Abstract
Background/aims:
Immunosuppression is one of the hallmarks of cancer; however, its molecular mechanism remains unknown. In the present study, we sought to investigate the expression and activation of yes-associated protein 1 (YAP-1) and its roles in T cells within hepatocellular carcinoma (HCC).
Methods:
The expression and activation of YAP-1 were accessed by real-time PCR, immunohistochemistry staining, western blot, and flow cytometry. The potential regulation effect of YAP-1 on Regulatory T cells (Tregs) differentiation was predicted using bioinformatics tools and verified by in vitro studies.
Results:
Significant overexpression and activation of YAP-1 was detected within peripheral blood mononuclear cells and showed positive linear correlation to Treg percentage; it may serve as a valuable indicator of a bad prognosis. Using in vitro studies, we found that overexpression and activation of YAP-1 can promote naïve T cell polarization stimulation to Tregs by increasing the expression of TGFBR2. The YAP-1/TEADs DNA binding site was spotted within the promoter region of TGFBR2 and related to its transcription activity. YAP-1 acted as a co-activator of TGFBR2 transcription by binding directly to the TGFBR2 promoter through TEADs.
Conclusion:
Overexpression and activation of YAP-1 in HCC T cells can induce immunosuppression by promoting Treg differentiation via transcriptional enhancement of TGFBR2.
Keywords:
HCC; TEADs; TGFBR2; Treg; YAP-1.
© 2017 The Author(s). Published by S. Karger AG, Basel.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / immunology
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Adult
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Binding Sites
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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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Case-Control Studies
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Cell Differentiation
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Cell Proliferation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / pathology
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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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Male
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Middle Aged
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology
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Phosphoproteins / genetics*
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Phosphoproteins / immunology
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Primary Cell Culture
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Promoter Regions, Genetic
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Protein Binding
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / immunology
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics*
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Receptors, Transforming Growth Factor beta / immunology
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Signal Transduction
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / pathology
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TEA Domain Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transcription, Genetic
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Nuclear Proteins
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Phosphoproteins
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Receptors, Transforming Growth Factor beta
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TEA Domain Transcription Factors
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TEAD1 protein, human
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Transcription Factors
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YAP-Signaling Proteins
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YAP1 protein, human
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II