Increased liver carcinogenesis, and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice
Dkk2, a secreted antagonist of the Wnt/βcatenin signaling pathway was demonstrated to be silenced in diverse cancers. However, an in depth analysis of its biological function in (liver) cancer was not yet performed. This is particularly important since recent data investigating Dkk family member function have also suggested Wnt independent functions in carcinogenesis.
We therefore analyzed the effects a Dkk2 Knock out on liver morphology and liver cancer development after DEN/Phenobarbital induction. In Dkk2 –/– Knock out mice, Dkk2 deleted animals showed moderate to focally stronger variation of hepatocyte size with special regard to variable nuclear size and chromatine density. Nodule formation was present with local loss of trabecular architecture and more only histologically detectable dysplastic foci were counted. Furthermore, after 9 months Dkk2 –/– mice demonstrated an enhanced growth of liver cancer compared to wildtype mice.
By means of advanced microarray analysis we characterized a large differentially expressed genetic network involving Wnt/β-Catenin signalling but also linkage to multiple other established networks way beyond Wnt/β-Catenin signalling. Furthermore, we demonstrated a significant deregulation of stem cell markers which was complemented significantly enhanced colony forming properties.
Finally, we demonstrated that the Dkk2 –/– signature could be translated into human and was strongly correlated to tumor grading and significantly associated with patients survival. The later were further confirmed in a second independent data set of 199 patients suffering from HCC.
In conclusion we demonstrated that Dkk2 deletion resulted in a change of liver morphology and supports the development of liver cancer. The genetic changes include networks way beyond Wnt/β-Catenin and were highly relevant for prognosis in HCC patients. These data were independently validated.