Publikationsserver der RWTH Aachen University
The function of TAK1 in hepatocarcinogenesis
Abstract
dc:descriptionThe MAP3-kinase TGF-beta-activated kinase 1 (TAK1) is activated in response to cytokines like TNF-alpha, TGF-beta as well as by the bacterial endotoxin lipopolysaccharide (LPS). TAK1 is involved in controlling the activation of p38MAPK, JNK, and NF-kappaB in various cellular systems thereby critically modulating innate and adaptive immune responses and connecting cytokine stimulation with activation of inflammatory signalling pathways. After activation of the TNF signalling cascade, TAK1 and its adaptors TAB2, TAB3, and NEMO are recruited to polyubiquinated RIP1, by which TAK1 phosphorylates and activates the catalytic IKK subunits. Although it has been shown that TAK1 is essential for innate and adaptive immune responses, its functional role in liver parenchymal cells remains elusive. In the present work, a conditional deletion of Tak1 in liver parenchymal cells (hepatocytes and cholangiocytes) was generated to investigate the role of TAK1 in the liver and was correlated to the liver parenchymal knockout of Nemo. The deletion of Tak1 in liver parenchymal cells (TAK1LPC-KO) causes spontaneous development of a severe phenotype causing lethal biliary chirrosis. These animals suffer from advanced hepatitis and an acute cholangitis at the age of 6 weeks, leading to enhanced mortality rate between 14 and 36 weeks of age. We showed that TAK1 prevents liver cell apoptosis and hepatic inflammation since it is necessary for NF-kappaB activation but not JNK activation in response to LPS stimulation, a potent inducer of TNF secretion from non-parenchymal liver cells. However, qRT-PCR analysis revealed that ablation of TAK1 in liver parenchymal cells spontaneously activates the TGF-beta signaling pathway. This data showed that the TGF-beta isoforms 1 to 3 were strongly upregulated, correlating with increased SMAD2 activation and upregulation of the matrix genes CollagenIalpha1, Mmp-1, and Mmp-9. Moreover, histological analysis of liver tissues from 6 week old TAK1LPC-KO mice displayed a strong reduction of biliary epithelial cells compared with age-matched WT and NEMOLPC-KO animals. Immunohistochemical stainings of liver sections from 3 to 4 week old TAK1LPC-KO mice showed enhanced apoptotis as well proliferation of cholangiocytes, indicating that the leakage of cholangiocytes might begin between 5 and 6 weeks of age. Characterization of liver tumours in 16 to 33 week old TAK1LPC-KO mice revealed an intriguing chromosomal signature. More than 85% of all investigated HCCs displayed amplifications on the entire chromosome 13 or large portions of it, whereas large amplifications on chromosomes 4 and 8 were detected but in a smaller proportion of TAK1LPC-KO livers. In addition, a 16-gene array analysis demonstrated that these tumours were highly proliferative active while NEMOLPC-KO HCCs were less proliferative but more differentiated. These results showed that the deletion of TAK1 in liver parenchymal cells promotes a 5 to 9 month earlier development of HCCs than in NEMOLPC-KO mice. In summary, the ablation of TAK1 in hepatocytes and cholangiocytes causes a dramatic phenotype which is characterized by dysplasia and an early-onset of HCC coinciding with biliary ductopenia and cholestasis.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2011
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Bettermann, Kira
- Contributors dc:contributor
-
- Baumgartner, Werner
Subjects
dc:subject × 14Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- eng
Identifiers
dc:identifier.*- OAI identifier oai:identifier
- oai:publications.rwth-aachen.de:63326