RESUMEN
The pathogenesis of NAFLD is multi-faceted and mechanisms underlying the progression from simple steatosis to NASH have not been fully deciphered. The emerging field of epigenetics, an inheritable phenomenon capable of changing gene expression without altering DNA sequence, unveils a new perspective on the development of NAFLD and subsequent progression to HCC. In fact, numerous studies have highlighted the potential involvement of unhealthy daily habits such as physical inactivity and over-nutrition in the onset and development of NAFLD through epigenetic mechanisms. This chapter will discuss several epigenetic modulations including DNA methylation, histone modifications, functions of non-coding RNAs as well as RNA methylation implicated in the pathogenesis of NAFLD-HCC. On the basis of currently wealthy knowledge of DNA epigenetics, the rapidly growing field of RNA epigenetics will certainly drive forward a new avenue of research direction shedding light on the advancement of better diagnostics, prognostics and therapeutics in the coming era of precision medicine.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
AIM: Deregulation of FOXM1 has been documented in various cancers. The aim of this study was to evaluate the role of FOXM1 in ovarian cancer tumorigenesis and paclitaxel resistance. EXPERIMENTAL DESIGN: Expression of FOXM1 was examined in 119 clinical samples by immunohistochemistry and correlated with clinicopathological parameters. Effects of FOXM1 knockdown on ovarian cancer cell migration, invasion and mitotic catastrophe were also studied. qPCR and ChIP-qPCR were used to establish KIF2C as a novel FOXM1 target gene implicated in chemoresistance. RESULTS: High nuclear FOXM1 expression in ovarian cancer patient samples was significantly associated with advanced stages (P = 0.035), shorter overall (P = 0.019) and disease-free (P = 0.014) survival. Multivariate analysis confirmed FOXM1 expression as an independent prognostic factor for ovarian cancer. FOXM1 knockdown significantly inhibited migration and invasion of ovarian cancer cells and enhanced paclitaxel-mediated cell death and mitotic catastrophe in a p53-independent manner. Bioinformatics analysis suggested a number of potential transcription targets of FOXM1. One of the potential targets, KIF2C, exhibited similar expression pattern to FOXM1 in chemosensitive and chemoresistant cells in response to paclitaxel treatment. FOXM1 could be detected at the promoter of KIF2C and FOXM1 silencing significantly down-regulated KIF2C. CONCLUSION: Our findings suggest that FOXM1 is associated with poor patient outcome and contributes to paclitaxel resistance by blocking mitotic catastrophe. KIF2C is identified as a novel FOXM1 transcriptional target that may be implicated in the acquisition of chemoresistance. FOXM1 should be further investigated as a potential prognostic marker and therapeutic target for ovarian cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , Neoplasias Ováricas/patología , Paclitaxel/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral , Movimiento Celular , Supervivencia sin Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/genética , Puntos de Control de la Fase G2 del Ciclo Celular , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Cinesinas/genética , Estadificación de Neoplasias , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Paclitaxel/uso terapéutico , Pronóstico , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation, progression, and drug resistance. Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling cascade. In addition, FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes, which are involved in chemotherapeutic drug sensitivity and resistance. Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients, and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.
Asunto(s)
Carcinogénesis , Resistencia a Antineoplásicos , Factores de Transcripción Forkhead/metabolismo , Neoplasias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinogénesis/genética , Carcinogénesis/metabolismo , Proteína Forkhead Box M1 , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
The forkhead transcription factors FOXO and FOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and resistance. Recent research shows that the forkhead transcription factor FOXM1 is a direct transcriptional target repressed by the forkhead protein FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling pathway. Intriguingly, FOXM1 and FOXO3a also compete for binding to the same gene targets, which have a role in chemotherapeutic drug action and sensitivity. An understanding of the role and regulation of the FOXO-FOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients, and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity.
Asunto(s)
Resistencia a Antineoplásicos/genética , Factores de Transcripción Forkhead/genética , Neoplasias/genética , Proteína Forkhead Box M1 , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/efectos de los fármacos , Humanos , Neoplasias/dietoterapiaRESUMEN
AIMS: Dedicator of cytokinesis I (Dock180) is a novel guanine nucleotide exchange factor for Rho guanosine triphosphates (GTPases) important for cell migration. The aim of this study was to evaluate the role of Dock180 in ovarian carcinogenesis. METHODS AND RESULTS: Using immunohistochemistry, real-time polymerase chain reaction and Western blotting, overexpression of Dock180 RNA and protein was demonstrated in the nucleus and cytoplasm of ovarian cancer cell lines (n = 5) and clinical samples of ovarian borderline tumours (n = 21) and invasive cancers (n = 108) when compared with ovarian epithelial cell lines (n = 3) and benign cystadenomas (n = 10) (P < 0.05). High Dock180 cytoplasmic expression in ovarian cancer (n = 108) was associated significantly with serous histological type, high-grade cancer and advanced stage (P < 0.05), as well as poor overall and disease-free survival (P = 0.004). Using multivariate progression analysis, high Dock180 cytoplasmic expression and advanced cancer stage were found to be independent prognostic factors for short overall survival and disease-free survival (P < 0.05). Exogenous expression of Dock180 by transient transfection enhanced cancer cell migration and invasion, whereas knockdown of Dock180 by an siRNA approach retarded cancer cell migration and invasion in association with down-regulation of matrix metalloproteinase 2. CONCLUSIONS: Our findings suggest that Dock180 contributes to ovarian carcinogenesis and dissemination and is a potential prognostic marker and therapeutic target.