aggressiveness. Cor relation between stage of hepatic ARRY-142886 AZD6244 differentiation and clinical manifestation, notably vascular invasion, metastatic spread, and patient survival, was also es tablished. These finding highlight the important role of dysregulated Wnt ??catenin signaling in the transformation of stem progenitor cells. Recently, EpCAM was identified as a direct transcriptional target of Wnt ??catenin signaling in HCC. Adult hepatocytes are EpCAM, while the bile duct epithelium is EpCAM. In addition, expres sion of EpCAM was observed during fetal liver de velopment, liver regeneration, and liver repair asso ciated with cirrhosis. Moreover, EpCAM is a marker of hepatic progenitors, suggesting that EpCAM HCCs are of hepatic progenitor cell origin.
The EpCAM signaling can be activated by regu lated intramembrane proteolysis and shedding of extracellular domain of EpCAM . Se quencial cleavage of EpCAM by tumor necrosis factor alpha converting enzyme and a gamma secretase BMS 777607 complex containing presenilin 2 result in release of EpEX into the culture me dium, and release of an intracellular domain of Ep CAM into the cytoplasm. EpICD becomes a part of a large nuclear complex containing transcrip tional regulators ??catenin and Lef, both of which are components of Wnt ??catenin signaling. Four and one half LIM domain protein 2 is essential for signal transduction by EpCAM. FHL2 further regu lates localization and activity of TACE and PS 2. Through its function as a co activator of ??catenin, FHL2 links EpICD with specific DNA sequences and gene regulation.
FHL2 has the potential to serve as a scaffolding protein for various signaling proteins used by EpCAM. A number of EpCAM regulated target genes have been identified including c myc and cyclins, and additional genes involved in cell growth and proliferation, cell cycle, and cell death. Upon in terference with E cadherin, EpCAM may increase the availability of its interaction partner ??catenin in the soluble fraction. Cross talk with the Wnt pathway is possible at the level of ??catenin and Lef 1 interactions with EpICD, and known for induction of the EPCAM promoter by Tcf4. These findings indicated that ex pression of EpCAM strongly linked with proliferation of stem cells and cancer development by cancer initi ating cells after aberrant EpCAM re expression.
TGF ??family The TGF ??signaling pathway appears to be most prominent at the interface between development and cancer in liver and gut epithelial cells. Smad sig naling has been shown to be pivotal for embryogenic hepatocyte proliferation, as well as in the formation of gastrointestinal cancers. Smad activation is modulated by various receptor or Smad interacting proteins that include ubiquitin and small ubiqui tin related modifier ligases, as well as multi ple adaptor proteins that include Smad anchor for receptor activation, Filamin and ?? SPECTRIN. ?? SPECTRIN is crucial for the prop agation of TGF ??signaling.