Impact of Mesenchymal Stem Cells and Vitamin D on Transforming Growth Factor Beta Signaling Pathway in Hepatocellular Carcinoma in Rats

Background: Transforming growth factor-beta (TGF-β) signaling is recognized as being critical for carcinogenesis. Vitamin D has proved to exert numerous tumor suppressive effects. Effects of bone marrow derived mesenchymal stem cells (BM-MSCs) on tumor progression are still controversial. The present study was conducted to evaluate the effects of BM-MSCs and vitamin D on TGF-β signaling in an experimental hepatocellular carcinoma (HCC) model in rats. Materials and Methods: The study was conducted on fifty female white albino rats divided equally into 5 groups: controls, HCC induced by diethyl-nitrosamine (DENA) and carbon tetrachloride (CCl4), HCC plus MSCs, HCC plus vitamin D and HCC plus both MSCs and vitamin D. The following parameters were assessed in rat liver tissues: TGF-β and Smad2 protein levels by ELISA and western blotting, respectively, gene expression of Smad3, Smad7, Snail, HNF4α and MMP-2 and histopathological lesions. Serum levels of alpha fetoprotein (AFP), ALT and albumin were also assessed. Results: TGF-β protein levels and gene expression of its downstream effectors (Smad3 and Snail), in addition to Smad2 protein levels were significantly higher in the HCC group than in the control group. On the other hand, they were significantly down-regulated in all treated groups with most significant amelioration with both MSCs and vitamin D. Also, the serum levels of AFP were significantly increased in the untreated HCC group, and this was again reversed in all treated groups. Histopathological examination of liver tissue revealed that administration of MSCs or vitamin D into HCC rat group improved the histopathological picture with residual tumor pathology, while administration of both MSCs and vitamin D showed better restoration of liver parenchyma. These data suggest that the TGF-β signaling pathway could be used as a therapeutic target in HCC.