Acyclic Retinoid Targets Platelet-Derived Growth Factor Signaling in the Prevention of Hepatic Fibrosis and Hepatocellular Carcinoma Development

Abstract

Hepatocellular carcinoma (HCC) often develops in association with liver cirrhosis, and its high recurrence rate leads to poor patient prognosis. Although recent evidence suggests that peretinoin, a member of the acyclic retinoid family, may be an effective chemopreventive drug for HCC, published data about its effects on hepatic mesenchymal cells, such as stellate cells and endothelial cells, remain limited. Using a mouse model in which platelet-derived growth factor (PDGF)-C is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis, steatosis, and eventually, HCC development, we show that peretinoin significantly represses the development of hepatic fibrosis and tumors. Peretinoin inhibited the signaling pathways of fibrogenesis, angiogenesis, and Wnt/b-catenin in Pdgfc transgenic mice. In vitro, peretinoin repressed the expression of PDGF receptors a/b in primary mouse hepatic stellate cells (HSC), hepatoma cells, fibroblasts, and endothelial cells. Peretinoin also inhibited PDGF-C-activated transformation of HSCs into myofibroblasts. Together, our findings show that PDGF signaling is a target of peretinoin in preventing the development of hepatic fibrosis and HCC. Cancer Res; 72(17); 4459-71. Ó2012 AACR.

Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model

“…This is reasonable as we previously showed enhanced inflammatory response and inhibited serum levels of TNFa and expression levels of TNFa, IL6, and IL1b mRNA in the liver of db/db mice treated with ACR compared with those treated with DEN alone (20). Furthermore, in a plateletderived growth factor-overexpressed mouse model, genomewide expression profile analysis revealed that the repressive effect of ACR on the development of hepatic fibrosis and tumors was related with inflammatory signaling pathways such as "MIF signaling" and "IL6 signaling" (44).…”

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

“…The spectrum of feasible therapies include cyclooxygenase inhibitors, proteaseactivated receptor inhibitors, and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors. (6,12,(34)(35)(36) HCC patients with mild thrombocytopenia are likely better candidates until more scientific data on the safety of those therapies accumulate because such patients can have less bleeding diathesis and greater metastasis risk. In addition, the stable late posttransplant phase might provide another time window for targeting the latent metastasis with less concern about bleeding complications or graft regeneration.…”

Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model

“…HSC were isolated from C57BL/6J mice by pronase-collagenase liver digestion as reported previously [34]. …”

“…Gene expression profiling of mouse liver was performed using a GeneChip Mouse Gene 1.0 ST Array (Affymetrix, Santa Clara, CA) [34]. Liver tissue from mice fed the basal, Ath+HF, or Ath+HF diet containing 3% BCAA for 30 or 60 weeks was obtained.…”