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© Research
Project

Molecular mechanisms regulating hepatitis B virus replication and liver carcinogenesis

Scientific Fields
Diseases
Organisms
Applications
Technique
Starting Date
06
Jul 2015
Status
Ongoing
Members
3

About

Despite the existence of safe and efficient vaccines for more than twenty-five years, hepatitis B remains a public health problem of worldwide importance. It is currently estimated that 240 million people are chronic carriers of hepatitis B virus (HBV), and disease caused by HBV infection is held responsible for 1.2 million deaths each year. Furthermore, these chronic carriers represent an important reservoir for viral dissemination. Chronic HBV infection is a major risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC), one of the most common killer tumors in human. Chronic hepatitis B (CHB) is characterized by an inefficient T cell response in the liver that results in incomplete clearance of the virus from infected hepatocytes. The liver is a notoriously tolerogenic organ with expression of high concentrations of anti-inflammatory mediators that inhibit local antigen-presenting cells (APCs) maturation under steady-state conditions. In addition, cell-intrinsic mechanisms within hepatic APCs participate to maintain the tolerogenic phenotype in which immune response is downregulated. Thus, several pathogens including HBV are able to exploit the liver’s favorable environment for escaping immune response and establishing persistent infection. However, inflammation can convert liver from a tolerogenic to an immune active state. One of our projects is studying how inflammation modulates T cell response to HBV.
In parallel, we are interested in signalling pathways controlling hepatocyte proliferation, death and liver carcinogenesis. Recent work has focused on the four and a half LIM-only protein 2 (FHL2), which belongs to the family of LIM proteins (named after lin-11, Islet-1 and mec-3). The LIM domain is a specialized double zinc finger protein motif, which lacks DNA-binding activity. FHL2 is characterized by an exclusive presence of four and a half LIM domains that is involved in the assembly of multi-protein complexes. In the cytoplasm, FHL2 interacts with alpha- and beta-integrin subunits and focal adhesion kinase at focal adhesions and is implicated in the interaction between extracellular matrix and integrin receptors. Ubiquitously expressed, FHL2 transcription can be activated by a variety of stimuli. Activation of FHL2 induces translocation of the protein to the nucleus where it plays the role of transcription coregulator in the control of a broad range of transcription programs. Activation of FHL2 has been observed in both physiological and pathological conditions. Its activation plays important roles in both normal prostate physiology and carcinogenesis. Up-regulation of FHL2 has been reported in a large number of human malignancies including acute myeloid leukaemia, glioma, lung, ovary, breast, prostate and colon cancers. We have shown that FHL2 is beta-catenin binding partner and collaborates with beta-catenin in regulation of gene expression, cell proliferation and tumorigenesis. Aberrant activation of the Wnt/beta-catenin pathway is a frequent event in liver carcinogenesis. Using both FHL2 liver transgenic and constitutive knockout mouse models, we have demonstrated that FHL2 is a crucial factor in the maintenance of liver homeostasis and in the development of liver disease. We generated a mouse model (Apo-FHL2) using apolipoprotein C-III enhancer and the apolipoprotein A-IV promoter to drive constitutive overexpression of FHL2 in the liver (collaboration with Agnès Ribeiro, Inserm UMRS872, Grégory Jouvion, IP, and Thierry Tordjmann, Université Paris Sud). In normal conditions, cell division is rarely seen in hepatocytes in the adult liver. However, hepatocytes in Apo-FHL2 mice exhibit an active cell division and concomitant apoptosis that give rise to a normal liver mass in the animals. To investigate the role of FHL2 in liver carcinogenesis associated with activation of the Wnt/beta-catenin signaling pathway, we crossed Apo-FHL2 with APC lox/lox mice in which livertargeted inactivation of Apc induces activation of beta-catenin and HCC development (collaboration with Sabine Colnot and Christine Perret, Institut Cochin). Overexpression of FHL2 increased the tumor frequency in ApoFHL2;APC-/- livers. These findings demonstrate crucial role of FHL2 in Wnt/beta-catenin-associated tumorigenesis. In collaboration with Ju Chen at University of California, San Diego, we treated wt and FHL2 -/- mice with diethylnitrosamine (DEN), which induces hepatocyte DNA damage, ensuing compensative proliferation involving both NF- B and STAT3 signaling, and resulting in HCC. While 100% of wt male mice developed HCC at 8 months, FHL2 -/- mice exhibited a decrease in hepatocarcinogenesis. We observed reduced phosphorylation of STAT3 and decreased hepatocyte proliferation in FHL2 -/- mice, suggesting that deficiency in FHL2 might inhibit carcinogenesis by compromising the activation of NF- B and STAT3 signaling is response to DEN. These results underscore the critical role of FHL2 in liver regeneration and carcinogenesis through its implication in the NFand STAT3 signaling pathways. Our recent findings suggest that FHL2 plays an important role in TGF-beta signaling. In collaboration with Laurence Lévy at Inserm U674, we detected interaction of FHL2 with a key molecule of TGF-beta signaling, the E3 ligase Arkadia. Arkadia activates Smad3/Smad4-dependent transcription by triggering the repressor SnoN degradation, which is absolutely required for TGF-beta response. We showed that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein. This work was the result of a fruitful collaboration with Ke Lan’s lab at the Institut Pasteur of Shanghai. Currently, we are dissecting the mechanismes of how FHL2 regulates TGF-beta expression and is related to fibrogenesis.