RESUMEN
Alcohol drinking is a leading risk factor for the development of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanisms of alcohol-associated ESCC remain poorly understood. One of the most commonly mutated genes in ESCC is nuclear factor erythroid 2 like 2 (NFE2L2 or NRF2), which is a critical transcription factor regulating oxidative stress response and drug detoxification. When NRF2 is hyperactive in cancer cells, however, it leads to metabolic reprogramming, cell proliferation, chemoradioresistance, and poor prognosis. In this study, hyperactive NRF2 was found to up-regulate acetyl-CoA synthetase short-chain family members 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in ESCC cells and mouse esophagus. We also showed that knockdown of NRF2 or ACSS2 led to decreased ACSS2 expression, which in turn reduced the levels of acetyl-CoA and ATP with or without ethanol exposure. In addition, ethanol exposure enhanced lipid synthesis in ESCC cells. Moreover, we observed a change in the metabolic profile of ESCC cells exposed to ethanol as a result of their NRF2 or ACSS2 status. We further showed that ACSS2 contributed to the invasive capability of NRF2high ESCC cells exposed to ethanol. In conclusion, the NRF2/ACSS2 axis mediates the metabolic effect of alcohol drinking on ESCC.
Asunto(s)
Acetato CoA Ligasa/metabolismo , Consumo de Bebidas Alcohólicas/efectos adversos , Reprogramación Celular , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Lipogénesis , Factor 2 Relacionado con NF-E2/metabolismo , Acetato CoA Ligasa/genética , Animales , Proliferación Celular , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/etiología , Carcinoma de Células Escamosas de Esófago/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genéticaRESUMEN
PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, Pax9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or Pax9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Diferenciación Celular , Transformación Celular Neoplásica/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Factor de Transcripción PAX9/metabolismo , Factores de Transcripción Paired Box/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Neoplasias de la Lengua/metabolismo , Consumo de Bebidas Alcohólicas/efectos adversos , Animales , Línea Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Metilación de ADN , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción PAX9/genética , Factores de Transcripción Paired Box/deficiencia , Factores de Transcripción Paired Box/genética , Regiones Promotoras Genéticas , Factores de Riesgo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/patología , TranscriptomaRESUMEN
Kenya belongs to a high incidence region known as Africa's esophageal cancer (EC) corridor. It has one of the highest incidence rates of EC worldwide, but research on EC in Kenya has gone highly unnoticed. EC in Kenya is unique in its high percentage of young cases (< 30 years of age). In this review, we show the current status of EC in the country. We mainly focus on significant risk factors such as alcohol drinking, genetic factors, malnutrition and hot food/drink. Future directions in the study and prevention of EC in Kenya are also discussed.