RESUMEN
The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Colangiocarcinoma/metabolismo , Hepatocitos/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Transactivadores/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Supervivencia Celular , Colangiocarcinoma/patología , Vía de Señalización Hippo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas Experimentales/patología , Melanoma/metabolismo , Melanoma/secundario , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Transactivadores/economía , Transactivadores/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Carga Tumoral , Proteínas Señalizadoras YAPRESUMEN
The conversion of simple steatosis into nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD) has attracted many attentions in recent years. The role of the hedgehog (HH) pathway in the regulation of lipogenesis has been addressed in the literature. This study aimed to investigate the levels of the sonic hedgehog (SHH) and Indian hedgehog (IHH) ligands and the correlation of these ligands with levels of proteins involved in the transforming growth factor-ß1 (TGF-ß1) pathway, as well as the evaluation of the transcriptional coactivator with PDZ binding motif (TAZ) expression in human simple steatosis, NASH cirrhosis, and controls. Patients were divided into two groups: the first group consisted of patients diagnosed with simple steatosis (n = 16) and the second group included those diagnosed with NASH cirrhosis (n = 15). As a control group, 18 histologically normal liver tissues were collected in this study. The expression of the TGF-ß1pathway components and SHH and IHH ligands were analyzed by means of the quantitative real-time polymerase chain reaction and western blot analyses. A significant decrease was found in the hepatic expression of the SHH, IHH, and TGF-ß1 pathways along with the expression of TAZ in tissue specimens with simple steatosis in comparison with patients affected by NASH cirrhosis and controls. Also, the levels of SHH and IHH proteins were significantly correlated with the expression of proteins involved in the TGF-ß1 pathway. Moreover, the expression of the HH pathway ligands was positively associated with the expression of TAZ, supporting the notion that TAZ may play a role in the activation of the HH pathway thereby regulating the expression of its ligands. It seems that in patients with NAFLD, the downregulation of the HH pathway ligands may stem from steatosis; however, at the same time, it may prevent the conversion of simple steatosis into NASH in patients with liver diseases. © 2019 IUBMB Life, 71(9):1382-1390, 2019.
