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1.
Oncol Res ; 28(5): 467-481, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-32560747

RESUMO

Sorafenib, a multityrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. Programmed death ligand-1 (PD-L1) is one of the most important inhibitory molecules involved in tumor immune evasion. Recently, it has been reported that PD-L1 could play crucial roles in drug resistance of many kinds of cancers. However, the expression, function, and regulation of PD-L1 in sorafenib-resistant hepatoma cells remain unclear. In this study, we reported that PD-L1 was overexpressed in sorafenib-resistant hepatoma cells, and shRNA-mediated PD-L1 depletion attenuated drug resistance and suppressed the migration, invasion, colony formation, and tumorigenesis in sorafenib-resistant hepatoma cells in vitro and in vivo. Mechanistic investigations indicated that loss of microRNA-1 (miR-1), a tumor-suppressive microRNA, contributed to the PD-L1 upregulation in sorafenib-resistant hepatoma cells, and PD-L1 was a direct regulatory target of miR-1. Further study revealed that an oncogenic transcriptional factor, nuclear factor E2-related factor 2 (NRF-2), was induced in sorafenib-resistant hepatoma cells and inhibited expression of miR-1 in vitro. From molecular mechanism insight back to the functional verification, we eventually demonstrated that miR-1 executed its tumor-suppressive effects on drug resistance and other malignant properties in sorafenib-resistant hepatoma cells partially by PD-L1 inhibition in vitro and in vivo. In conclusion, our data suggested that a NRF-2/miR-1/PD-L1 regulatory axis contributed to the development and maintenance of drug resistance and other tumorigenic properties in sorafenib-resistant hepatoma cells and provided a potential therapeutic target for overcoming sorafenib resistance in HCC.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/metabolismo , Sorafenibe/farmacologia
2.
FEBS Lett ; 589(1): 68-76, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25433291

RESUMO

Although microRNA-1 (miR-1) is a known liver cancer suppressor, the role of miR-1 in apoptosis of hepatoma cells has remained largely unknown. Our study shows that ectopic miR-1 overexpression induced apoptosis of liver hepatocellular carcinoma (HepG2) cells. Apoptosis inhibitor 5 (API-5) was found to be a potential regulator of miR-1 induced apoptosis, using a bioinformatics approach. Furthermore, an inverse relationship between miR-1 and API-5 expression was observed in human liver cancer tissues and adjacent normal liver tissues. Negative regulation of API-5 expression by miR-1 was demonstrated to promote apoptosis of HepG2 cells. Our study provides a novel regulatory mechanism of miR-1 in the apoptosis of hepatoma cells.


Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Apoptose , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas Nucleares/biossíntese , RNA Neoplásico/biossíntese , Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , RNA Neoplásico/genética
3.
PLoS One ; 8(8): e70990, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23976970

RESUMO

BACKGROUND: Peptidylprolyl cis/trans isomerase NIMA-interacting 1 (PIN1) is involved in the process of tumorigenesis. The two single nucleotide polymorphisms (-677T>C, -842G>C) in the PIN1 promoter region have been suspected of being associated with cancer risk for years, but the conclusion is still inconclusive. METHODS: Eligible case-control studies were retrieved by searching databases and references of related reviews and studies. Genotype distribution data, adjusted odds ratios (ORs) and 95% confidence (CIs) intervals were extracted to calculate pooled ORs. RESULTS: A total of 4619 cancer cases and 4661 controls were included in this meta-analysis. Overall, the PIN1 -667T>C polymorphism was not associated with cancer risk, while the -842C allele was significantly associated with reduced cancer risk (CC+GC vs. GG, OR = 0.725, 95% CI: 0.607-0.865; P(heterogeneity) = 0.012 and GC vs. GG: OR = 0.721, 95% CI: 0.591-0.880; P(heterogeneity) = 0.003). Results from genotype distribution data were in agreement with those calculated with adjusted ORs and 95% CIs. No publication bias was detected. CONCLUSIONS: Results of this meta-analysis suggest that the PIN1 -842G>C polymorphism is associated with decreased cancer risk, but that the -667T>C polymorphism is not.


Assuntos
Predisposição Genética para Doença , Neoplasias/genética , Peptidilprolil Isomerase/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Alelos , Povo Asiático , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Peptidilprolil Isomerase de Interação com NIMA , Neoplasias/etnologia , Razão de Chances , Risco , População Branca
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