RESUMEN
Alcohol intake is associated with numbers of different human cancers, such as hepatocellular carcinoma (HCC) and breast cancer. However, the molecular mechanism remains to be elucidated. RNA polymerase III-dependent genes (Pol III genes) deregulation elevates cellular production of tRNAs and 5S rRNA, resulting in an increase in translational capacity, which promote cell transformation and tumor formation. To explore a common mechanism of alcohol-associated human cancers, we have comparably analyzed that alcohol causes deregulation of Pol III genes in liver and breast cells. Our results reveal that alcohol enhances RNA Pol III gene transcription in both liver and breast cells. The induction of Pol III genes caused by alcohol in ER+ breast cancer lines or liver tumor lines are significantly higher than in their non-tumor cell lines. Alcohol increases cellular levels of Brf1 mRNA and protein, (which depeted) Brf1 is a key transcription factor and specifically regulate Pol III gene activity. Alcohol activates JNK1 to upregulate transcription of Brf1 and Pol III genes, whereas inhibition of JNK1 by SP600125 or its siRNA significantly decreases the induction of these genes. Furthermore, alcohol increases the rates of transformation of liver and breast cells, repressed JNK1 and Brf1 expression decrease transcription of Pol III genes and reduce the rates of colony formation of AML-12 and MCF-10 cells. Together, these studies support the idea that alcohol induces deregulation of Brf1 and RNA Pol III genes in liver and breast cells, which share a common signaling pathway to promote cell transformation. Through the common mechanism, alcohol-induced deregulation of RNA Pol III genes brings about greater phenotypic changes.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Hepatocelular/metabolismo , ADN Polimerasa III/genética , Etanol/farmacología , Neoplasias Hepáticas/microbiología , Animales , Línea Celular , Transformación Celular Neoplásica/efectos de los fármacos , ADN Polimerasa III/metabolismo , Etanol/toxicidad , Regulación Neoplásica de la Expresión Génica , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Células MCF-7 , Ratones , Proteína Quinasa 8 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Factores Asociados con la Proteína de Unión a TATA/genética , Factores Asociados con la Proteína de Unión a TATA/metabolismoRESUMEN
Esophageal cancer (EC) is one of the most common gastrointestinal cancers, which leads to the sixth ranking of cancer-related death. Long non-coding RNAs (lncRNAs) play pivotal roles in many biological processes. lncRNA human urothelial carcinoma associated 1 (UCA1) is significantly upregulated and functions as an important oncogene in many types of human cancers. However, the role of UCA1 in EC and its underlying mechanism remains unclear. In the present study, we demonstrated that UCA1 was significantly upregulated in EC tissues and associated with poor prognosis. Overexpression of UCA1 promoted the proliferation of EC cells, while silence of UCA1 inhibited EC cells growth. Furthermore, we found that Sox4 was a direct target gene of UCA1. UCA1 regulated Sox4 expression through functioning as a competing endogenous RNA (ceRNA). UCA1 directly interacted with miR-204 and decreased the binding of miR-204 to Sox4 3'UTR, which suppressed the degradation of Sox4 mRNA by miR-204. This study provides the first evidence that UCA1 promotes cell proliferation through Sox4 in EC, suggesting that UCA1 and Sox4 may be potential therapeutic targets for EC.