Abstract 2700: LSKL peptide inhibits thrombospondin-1-mediated TGF-β signal activation and accelerates liver regeneration after hepatectomy in mice
Authors: Hideyuki Kuroki, Hiromitsu Hayashi, Shigeki Nakagawa, Keita Sakamoto, Takaaki Higashi, Hidetoshi Nitta, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba
Journal: Cancer Research (2014)

Abstract Background Worldwide, while a hepatectomy has been performed as the curative procedure for liver cancers, a failure in liver regeneration following hepatectomy can result in functional liver disorders and hepatic failure. Therefore, a novel therapeutic strategy to accelerate liver regeneration enables to undergo safety curative hepatectomy for liver cancers. Transforming growth factor-β1 (TGF-β1) is a potent inhibitor of mitogen-stimulated DNA synthesis in hepatocyte. Since TGF-β is synthesized and secreted as a latent complex, an important step in regulating its biological activity is the conversion of the latent form into the active one. We reported that matricellular protein thrombospondin-1 (TSP-1), a major activator of latent TGF-β1 is a negative regulator of liver regeneration after hepatectomy using TSP-1 null mouse. In response to partial hepatectomy, TSP-1 production is acutely and transiently induced in the endothelial cells of the regenerative liver. These findings indicate the possibility of a novel therapeutic strategy for accelerating liver regeneration by targeting TSP-1 mediated TGF-β1 activation. This study aimed to clarify whether LSKL peptide, inhibiting TSP-1-mediated TGF-β activation, promoted liver regeneration after hepatectomy in mice. Method We performed 70% hepatectomy in mice receiving normal saline, LSKL peptide, and sham operation. LSKL peptide was administered intraperitoneally at abdominal closure and 6 h after hepatectomy. LSKL peptide (30 mg/6 mL/kg) was intraperitoneally administered before abdominal wall closure and at 6 h after 70% hepatectomy. Mice received an intraperitoneal injection of 5-bromo-2-deoxyuridine (BrdU), a marker for the S-phase of the cell cycle ,2 h prior to sacrifice. Result LSKL peptide administration attenuated Smad2 phosphorylation at 6 h after hepatectomy and thereafter accelerated S-phase entry of hepatocytes at 24 and 48 h. The accelerated hepatocyte proliferation by LSKL peptide administration resulted in faster recovery of the residual liver weight at 48 h and body weight at 168 h. H&amp;E staining and blood biochemical examinations revealed no significant adverse effects occurred following the two LSKL peptide administrations during the early period after hepatectomy. Conclusion Only two doses of LSKL peptide during the early period after partial hepatectomy can promote liver regeneration and body weight recovery without any significant side effects. The transient inhibition of TGF-β signal activation in the early period after hepatectomy was sufficient for accelerating hepatocyte. Inhibiting TSP-1-medaited TGF-β activation using LSKL peptide may thus be a promising strategy to promote liver regeneration following hepatectomy. Citation Format: Hideyuki Kuroki, Hiromitsu Hayashi, Shigeki Nakagawa, Keita Sakamoto, Takaaki Higashi, Hidetoshi Nitta, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba. LSKL peptide inhibits thrombospondin-1-mediated TGF-β signal activation and accelerates liver regeneration after hepatectomy in mice. [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 2700. doi:10.1158/1538-7445.AM2014-2700