RESUMO
Recently, the non-protein-coding functional elements in the human genome have been identified as key regulators in postgenomic biology, and a large number of pseudogenes as well as long non-coding RNAs (lncRNAs) have been found to be transcribed in multiple human cancers. However, only a small proportion of these pseudogenes has been functionally characterized. In this study, we screened for pseudogenes associated with human non-small-cell lung cancer (NSCLC) by comparative analysis of several independent datasets from the GEO. We identified a transcribed pseudogene named DUXAP8 that is upregulated in tumor tissues. Patients with higher DUXAP8 expression exhibited shorter survival, suggesting DUXAP8 as a new candidate prognostic marker for NSCLC patients. Knockdown of DUXAP8 impairs cell growth, migration, and invasion, and induces apoptosis both in vitro and in vivo. Mechanistically, DUXAP8 represses the tumor suppressors EGR1 and RHOB by recruiting histone demethylase LSD1 and histone methyltransferase EZH2, thereby promoting cell proliferation, migration, and invasion. These findings indicate that the pseudogene DUXAP8 may act as an oncogene in NSCLC by silencing EGR1 and RHOB transcription by binding with EZH2 and LSD1, which may offer a novel therapeutic target for this disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Canal de Potássio ERG1/genética , Epigênese Genética , Inativação Gênica , Neoplasias Pulmonares/genética , Pseudogenes/genética , Proteína rhoB de Ligação ao GTP/genética , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Análise por Conglomerados , Canal de Potássio ERG1/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Histona Desmetilases/metabolismo , Humanos , Neoplasias Pulmonares/mortalidade , Prognóstico , Ligação Proteica , Proteína rhoB de Ligação ao GTP/metabolismoRESUMO
Pulmonary carcinoma-associated proteins have emerged as crucial players in governing fundamental biological processes such as cell proliferation, apoptosis and metastasis in human cancers. Placenta-specific protein 1 (PLAC1) is a cancer-related protein, which is activated and upregulated in a variety of malignant tissues, including prostate cancer, gastric adenocarcinoma, colorectal, epithelial ovarian and breast cancer. However, its biological role and clinical significance in non-small cell lung cancer (NSCLC) development and progression are still unknown. In the present study, we found that PLAC1 was significantly upregulated in NSCLC tissues, and its expression level was associated with advanced pathological stage and it was also correlated with shorter progression-free survival of lung cancer patients. Furthermore, knockdown of PLAC1 expression by siRNA inhibited cell proliferation, induced apoptosis and impaired invasive ability in NSCLC cells partly via regulation of epithelial-mesenchymal transition (EMT)-related protein expression. Our findings present that increased PLAC1 could be identified as a negative prognostic biomarker in NSCLC and regulate cell proliferation and invasion. Thus, we conclusively demonstrated that PLAC1 plays a key role in NSCLC development and progression, which may provide novel insights on the function of tumor-related gene-driven tumorigenesis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proteínas da Gravidez/genética , Regulação para Cima , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Análise de Sobrevida , Carga TumoralRESUMO
Long non-coding RNAs are emerging as crucial regulators and prognostic markers in multiple cancers including non small cell lung cancer (NSCLC). In this study, we screened LINCO1133 as a new candidate lncRNA which promotes NSCLC development and progression, in two independent datasets (GSE18842 and GSE19804) from the Gene Expression Omnibus (GEO). LINC01133 is previously found to be over-expressed in lung squamous cell cancer (LSCC) and knockdown its expression inhibits LSCC cells invasion. However, its' molecular mechanism and downstream targets involving in regulation of cancer cells phenotype is not known. Here, we found that LINC01133 expression is up-regulated in NSCLC tissues, and its' over-expression is associated with patients poor prognosis and short survival time. LINC01133 knockdown decreased NSCLC cells proliferation, migration, invasion and induced cell cycle G1/S phase arrest and cell apoptosis. Mechanistic investigations showed that LINC01133 could interact with EZH2, LSD1 and recruit them to KLF2, P21 or E-cadherin promoter regions to repress their transcription. Furthermore, rescue experiments demonstrated that LINC01133 oncogenic function is partly through regulating KLF2. Lastly, we found that there was negative correlation between LINC01133 and KLF2, P21 or E-cadherin in NSCLC. Overall, our findings illuminate how LINC01133 over-expression confers an oncogenic function in NSCLC that may offer a novel therapy target in this disease.