Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development.
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/β-catenin in Pdgf-c transgenic mice. In vitro, peretinoin repressed the expression of PDGF receptors α/β 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.
Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Takara-Machi 13-1, Kanazawa 920-8641, Japan.
Hikari
H
Okada
Masao
M
Honda
Jean S
JS
Campbell
Yoshio
Y
Sakai
Taro
T
Yamashita
Yuuki
Y
Takebuchi
Kazuhiro
K
Hada
Takayoshi
T
Shirasaki
Riuta
R
Takabatake
Mikiko
M
Nakamura
Hajime
H
Sunagozaka
Takuji
T
Tanaka
Nelson
N
Fausto
Shuichi
S
Kaneko
D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D051153:Wnt Proteins; D051176:beta Catenin; C411423:platelet-derived growth factor C; D014212:Tretinoin; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; D017479:Receptors, Platelet-Derived Growth Factor