Inhibition of the signaling pathway of syndecan-1 by synstatin: A promising anti-integrin inhibitor of angiogenesis and proliferation in HCC in rats.

AIM OF WORK: The study was conducted for evaluation of the antitumor activity of SSTN92-119 against HCC induced by thioacetamide in rats.

METHODS: Sixty male Sprague-Dawley rats were randomized into four equal groups: Control, SSTN92-119 , HCC, and HCC + SSTN92-119 . Liver function tests were measured in serum. Liver homogenate was used for determination of: i) integrinαѴβ3 (ITGαѴβ3), insulin like growth factor-1 receptor (IGF-1R), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and alpha-fetoprotein (AFP) levels by ELISA, ii) syndecan-1 (CD-138), IGF-1R and VEGF genes expressions by qRT-PCR, iii) MDA, NO, GSH concentrations and SOD activity. Histopathological and immunohistochemical examination of liver tissue was performed.

RESULTS: SSTN92-119 decreased HCC-induced elevation in ALT, AST, ALP and GGT activities and reversed HCC-induced reduction in total protein and albumin concentrations significantly. SSTN92-119 significantly elevated hepatic SOD and GSH and reduced both NO and MDA levels. Protein levels of ITGαѴβ3, IGF-1R, VEGF, FGF-2 and AFP were decreased in HCC- SSTN92-119 group as well as gene expression of CD-138, IGF-1R and VEGF compared with HCC group.

CONCLUSIONS: SSTN92-119 down regulates ITGαѴβ3 receptor and subsequently reduces the activation of angiogenic growth factors VEGF and FGF-2. Therefore, SSTN92-119 is becoming a promising anti-integrin αѴβ3 that inhibits angiogenesis and proliferation in HCC.