Crosstalk between IKKγ/Nemo and the Jnk genes in the progression from hepatitis to hepatocellular carcinoma

FJ Cubero; G Zhao; YA Nevzorova; M Hatting; N Hermanns; F Schäfer; O Drvarov; N Gaßler; C Liedtke; C Trautwein

doi:10.1055/s-0032-1331909

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Crosstalk between IKKγ/Nemo and the Jnk genes in the progression from hepatitis to hepatocellular carcinoma

FJ Cubero ¹, G Zhao ¹, YA Nevzorova ¹, M Hatting ¹, N Hermanns ¹, F Schäfer ¹, O Drvarov ¹, N Gaßler ², C Liedtke ¹, C Trautwein ¹

¹University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
²University Hospital RWTH Aachen, Department of Pathology, Aachen, Germany

Abstract

Background and Aim: Increased hepatocyte damage is a common mechanism observed in NAFLD patients which contributes to hepatitis and development of hepatocellular carcinoma (HCC). During the progression of liver injury, the crosstalk between the regulatory subunit of NF-κB, IKKγ/Nemo and the JNK genes might be a major determinant in the fate of hepatocytes towards survival or apoptosis. Thus, we investigated the interaction between Jnk1 and Jnk2 and Nemo during chronic liver disease. Methods: We generated hepatocyte-specific Nemo knockout mice (NemoΔhepa) and crossed them with Jnk1-/- (Jnk1-/-/NemoΔhepa) and Jnk2-/- (Jnk2-/-/NemoΔhepa), and characterized their phenotype during progression of liver inflammation and progressive fibrosis leading to HCC. Results: Genetic inactivation of Jnk1 exacerbated the spontaneous phenotype observed in NemoΔhepa mice. Serum ALT levels were significantly higher in Jnk1-/-/NemoΔhepa compared to Jnk2-/-/NemoΔhepa and NemoΔhepa mice. Anatomo-pathological analysis of 8–13 weeks Jnk1-/-/Nemo Δhepa livers revealed strong hypereosinophilia, fragmentation of cytoskeleton, cell death and mitotic instability. In contrast, Jnk2-/-/NemoΔhepa specimens manifested cell enlargement and reduced number of mitotic figures. Hepatocyte apoptosis was significantly elevated in Jnk1-/-/NemoΔhepa as assessed by TUNEL assay, Caspase-3/8 activity, cleaved Caspase-3, and down-regulation of antiapoptotic Bcl-XL and c-FLIP. Furthermore, higher compensatory hepatocyte proliferation in response to injury observed in Jnk1-/-/NemoΔhepa was associated with overexpression of Ki-67, Cyclin D, p21 and PCNA. Jnk1-/-/NemoΔhepa elicited higher parameter of liver fibrosis such as Hydroxyprolin, α-SMA and Collagen IA1 than Jnk2-/-/NemoΔhepa and NemoΔhepa mice. Hepatocyte proliferation and liver inflammation, lastly promote the development of HCC. Macroscopic examination and MRT of livers of 1 year-old Jnk1-/-/NemoΔhepa showed larger vascularized foci associated with microscopically ruptured liver architecture and regional distribution of HCC whereas examination of Jnk2-/-/NemoΔhepa livers elicited non-vascularized nodules associated with increased lipid deposition and triglyceride synthesis and presence of micro- and macrosteatosis. Conclusions: Jnk1 and Jnk2 have different roles in the modulation of NF-κB during the progression of liver injury in NemoΔhepa mice. Jnk1 plays a pivotal role in hepatocyte death, compensatory proliferation, inflammation, and tumor development whereas Jnk2 is crucial in the progression of steatohepatitis and tumor initiation.