Autoren:	Ridder, Dirk Andreas Urbansky, Lana Louisa Witzel, Hagen Roland Schindeldecker, Mario Weinmann, Arndt Berndt, Kristina Gerber, Tiemo Sven Köhler, Bruno Christian Nichetti, Federico Ludt, Annekathrin Gehrke, Nadine Schattenberg, Jörn Markus Heinrich, Stefan Roth, Wilfried Straub, Beate Katharina
Titel:	Transforming growth factor-β activated kinase 1 (Tak1) is activated in hepatocellular carcinoma, mediates tumor progression, and predicts unfavorable outcome
Online-Publikationsdatum:	13-Jan-2023
Erscheinungsdatum:	2022
Sprache des Dokuments:	Englisch
Zusammenfassung/Abstract:	Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.
DDC-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-7251
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Weitere Angaben zur Dokumentart:	Scientific article
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	Cancers 14 2
Seitenzahl oder Artikelnummer:	430
Verlag:	MDPI
Verlagsort:	Basel
Erscheinungsdatum:	2022
ISSN:	2072-6694
DOI der Originalveröffentlichung:	10.3390/cancers14020430
Enthalten in den Sammlungen:	DFG-491381577-G