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

Abstract

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