 10.1038/ncomms15129.

Abstract

Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma (HCC). Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology
  • Cell Differentiation / genetics*
  • Cell Proliferation
  • Computational Biology
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Evasion*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mice
  • Middle Aged
  • Models, Biological
  • NFATC Transcription Factors / metabolism
  • Proto-Oncogene Proteins c-cbl / metabolism
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcriptome / genetics
  • Tyrosine / metabolism
  • Ubiquitination

Substances

  • NFATC Transcription Factors
  • RNA, Long Noncoding
  • RNA, Messenger
  • Transcription Factor AP-1
  • Tyrosine
  • Proto-Oncogene Proteins c-cbl
  • EGFR protein, human
  • ErbB Receptors