pSpecifically, ?? SPECTRIN associates with Smad3, presenting it to the cytoplasmic domain of the TGF ??Type I receptor complex, followed by heteromeric complex associa tion with Smad4, nuclear translocation and target gene activation. Disruption of ?? SPECTRIN in mice leads to disruption of TGF ??signaling AZD7762 and re sults in a phenotype similar to Smad2 Smad3 mutant mice, mid gestational death due to gastroin testinal, liver, neural and heart defects, and loss of intrahepatic bile ducts. Interestingly, while the liver lineage is established, hepatocytes are poorly formed and liver architecture is lost with an absence of prim itive bile ducts as in the Smad2 Smad3 mutants. Moreover, bile duct formation can be induced in liver explants cultures treated with TGF ?? Many studies have reported a reduction of TGF ??receptors in up to 70 of HCC.
How ever, BMS 794833 Smad proteins shown to be impaired in other cancers appear to play a minor role in HCC. Yet, TGF ??levels in serum and urine are increased in HCC patients. In addition, up to 40 of HCC have increased TGF ??expression based on immuno histochemical analysis. High TGF ??levels have been correlated with advanced clinical stage of HCC. This dual role of TGF ??signaling in HCC was explained by its effect on the tumor tissue microenvironment and on selective loss of the TGF ??induced antiproliferative pathway. Tumor cells that have selectively lost their growth inhibitory responsiveness to TGF ??but retain an otherwise functional TGF ??signaling pathway may exhibit en hanced migration and invasive behavior in response to TGF ??stimulation.
TGF ??signaling also has been shown to induce an epithelial to mesenchymal transi tion process in tumor cells. EMT leads to en hanced migration and invasiveness. Recently, loss of ELF, a TGF ??adaptor and signaling molecule, in the liver leads to cancer formation by deregulated hepatocyte proliferation and stimulation of angio genesis. More recently, it was reported that STAT3 Oct4 positive HCC cells, which have dys functional TGF ??signaling, are likely cancer progen itor cells that have the potential to give rise to HCC. Notch pathway The Notch signaling pathway plays an im portant role in stem cell self renewal and differentia tion. However, other signaling pathways in fluence whether Notch functions as a tumor sup pressor or oncogene in a particular tissue.
Notch signaling is activated through four receptors that can interact in a redundant manner with five ligands of the Delta Jagged family. Ligand binding triggers a ??sevretase dependent proteolytic cleavage of Notch receptor and the release of Notch intracellular domain to the nucleus , which in turn displaces the co receptors associated with CSL transcription factors. Activating transcription factors are then re cruited and expression of target genes such as Hairy and Enhancer of Split and Deltex1 is induced. Notch signaling plays a well defined role in liver embryogenesis and bile duct formation. In addition, Notch fam