Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocarcinogenesis via modulating TGF-β/tβr and imp7/8

Compound Astragalus and Salvia miltiorrhiza extract (CASE) is a Chinese herbal formula consisting of astragalosides, astragalus polysaccharide and salvi-anolic acids extracted from Astragalus membranaceus and Salvia miltiorhiza. Previous studies by our group have demonstrated that CASE effectively suppresses diethylinitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats via modulating transforming growth factor β/Mothers against decapentaplegic (TGFβ/Smad) signaling. To further elucidate the mechanism of CASE, the effects of CASE on TGF-β, the serine/threonine kinase receptors of TGF-β [TGF-β receptor type-I (TβRΙ) and TβRII] and karyopherins [Importin 7 (Imp7) and Imp8], which are crucial for TGF-β/Smad signaling in fibro-hepatocarcinogenesis, were assessed in the present study using in vivo (DEN-induced HCC in rats) and in vitro [TGF-β-stimulated rat myofibroblasts (MFBs) and HepG2 cells] models of fibro-hepatocarcinogenesis. Hematoxylin and eosin staining revealed that CASE may suppress inflammatory reactions and fibrosis in HCC as well as increasing the differentiation of HCC cells. Positive TGF-β staining was increased in HCC nodule areas and in adjacent normal liver tissues in DEN-treated rats, while TβRΙ staining was increased only in normal adjacent liver tissues. The elevated expression of TGF-β, TβRΙ and TβRII was suppressed by CASE. CASE treatment also reduced glutathione S-transferase P 1 and Imp7/8 protein expression in fibro-hepatocarcinogenesis. In vitro experiments confirmed that CASE was able to decrease the expression of TβRΙ and TβRII in TGF-β-stimulated MFBs and HepG2 cells. These results indicate that the anti-HCC effect of CASE may be achieved by mediating TGF-β/TβR and Imp7/8 protein expression, suggesting that CASE has multiple targets in HCC treatment