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Fig. 2 | Journal of Ovarian Research

Fig. 2

From: Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis

Fig. 2

Proposed mechanisms of Wnt/β-catenin dysregulation in ovarian cancer. The Wnt/β-catenin pathway is regulated by many factors, whose aberrant expression leads to the hyperactivation of β-catenin in the EOC. Note that green arrows indicate proteins whose expression is upregulated in EOC, while red arrows indicate downregulation. DKK1 and SFRP2, which inhibit the dimerization of FZD and LRP5/6 and directly prevent FZD activation, respectively, are downregulated in EOC tumors. In contrast, Wnt ligands activate the pathway by forming a receptor complex with FZD and LRP5/6, while R-spondins bind LGRs and prevent the sequestration of the FZD. Both ligands and LGRs are overexpressed EOC. CCNY and CDK14 are also upregulated in EOC and have been suggested to work together to promote LRP5/6 phosphorylation and therefore activation. CCNG2, which is downregulated in EOC, decreases LPR6 and DVL levels. It may also interact with DACT1, also downregulated in EOC tumors, to promote DVL degradation. TNKS destabilizes AXIN to increase β-catenin activity and TNKS1 is known to be up-regulated in EOC. RAB14 inhibits the activity of GSK-3β and its upregulation contributes to higher β-catenin activity in EOC. FLIP1L, whose expression is negatively correlated with EOC progression, enhances GSK-3β activation in the destruction complex and is downregulated in EOC. This inhibition of the destruction complex results in the accumulation of β-catenin within the cytosol and its translocation into the nucleus. In addition, TG2, which is overexpressed in EOC, binds to integrin and fibronectin. This results in the recruitment of c-Src and disruption of E-cadherin/β-catenin complex on the membrane, which contributes to the accumulation of β-catenin within the cytoplasm. Finally, within the nucleus, higher expression of several co-activators of β-catenin/TCF, such as PYGO, JRK, and FOXM1, and lower expression of SOX7, which is known to inhibit the interaction between β-catenin and TCF, lead to the higher transcriptional activity of this complex

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