RESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive leukemia with inferior prognosis. Although activating mutations of NOTCH1 are observed in most T-ALL cases, these mutations alone are not sufficient to drive the full development of T-ALL. ß-Arrestins (ARRB) are versatile and multifunctional adapter proteins that regulate diverse cellular functions, including promoting the development of cancer. However, the role of ARRBs in T-ALL has largely remained elusive. In this study, we showed that ARRB1 is expressed at low levels in assayed T-ALL clinical samples and cell lines. Exogenous ARRB1 expression inhibited T-ALL proliferation and improved the survival of T-ALL xenograft animals. ARRB1 facilitated NOTCH1 ubiquitination and degradation through interactions with NOTCH1 and DTX1. Mechanistically, the oncogenic miRNA (oncomiR) miR-223 targets the 3'-UTR of ARRB1 (BUTR) and inhibits its expression in T-ALL. Furthermore, overexpression of the ARRB1-derived miR-223 sponge suppressed T-ALL cell proliferation and induced apoptosis. Collectively, these results demonstrate that ARRB1 acts as a tumor suppressor in T-ALL by promoting NOTCH1 degradation, which is inhibited by elevated miR-223, suggesting that ARRB1 may serve as a valid drug target in the development of novel T-ALL therapeutics.Significance: These findings highlight a novel tumor suppressive function of the adaptor protein ß-arrestin1 in T-ALL.
Assuntos
MicroRNAs/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/metabolismo , Proteínas Supressoras de Tumor/genética , beta-Arrestina 1/genética , Regiões 3' não Traduzidas/genética , Adolescente , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Criança , Pré-Escolar , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Masculino , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Proteólise , RNA-Seq , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Arrestina 1/metabolismoRESUMO
OBJECTIVE: To explore the key genes in T-cell acute lymphoblastic leukemia (T-ALL) using bioinformatics method to better understand the pathogenic mechanisms of T-ALL. METHODS: The gene expression profiles of GSE14317 were obtained from Gene Expression Omnibus database. The differentially expressed genes (DEGs) in T-ALL were analyzed using R package Limma. The online analysis tool DAVID was used to perform the functional and pathway enrichment analysis. The protein-protein interaction network was constructed by STRING and visualized by Cytoscape. Based on the JASPAR database, the transcription factors (TFs) of the hub genes were obtained. RT-PCR was used to test the mRNA expression level of the key genes. RESULTS: A total of 1443 DEGs were identified, including 800 up-regulated genes and 643 down-regulated genes. These DEGs were significantly enriched in the cell cycle, hematopoietic cell lineage, cytokine-cytokine receptor interaction and T cell receptor signaling pathway. The top 10 hub genes identified from the PPI networks included CDK1, PIK3R1, CCNB1, CCNA2, CDC20, JUN, GNG11, PLK1, PCNA and CCNB2, which were enriched in chemokine signaling pathway, ubiquition mediated proteolysis and cell cycle. In the TF-target gene network, 42 differentially expressed TFs were identified, among which ELF5, HIC2 and MEISI had binding sites with 9 of the candidate hub genes. RT-PCR showed that the mRNA expression level of all the candidate hub genes except for GNG11 were consistent with the gene expression profiles. CONCLUSION: The hub genes CDK1, PIK3R1, CCNB1, CCNA2, CDC20, JUN, PLK1, PCNA, CCNB2, ELF5, HIC2 and MEISI participate in the occurrence of T-ALL. Our finding provides new insights into the pathogenesis of T-ALL.