RESUMEN
Histone deacetylase 2 (HDAC2) is aberrantly regulated and plays a pivotal role in the development of hepatocellular carcinoma (HCC) through regulation of cell-cycle components at the transcriptional level, but the underlying mechanism leading to oncogenic HDAC2 remains unknown. In this study, we show that expression of CK2α (casein kinase II α subunit) was up-regulated in a large cohort of human HCC patients, and that high expression of CK2α was significantly associated with poor prognosis of HCC patients in terms of five-year overall survival. It was also found that CK2α over-expression positively correlated with HDAC2 over-expression in a subset of HCCs. We observed that treatment with epidermal growth factor (EGF) elicited an increase in CK2α expression and Akt phosphorylation, causing induction of HDAC2 expression in liver cancer cells. It was also observed that ectopic expression of dominant-negative CK2α blocked EGF-induced HDAC2 expression, and that ectopic CK2α expression attenuated the suppressive effect of Akt knockdown on HDAC2 expression in liver cancer cells. Targeted disruption of CK2α influenced the cell cycle, causing a significant increase in the number of liver cancer cells remaining in G2/M phase, and suppressed growth via repression of Cdc25c and cyclin B in liver cancer cells. Taken together, our findings suggest the oncogenic potential of CK2α in liver tumorigenesis. Furthermore, a regulatory mechanism for HDAC2 expression is proposed whereby EGF induces transcriptional activation of HDAC2 by CK2α/Akt activation in liver cancer cells. Therefore, this makes CK2α a promising target in cancer therapy.
Asunto(s)
Carcinogénesis , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/agonistas , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 2/metabolismo , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/metabolismo , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Línea Celular Tumoral , Proliferación Celular , Estudios de Cohortes , Receptores ErbB/metabolismo , Histona Desacetilasa 2/genética , Humanos , Hígado/metabolismo , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Transducción de Señal , Análisis de SupervivenciaRESUMEN
Nemo-like kinase (NLK), an evolutionarily conserved MAP kinase-related kinase, has been reported to be involved in the development of hepatocellular carcinoma (HCC), but the underlying mechanisms leading to oncogenic NLK are poorly understood. A comprehensive microRNA (miRNA) profiling analysis on human HCC tissues identified four downregulated miRNAs that may target NLK. Ectopic expression of miRNA mimics suggested that miR-101 could suppress NLK in HCC cells. Notably, ectopic miR-101 expression repressed cancer cell growth and proliferation and imitated NLK knockdown effect on HCC cells. In conclusion, we suggest that miR-101 functions as a tumor suppressor by regulating abnormal NLK activity in liver.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/genética , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , MicroARNs/genética , Línea Celular Tumoral , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Humanos , Quinasa I-kappa B/metabolismo , MicroARNs/biosíntesis , TransfecciónRESUMEN
OBJECTIVE: Investigation on whether the characteristic molecular signatures can discriminate individual volatile organic compounds (VOCs) and provide predictive markers for the detection of VOC exposure. METHODS: Transcriptomic analysis of liver tissues was performed 48 h after the single oral administration of three VOCs doses at LD25 or LD5 values, to Sprague-Dawley. RESULTS: Combination analysis of different multi-classifications suggested that 145 genes predicted VOC exposure. Additionally, Gene Set Enrichment Analysis of genes deregulated by VOCs revealed that T cell prolymphatic leukemia signaling was inactivated in all VOCs. CONCLUSIONS: These molecular markers could be widely implemented to assess and predict environmental exposure to VOCs.