Yi Zhou1,2, Liang Hu3, Wenqing Tang1, Dongping Li2, Lijie Ma4, Hongchun Liu2, Shuncai Zhang2, Xiaojie Zhang5, Ling Dong2, Xizhong Shen2, She Chen6, Ruyi Xue7, Si Zhang8. 1. Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. 2. Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. 3. Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, China. 4. Department of General Surgery, Zhongshan Hospital (South), Shanghai Public Health Clinical Center, Fudan University, Shanghai, China. 5. Department of Rheumatology, Qilu Hospital of Shandong University, Jinan, Shandong, China. 6. Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. shechen@fudan.edu.cn. 7. Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. xue.ruyi@zs-hospital.sh.cn. 8. Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. zhangsi@fudan.edu.cn.
Abstract
BACKGROUND: Key hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (-) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis. METHODS: NOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2-knockout (Nod2△hep), Rip2-knockout (Rip2△hep), Lamin A/C-knockout (Lamn△hep) and Rip2/Lamin A/C double-knockout (Rip2/Lamn△hep) mice models of diethylnitrosamine (DEN)/CCl4-induced HCC. RESULTS: NOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCC patients. Hepatic NOD2 deletion in vivo decreased DEN/CCl4-induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability. CONCLUSIONS: We reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.
BACKGROUND: Key hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (-) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis. METHODS:NOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2-knockout (Nod2△hep), Rip2-knockout (Rip2△hep), Lamin A/C-knockout (Lamn△hep) and Rip2/Lamin A/C double-knockout (Rip2/Lamn△hep) mice models of diethylnitrosamine (DEN)/CCl4-induced HCC. RESULTS:NOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCCpatients. Hepatic NOD2 deletion in vivo decreased DEN/CCl4-induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability. CONCLUSIONS: We reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.
Authors: Maria E Johansson; Xiao-Ying Zhang; Kristina Edfeldt; Anna M Lundberg; Malin C Levin; Jan Borén; Wei Li; Xi-Ming Yuan; Lasse Folkersen; Per Eriksson; Ulf Hedin; Hann Low; Dmitri Sviridov; Francisco J Rios; Göran K Hansson; Zhong-Qun Yan Journal: Eur J Immunol Date: 2014-08-25 Impact factor: 5.532
Authors: Yannick Boege; Mohsen Malehmir; Marc E Healy; Kira Bettermann; Anna Lorentzen; Mihael Vucur; Akshay K Ahuja; Friederike Böhm; Joachim C Mertens; Yutaka Shimizu; Lukas Frick; Caroline Remouchamps; Karun Mutreja; Thilo Kähne; Devakumar Sundaravinayagam; Monika J Wolf; Hubert Rehrauer; Christiane Koppe; Tobias Speicher; Susagna Padrissa-Altés; Renaud Maire; Jörn M Schattenberg; Ju-Seong Jeong; Lei Liu; Stefan Zwirner; Regina Boger; Norbert Hüser; Roger J Davis; Beat Müllhaupt; Holger Moch; Henning Schulze-Bergkamen; Pierre-Alain Clavien; Sabine Werner; Lubor Borsig; Sanjiv A Luther; Philipp J Jost; Ricardo Weinlich; Kristian Unger; Axel Behrens; Laura Hillert; Christopher Dillon; Michela Di Virgilio; David Wallach; Emmanuel Dejardin; Lars Zender; Michael Naumann; Henning Walczak; Douglas R Green; Massimo Lopes; Inna Lavrik; Tom Luedde; Mathias Heikenwalder; Achim Weber Journal: Cancer Cell Date: 2017-09-11 Impact factor: 31.743