Our results with CM1-treated cells are consistent with other studies where down-regulation of Wnt/��-catenin pathway during hepatic differentiation is observed [6], [7], [8]. On the other hand, in protocol CM2, dexamethasone was administered, and the administration of high dose of this glucocorticoid may be selleck chem inhibitor responsible of the nuclear ��-catenin translocation observed. Others authors have demonstrated that equal concentration of dexamethasone induced osteogenesis of murine MSC via nuclear ��-catenin translocation [15]. These data suggest that the down-regulation of this pathway is not essential for the differentiation of human MSC into hepatocytes. Therefore, in our hands the activation or inhibition of Wnt/��-catenin signaling pathway did not lead the hepatogenesis of human MSCs.

However, the activation of Wnt signaling during hepatocytes differentiation might be associated with the generation of a tumoral phenotype and the expression of proteins related to liver cancer. Wnt/��-catenin pathway has been involved in the development, maintenance and differentiation of normal and malignant liver progenitor cells or MSC [16]. The sequence of molecular events leading to liver carcinogenesis is not well known. The accumulation of genetic alterations driving a cirrhotic liver to cancer is a multistep process originating from stem cells or mature hepatocytes [21]. Adult human MSC may be targets for malignant transformation and may undergo spontaneous transformation after long-term in vitro culture, supporting the hypothesis that some CSC originate from multipotential stem cells [22], [23].

In vitro data from transgenic mice suggest that activation of the Wnt/��-catenin pathway in epidermal stem cells leads to epithelial cancers [24]. The nuclear translocation of ��-catenin in neoplastic hepatocytes leads to retrodifferentiation into immature hepatocyte progenitors [10]. Many in vivo studies have associated Wnt/��-catenin pathway activation with hepatic tumoral processes, such as hepatocellular carcinoma or hepatoblastoma [9], [25], [26]. Aberrant deregulation of Wnt signaling has been implicated as a major mechanism of liver tumorigenesis [27], [28] and up-regulation of Wnt signaling is a hallmark of hepatoblastoma, the predominant hepatic neoplasm in infants and children. Wnt/��-catenin activation has been found to be associated with increases in c-myc and cyclin D1 staining in tumours of patients with hepatoblastoma [29].

In the case of hepatocellular carcinoma molecular alterations responsible for its development and progression include: 1) loss of tumor suppressors genes, as p53 and/or activation of cyclin D1, 2) activation of oncoproteins as c-myc, and 3) alterations in Wnt signaling leading Entinostat to nuclear accumulation of ��-catenin [10], [30].