Abstract 2337: Loss of the LIM-only protein FHL2 enhances TGF-β expression and fibrogenesis

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The four and a half LIM-only protein 2 (FHL2) is a multifunctional protein involved in many biological and physiopathological processes. We previously showed that enhanced expression of FHL2 in hepatocytes increases both cell proliferation and apoptosis, and promotes liver tumorigenesis associated with activation of the Wnt/β-catenin signaling (Nouet et al, J Hepatol., 2012) and that deletion of FHL2 suppresses in vitro and in vivo an array of NF-κB-mediated effects including cytokine expression, hepatocyte proliferation, and DEN-induced hepatocarcinogenesis (Dahan et al, Mol. Cell. Biol., 2013). Here we report that FHL2-deficient mice developed more severe hepatic fibrosis compared to wild type (wt) counterparts after bile duct ligation operation or administration of chemical agents thioacetamide and carbon tetrachloride, as demonstrated by Sirius red staining and mRNA expression of α-smooth muscle actin, collagen-α1 and transforming growth factor (TGF)-β1. Moreover, in the absence of any treatment, the resident hepatic macrophages (Kupffer cells) and peritoneal macrophages in FHL2-deficient mice produce elevated levels of the profibrotic cytokine TGF-β1. Because FHL2 exerts dual functions as a transcription co-activator or co-repressor, we searched for a direct effect of FHL2 on the TGF-β1 promoter. Co-transfection of murine TGF-β1 promoter-luciferase reporter constructs with FHL2 into 293T cells did not evidence significant repressive effects of FHL2 overexpression on the TGF-β1 promoter. Remarkably however, the TGF-β1 promoter activity was drastically increased in FHL2-/- mouse embryonic fibroblasts (MEFs) compared to wt MEFs. The hypothesis that FHL2 may play a part in chromatin remodeling is currently investigated by analyzing the role of FHL2 on histone modifications including acetylation, phosphorylation and methylation. Of note, we have recently shown that FHL2 activates TGF-β signaling by increasing the activity of Arkadia, a positive regulator of the pathway (Xia et al, J Biol. Chem. 2013). All together, these data suggest a complex regulation of TGF-β signaling by FHL2. Finally, in line with recently published data by Huss et al (BMC Gastroenterology, 2013) and Alnajar et al (PLoS ONE, 2013), we also observed increased renal fibrogenesis in FHL2-mutant mice following Leptospira infection, implicating FHL2 in the control of fibrogenesis in multiple tissues. Note: This abstract was not presented at the meeting. Citation Format: Jennifer Dahan, Florence Levillayer, Catherine Werts, Gregory Jouvion, Yann Nouet, Minou Adib-Conquy, Anne-Marie Cassard-Doulcier, Tian Xia, Ju Chen, Thierry Tordjmann, Marie-Annick Buendia, Yu Wei. Loss of the LIM-only protein FHL2 enhances TGF-β expression and fibrogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2337. doi:10.1158/1538-7445.AM2014-2337