concentration. The Wnt Fzd G protein complex can also stimulate p38 kinase and activate phosphodiesterase 6, AZD-5438 AZD5438 which hydrolyzes cyclic GMP and results in the inactivation of protein kinase G and an increase in intracellular calcium. Wnt mediated increase in intracellular Ca2 activates protein kinase C and calmodulin dependent kinase 2. CamK??can activate calcineurin, and subse quently the NF AT family of calcineurin dependent transcription factors, as well as TAK1 NLK kinases. Signaling through the TAK NLK kinases are pro posed to inhibit canonical Wnt signaling. This path way stimulates the Jun NH2 terminal kinase, Ca2 CaMK??and PKC pathways. Both pathways interact with each other, and in some cases, non canonical signaling antagonizes the canonical pathway.
The Wnt receptor, FZD 7 is found to be overex pressed in up to 90 of HCCs. Twenty to 40 of HCCs bear abnormal cytoplasmic and nuclear ac cumulation of ??catenin. However, not all studies show a correlation between elevated nuclear ??catenin and expression of its transcriptional targets AC480 implying that the expression of these target genes is likely to be regulated by alternative signaling mecha nisms. While most of the proceeding muta tions have not been detected in allelotype analysis, it is salient to note that deletions in the AXIN1 locus have been described in HCC. Axin1 and ??catenin mutations have also been identified in ap proximately 25 of HCCs , while overexpression of the FZD 7 receptor and glycogen synthase kinase 3 inactivation can also lead to aberrant ??catenin pathway activation.
Elevated expression of Wnt and its downstream mediators was also reported in EpCAM liver CSCs. It has been demonstrated that murine hepatic stem progenitor cells transduced with mutant ??catenin acquired ex cessive self renewal capability and tumorigenicity in a similar fashion to BMI1. In addition, the Wnt ??catenin pathway is activated in both rodent oval cells and OV6 positive tumor cells, and it leads to HCC chemoresistance. These findings indicate that Wnt ??catenin signaling plays an important role in the maintainance of CSCs. Recently, the mechanisms leading to malignant transformation of stem progenitor cells were effec tively addressed in pediatric tumors.
Hepato blastoma is a malignant embryonal tumor of the liver, which differs from HCC by distinct morphological patterns reminiscent of hepatoblasts, the bipotent precursors of hepatocytes and cholangiocytes, and of their arrangement in the developing liver. Integrated molecular and genetic studies of hepatoblastoma dis closed two major molecular subclasses of tumors that relate early and late phases of prenatal liver devel opment. It has been suggested that hepatoblastoma might arise from impairment of the normal liver dif ferentiation program associated with excessive Wnt ??catenin signaling. In addition, the inter play of Wnt ??catenin and Myc signaling in imma ture tumors activates a distinct transcript