Carregant...
Tipus de document
ArticleVersió
Versió publicadaData de publicació
Llicència de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/204329
Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma
Títol de la revista
Director/Tutor
ISSN de la revista
Títol del volum
Recurs relacionat
Resum
The NADPH oxidase NOX4 has been proposed as necessary for the apoptosis induced by the Transforming Growth Factor-beta (TGF-I3) in hepatocytes and hepatocellular carcinoma (HCC) cells. However, whether NOX4 is required for TGF-I3-induced canonical (SMADs) or non-canonical signals is not fully understood yet, neither its potential involvement in other parallel actions induced by TGF-I3. In this work we have used CRISPR Cas9 technology to stable attenuate NOX4 expression in HCC cells. Results have indicated that NOX4 is required for an efficient SMAD2/3 phosphorylation in response to TGF-I3, whereas non-canonical signals, such as the phos-phorylation of the Epidermal Growth Receptor or AKT, are higher in NOX4 silenced cells. TGF-I3-mediated in-hibition of cell proliferation and viability is attenuated in NOX4 silenced cells, correlating with decreased response in terms of apoptosis, and maintenance of high expression of MYC and CYCLIN D1. These results would indicate that NOX4 is required for all the tumor suppressor actions of TGF-I3 in HCC. However, analysis in human HCC tumors has revealed a worse prognosis for patients showing high expression of TGF-I31-related genes concomitant with high expression of NOX4. Deepening into other tumorigenic actions of TGF-I3 that may contribute to tumor progression, we found that NOX4 is also required for TGF-I3-induced migratory effects. The Epithelial-Mesenchymal transition (EMT) program does not appear to be affected by attenuation of NOX4 levels. However, TGF-I3-mediated regulation of cytoskeleton dynamics and focal adhesions require NOX4, which is necessary for TGF-I3-induced increase in the chaperone Hsp27 and correct subcellular localization of Hic-5 within focal adhesions, as well for upregulation of the metalloprotease MMP9. All these results together point to NOX4 as a key element in the whole TGF-I3 signaling in HCC cells, revealing an unknown role for NOX4 as tumor promoter in HCC patients presenting activation of the TGF-I3 pathway.
Matèries
Matèries (anglès)
Citació
Citació
ESPINOSA SOTELO, Rut, FUSTÉ, Noel p., PEÑUELAS HARO, Irene, ALAY, Ania, PONS I IRAZAZÁBAL, Gabriel, ALMODÓVAR, Xènia, ALBALADEJO, Júlia, SÁNCHEZ VERA, Ismael, BONILLA AMADEO, Ricard, DITURI, Francesco, SERINO, Grazia, RAMOS GUERRERO, Emilio, SERRANO PIÑOL, M. teresa, CALVO, Mariona, MARTÍNEZ CHANTAR, María luz, GIANNELLI, Gianluigi, BERTRAN RODRÍGUEZ, Esther, FABREGAT ROMERO, Isabel. Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma. _Redox Biology_. 2023. Vol. 65. [consulta: 15 de gener de 2026]. ISSN: 2213-2317. [Disponible a: https://hdl.handle.net/2445/204329]