RESUMO
PURPOSE: This study was set out to explore the role of MAPK activity in programmed cell death ligand-1 (PD-L1) expression in hepatocellular carcinoma (HCC) cells. METHODS: The protein expression of PD-L1 was determined by immunofluorescence and immunohistochemistry, and the expression levels of PD-L1 and MAPK-related proteins were determined by flow cytometry and Western blotting. Meanwhile, the RNA transcription level of CD274 was determined by qRT-PCR. RESULTS: Interferon-γ (IFN-γ), epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling pathways were associated with CD274 gene expression in HCC. Epidermal growth factor (EGF) or IFN-γ stimulation increased CD274 mRNA and PD-L1 protein levels in a representative HCC cell line group, further enhanced by EGF and IFN-γ stimulation. Inhibition of the MAPK pathway by EGFR inhibitors ositinib or MEK 1 and 2 inhibitors selumetinib prevented the up-regulation of CD274 mRNA and PD-L1 proteins and membranes induced by EGF and IFN-γ. IFN-γ increased the transcriptional activity of CD274, while MAPK signaling enhanced the stability of CD274 mRNA. CONCLUSION: MAPK pathway activity plays a key role in PD-L1 expression in EGF and IFNγ-induced HCC and may provide a target for improving the efficacy of immunotherapy.
Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Transdução de SinaisRESUMO
Substantial researches indicated that long non-coding RNAs (lncRNAs) exerted profound effects on chemo-resistance in cancer treatment. Nonetheless, the role of NORAD in non-small-cell lung cancer (NSCLC) remains unclear. In the present study, we chose NSCLC cell lines H446 and A549 to explore the function of non-coding RNA activated damage (NORAD) in response to cisplatin (DDP) resistance of NSCLC. Experimental data manifested that NORAD was up-regulated in DDP-resistant NSCLC tissues and cells. NSCLC patients with high NORAD expression suffered a poor prognosis. NORAD knockdown resensitized H446/DDP and A549/DDP to DDP. Besides, NORAD acted as a molecular sponge of miR-129-1-3p. MiR-129-1-3p showed a low level of expression in DDP-resistant NSCLC tissues. Moreover, miR-129-1-3p overexpression impaired DDP resistance in H446/DDP and A549/DDP cells. SOX4 was the downstream target of miR-129-1-3p. Especially, SOX4 overexpression offset the effects of NORAD silence on H446/DDP and A549/DDP cells resistance to DDP. NORAD knockdown resensitized H446/DDP and A549/DDP to DDP in NSCLC via targeting miR-129-1-3p/SOX4 axis, offering a brand-new target for NSCLC chemo-resistance.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição SOXC/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição SOXC/genética , Transdução de SinaisRESUMO
BACKGROUND: Solid tumors have a markedly decreased incidence in individuals with Down syndrome (DS), including lung cancers. METHODS: The clinical presentation of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) in DS was reported and literature on the subject reviewed. RESULTS: In individuals with DS, the risk of lung cancer appears markedly lower. EGFR mutation and EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance also exist in DS with lung cancer. CONCLUSIONS: Clinicians should consider EGFR mutation and EGFR-TKIs resistance in lung cancer patients with DS.
