Into the nucleus where it binds to the lymphoid enhancer factor

Into the nucleus where it binds to the lymphoid enhancer factor (LEF) or T-cell factor (TCF) transcriptional factors, displacing the transcriptional inhibitor Groucho, and in complex with LEF/TCF activates the expression of different genes which regulate cell proliferation and apoptosis (Figure 3). A role for Wnt/-Luminespib chemical information catenin signaling in HCC was discovered over a decade ago [106]. Activating mutations in the -catenin gene (CTNNB1) were found in different human HCC cell lines and in HCC clinical samples in around 20 -40 of all cases [106-112]. These mutations impair the GSK-3-mediated phosphorylation of the protein at serine and threonine residues in its N-terminus region. Intriguingly, HCC occurring in HCV patients showed a high incidence of -catenin gene mutations (upwww.impactjournals.com/oncotargetto 40 of cases) [109, 113], whereas in HCC occurring in HBV patients -catenin Necrostatin-1 biological activity activation is induced in a mutation-independent manner by the expression of HBx protein [114, 115]. However, in the absence of -catenin gene mutations, aberrant activation of -catenin has been identified in a significant subset of HCC patients with mutations in axin1/2 (5 ) [116]. The observation that expression of the wild-type AXIN1 gene by adenovirus mediated gene transfer induced apoptosis in HCC cells, which had accumulated -catenin as a consequence of either APC, CTNNB1 or AXIN1 gene mutation, highlights the fact that axin may be an effective therapeutic molecule for suppressing HCC growth [116]. Recently, since axin is the concentration-limiting component of the -catenin destruction complex, stabilization of axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2 with small molecule inhibitor XAV939 has been presented as a new avenue for targeted Wnt/-catenin pathway therapies [117]. Moreover, accumulation of -catenin in human HCC tumors containing the wild-type -catenin gene has been observed in the context of up-regulation of the FZD7 receptor, which has been found up-regulated in 90 of human HCC [118-120], suggesting that FZD7 gene expression is the most common abnormality observed in HCC and consequently activation of Wnt/ Frizzled-mediated signaling plays a key role in liver carcinogenesis. Accordingly, Nambotin et al. demonstrated that pharmacological inhibition of FZD7 displayed anticancerous properties against HCC in vitro (on a panel of human HCC cell lines) and in vivo (on the SV40 Ag transgenic mouse model of HCC) [121]. Therefore, these observations suggest that the Wnt/-catenin signal transduction pathway is much more commonly involved in the molecular pathogenesis of HCC than previously recognized. Although no clinical studies are available, a preclinical study in which -catenin suppression was achieved by antisense modalities has shown that -catenin is essential for the survival and growth of hepatoma cells, independently of mutations in the -catenin gene, and therefore this provides a proof of principle for the significance of the therapeutic inhibition of -catenin in HCC [122].HEDGEHOG PATHWAYThe Hedgehog (Hh) pathway is essential for embryonic development, tissue polarity and cell differentiation [123-125]. This pathway is critical in the early development of the liver and contributes to differentiation between hepatic and pancreatic tissue formation [126]. It remains inactive in healthy adult liver tissue, except during tissue regeneration and remodeling tissue repair, and Hh signaling may also play a role in prim.Into the nucleus where it binds to the lymphoid enhancer factor (LEF) or T-cell factor (TCF) transcriptional factors, displacing the transcriptional inhibitor Groucho, and in complex with LEF/TCF activates the expression of different genes which regulate cell proliferation and apoptosis (Figure 3). A role for Wnt/-catenin signaling in HCC was discovered over a decade ago [106]. Activating mutations in the -catenin gene (CTNNB1) were found in different human HCC cell lines and in HCC clinical samples in around 20 -40 of all cases [106-112]. These mutations impair the GSK-3-mediated phosphorylation of the protein at serine and threonine residues in its N-terminus region. Intriguingly, HCC occurring in HCV patients showed a high incidence of -catenin gene mutations (upwww.impactjournals.com/oncotargetto 40 of cases) [109, 113], whereas in HCC occurring in HBV patients -catenin activation is induced in a mutation-independent manner by the expression of HBx protein [114, 115]. However, in the absence of -catenin gene mutations, aberrant activation of -catenin has been identified in a significant subset of HCC patients with mutations in axin1/2 (5 ) [116]. The observation that expression of the wild-type AXIN1 gene by adenovirus mediated gene transfer induced apoptosis in HCC cells, which had accumulated -catenin as a consequence of either APC, CTNNB1 or AXIN1 gene mutation, highlights the fact that axin may be an effective therapeutic molecule for suppressing HCC growth [116]. Recently, since axin is the concentration-limiting component of the -catenin destruction complex, stabilization of axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2 with small molecule inhibitor XAV939 has been presented as a new avenue for targeted Wnt/-catenin pathway therapies [117]. Moreover, accumulation of -catenin in human HCC tumors containing the wild-type -catenin gene has been observed in the context of up-regulation of the FZD7 receptor, which has been found up-regulated in 90 of human HCC [118-120], suggesting that FZD7 gene expression is the most common abnormality observed in HCC and consequently activation of Wnt/ Frizzled-mediated signaling plays a key role in liver carcinogenesis. Accordingly, Nambotin et al. demonstrated that pharmacological inhibition of FZD7 displayed anticancerous properties against HCC in vitro (on a panel of human HCC cell lines) and in vivo (on the SV40 Ag transgenic mouse model of HCC) [121]. Therefore, these observations suggest that the Wnt/-catenin signal transduction pathway is much more commonly involved in the molecular pathogenesis of HCC than previously recognized. Although no clinical studies are available, a preclinical study in which -catenin suppression was achieved by antisense modalities has shown that -catenin is essential for the survival and growth of hepatoma cells, independently of mutations in the -catenin gene, and therefore this provides a proof of principle for the significance of the therapeutic inhibition of -catenin in HCC [122].HEDGEHOG PATHWAYThe Hedgehog (Hh) pathway is essential for embryonic development, tissue polarity and cell differentiation [123-125]. This pathway is critical in the early development of the liver and contributes to differentiation between hepatic and pancreatic tissue formation [126]. It remains inactive in healthy adult liver tissue, except during tissue regeneration and remodeling tissue repair, and Hh signaling may also play a role in prim.

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