The role of Pygo2 during intestinal tumor initiation and progression in vivo
by Suranand Babu Talla
Date of Examination:2016-05-10
Date of issue:2016-05-12
Advisor:Prof. Dr. Felix Brembeck
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Heidi Hahn
Referee:Prof. Dr. Ralf Dressel
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EnglishCanonical Wnt signaling pathway is an essential regulator of embryonic development as well homeostasis of adult tissues and stem cell proliferation. Familial or sporadic mutations of genes of Wnt signaling components are reported to aberrantly activate the pathway, which is frequently found in human cancers, including colon cancer. Pygopus, as a nuclear co-factor of ß-catenin, demonstrated to be indispensable for Wnt signaling in Drosophila. On the contrary, Pygopus homologues in mammalians have rather a context dependent role, and they are expressed differentially especially in human and mice. Pygopus2 in particular, is expressed more frequently including in human intestinal epithelium, where genetic mutations within Wnt signaling primarily initiate early intestinal hyperproliferation and induce colon cancer. Nonetheless, until now a specific role for Pygo2, as a co-factor of Wnt signaling, during intestinal tumorigenesis has not been studied. Our data confirmed, that conditional deletion of Pygo2 did not affect the Wnt target gene cascade in normal intestinal epithelium, supporting that Pygo2 is dispensable for Wnt-signaling in the normal intestine. In addition, we also found that Pygo2 is redundant for the epithelial regeneration following the intestinal inflammation. In contrast, we found that Pygo2 is required for the early intestinal hyperproliferation induced by stabilized ß-catenin since Pygo2 knockout blocked specific upregulated Wnt target genes thereby rescued the intestinal hyperproliferation in ß-catenin mutant mice. In contrast, Pygo2 deletion cannot rescue the hyperproliferation in APC mutants, which might be due to the deregulation of additional APC functions. Moreover, Pygo2 constitutive knockout reduced the colon tumors size and number in chemically induced cancer models and downregulated Wnt target gene expression in a subgroup of these tumors. Importantly, we found c-myc overexpressed in both conditional mutants, and chemically induced tumors. Pygo2 knockout completely downregulated c-myc only in ß-catenin mutants whereas it failed to act on c-myc similarly in APC mutants and chemically induced tumor models which might be the key player for promoting intestinal tumorigenesis in the context of hyperactivated Wnt signaling. Together, these data revealed an important role of Pygo2 during early intestinal hyperproliferation and during tumor progression. Thus, targeting Pygo2 in cancers with ß-catenin mutation can be an attractive therapeutic intervention to inhibit the tumor growth.
Keywords: Colon cancer, Pygo2, Wnt signaling, ß-catenin.