FZD binding to Wnt ligand also promotes the escape of β-catenin from its association with

E-cadherin[23,25]. The cytoplasmic elements of the activated Wnt pathway prevent β-catenin from being phosphorylated by degradation complex composed of a serine-threonine kinase, glycogen synthase kinase-3β (GSK3β), protein scaffolds, AXIN and adenomatosis polyposis coli (APC)[25]. selleck chemicals Mutations of these proteins allow β-catenin to accumulate in the nucleus to enhance the transcription of its target genes which are found in many cancers[9]. For example, in hepatocellular carcinoma (HCC), mutations of β-catenin are located in exon 3 of CTNNB1 gene which is the phosphorylation site for GSK3B, AXIN1 and AXIN2 mutation[26]. It is worth noting that 20%-40% of human HCC exhibit abnormal cytoplasmic and nuclear accumulation of β-catenin by immunohistochemistry (IHC)[27]. Β-Catenin can also undergo downregulation via the non-canonical Notch pathway.

In this case, membrane-bound Notch forms a complex with active Β-Catenin in the presence of Wnts. This action degrades active Β-Catenin and thus inhibits its pathway. This process allows for regulation of SC and its dysfunction could lead to expansion of CSC[13]. Markers for elevated expression of Wnt include CD133+ and EpCAM+[28]. The knockdown of expression of EpCAM, in HCC stem cells resulted in decreased proliferation, colony formation, migration and drug resistance which highlight the role and Wnt signaling in tumor survival[28,29]. Additionally, knockdown of β-catenin

resulted in inhibition of CSC[30]. Similarly mutations in APC gene acts to suppress Wnt signaling and result in familial adenomatous polyposis (FAP) syndrome[31]. In the majority of sporadic colorectal cancers, loss of APC or β-catenin mutations seems to be early events in carcinogenesis[32]. Of note, Apc 1638N has been shown to result in multiple intestinal tumors in mice[32]. TGF-β pathway TGF-β signaling is crucial for self-renewal and maintenance of SC and in the formation of gastrointestinal cancers[8,33]. TGF-β forms a complex with the serine-threonine kinase receptor type I and II[34]. The receptors are activated sequentially and subsequently phosphorylate one of the receptor-activated R-mads[35]. The activated R-mad will heterodimerize with Smad4 and then translocate to the nuclear to regulate gene transcription[36]. Disruption of TGF-β signaling results in dysregulated gene expression and hence gastrointestinal malignancies are Entinostat associated with suppressed activity of different members of TGF-β pathway[37,38]. For example, inactivation of Smad4 is seen in approximately 50% of patients with pancreatic cancer[39]. Similarly, reduced Smad4 expression and loss of ELF, a modulator of activity of Smad3, are observed in human colon and gastric cancer tissue[40,41]. Additionally, inactivating mutation of TGF-β II receptor was described in colon cancer[37].