Z Gastroenterol 2020; 58(01): e47
DOI: 10.1055/s-0039-3402228
Poster Visit Session IV Tumors: Saturday, February 15, 2020, 8:30 am – 09:15 am, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

TGFβ-activated kinase 1 (TAK1) is activated and predicts prognosis in hepatocellular carcinoma

D Ridder
1   University Medical Center of the Johannes Gutenberg University, Institute of Pathology, Mainz, Germany
,
L Urbansky
1   University Medical Center of the Johannes Gutenberg University, Institute of Pathology, Mainz, Germany
,
HR Witzel
1   University Medical Center of the Johannes Gutenberg University, Institute of Pathology, Mainz, Germany
,
A Weinmann
2   University Medical Center of the Johannes Gutenberg University, Department of Internal Medicine, Mainz, Germany
,
JU Marquardt
2   University Medical Center of the Johannes Gutenberg University, Department of Internal Medicine, Mainz, Germany
,
M Schindeldecker
1   University Medical Center of the Johannes Gutenberg University, Institute of Pathology, Mainz, Germany
3   University Medical Center of the Johannes Gutenberg University, Tissue Bank, Mainz, Germany
,
S Heinrich
4   University Medical Center of the Johannes Gutenberg University, Department of General-, Visceral- and Transplant Surgery, Mainz, Germany
,
B Koehler
5   NCT Heidelberg, University Clinic, Ruprecht-Karls-University, Heidelberg, Germany
,
W Roth
1   University Medical Center of the Johannes Gutenberg University, Institute of Pathology, Mainz, Germany
,
B Straub
1   University Medical Center of the Johannes Gutenberg University, Institute of Pathology, Mainz, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

Also available at
 

Aim:

Liver cancer is the second most common cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being its predominant form. There is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Tak1 is a master regulator of proinflammatory and prosurvival signaling pathways. Mice with a hepatocyte-specific deletion of Tak1 develop steatohepatitis, dysplastic nodules and HCCs, whereas on the other hand constitutive activation of Tak1 in mice also results in HCC development (Roh, J Gastroenterol. 2014, 49(2): 185 – 194). Despite detailed preclinical data, comprehensive studies on Tak1 expression in human HCC are lacking.

Methods:

In order to investigate Tak1 expression in HCCs in a large cohort of patients by immunohistochemistry, we established a tissue microarray (TMA) of HCCs of 574 patients who underwent tumor resection at the University Medical Center Mainz from 1998 to 2017. Kaplan-Meier, Wilcoxon rank-sum test, log rank and univariate Cox's regression analysis and Spearman's rank correlation were used to determine associations between Tak1 expression, patients' survival, etiology of underlying liver disease and other clinical parameters such as liver enzymes.

Results:

In the majority of HCCs, we detected Tak1 immunoreactivity predominantly in the nucleus. Tak1 was significantly induced in HCCs compared to surrounding non-neoplastic normal and cirrhotic liver tissue and was even further increased in distant metastases. Increased Tak1 expression in primary HCCs correlated with decreased survival (HR 1.27; 95% CI, 1.01 – 1.59, p < 0.05) and was associated with macro- and microvascular invasion. HCCs and surrounding liver tissue from patients suffering from HBV- or HCV-infection, hemochromatosis, liver cirrhosis, alcoholic and non-alcoholic steatohepatitis showed significantly lower Tak1 levels compared to tissues from patients without a known underlying liver disease.

Conclusion:

Tak1 expression was induced in HCC and even further increased in distant metastases, as determined by immunohistochemistry, and higher Tak1 levels were associated with unfavorable prognosis and macro- and microvascular invasion. Interestingly, HCCs and surrounding liver tissue of patients without any known underlying liver disease showed increased Tak1 expression levels. Further in vitro and immunohistochemical studies are currently undertaken to elucidate the underlying mechanism.