Abstract
Anti-PD-1/PD-L1 therapies have demonstrated prominent clinical effects in the treatment of non-small cell lung cancer (NSCLC). However, limited understanding of the regulatory mechanisms of PD-L1 has become one of the biggest challenges for further improving efficacy. In this study, we observed that in wild-type EFGR cell lines A549 and H460, the ubiquitin ligases Cbl-b and c-Cbl inhibit PD-L1 by inactivating STAT, AKT, and ERK signaling. MiR-181a and miR-940 were screened and validated to target Cbl-b and c-Cbl, respectively. Furthermore, in NSCLC tissues, the expression of Cbl-b/c-Cbl is negatively correlated with PD-L1 expression. Taken together, these findings indicated a new regulatory mechanism for PD-L1 in wild-type EGFR NSCLC cell lines by Cbl-b and c-Cbl.
Keywords:
EGFR; Cbl-b; PD-L1; c-Cbl; lung cancer.
© 2018 Federation of European Biochemical Societies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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B7-H1 Antigen / metabolism*
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Carcinoma, Non-Small-Cell Lung / diagnosis
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism*
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Carcinoma, Non-Small-Cell Lung / pathology
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Down-Regulation*
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ErbB Receptors / metabolism
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Humans
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Lung Neoplasms / diagnosis
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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MicroRNAs / genetics
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Prognosis
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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B7-H1 Antigen
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CD274 protein, human
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MIRN940 microRNA, human
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MIrn181 microRNA, human
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MicroRNAs
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STAT3 Transcription Factor
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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EGFR protein, human
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ErbB Receptors
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Proto-Oncogene Proteins c-akt