Gankyrin deficiency both in non-parenchymal cells and parenchymal cells, but not in parenchymal cells alone, reduced STAT3 activity, interleukin-6 production, and cancer stem cell marker expression, leading to attenuated tumorigenic potential in the diethylnitrosamine hepatocarcinogenesis model.
These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.
The finding of IL-1β/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis.
Our findings demonstrate that Gankyrin is aberrantly expressed beginning at the initiation stage and plays an important role in the initiation, promotion, and progression of hepatocarcinogenesis.
Moreover, elevated expression of gankyrin closely correlated with the expression of HCC stem/progenitor cell markers in DEN-triggered hepatocarcinogenesis and human HCCs.
Studies with chemical models of liver carcinogenesis and with human HCC have shown that the elevation of gankyrin is responsible for the elimination of these three proteins at early steps of carcinogenesis.
These results suggest that gankyrin plays an oncogenic role(s) mainly at the early stages of human hepatocarcinogenesis, and that IGFBP-5 inducible by gankyrin overexpression may be involved in it.