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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / immunology*
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Carcinoma, Hepatocellular / pathology
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Cell Differentiation / genetics*
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Cell Proliferation
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Computational Biology
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ErbB Receptors / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Immune Evasion*
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Liver Neoplasms / genetics*
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Liver Neoplasms / immunology*
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Liver Neoplasms / pathology
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Lymphocytes, Tumor-Infiltrating / immunology
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Male
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Mice
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Middle Aged
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Models, Biological
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NFATC Transcription Factors / metabolism
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Proto-Oncogene Proteins c-cbl / metabolism
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RNA, Long Noncoding / genetics*
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RNA, Long Noncoding / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Regulatory / cytology*
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T-Lymphocytes, Regulatory / metabolism
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Transcription Factor AP-1 / metabolism
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Transcriptome / genetics
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Tyrosine / metabolism
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Ubiquitination
Substances
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NFATC Transcription Factors
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RNA, Long Noncoding
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RNA, Messenger
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Transcription Factor AP-1
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Tyrosine
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Proto-Oncogene Proteins c-cbl
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EGFR protein, human
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ErbB Receptors