Gankyrin sustains PI3K/GSK-3ß/ß-catenin signal activation and promotes colorectal cancer aggressiveness and progression.

ABSTRACT

High levels of angiogenesis, metastasis and chemoresistance are major clinical features of colorectal cancer (CRC), a lethal disease with a high incidence worldwide. Aberrant activation of Wnt/ß-catenin pathway contributes to CRC progression. However, little is known about regulatory mechanisms of the ß-catenin activity in cancer progression. Here we report that Gankyrin was markedly upregulated in primary tumor tissues from CRC patients and was associated with poor survival. Moreover, we demonstrated that overexpressing Gankyrin promoted, while knockdown of Gankyrin impaired, the aggressive phenotype of proliferation, angiogenesis, chemoresistance and metastasis of CRC cells both in vitro and in vivo. Importantly, we found a unique molecular mechanism of Gankyrin in CRC cells signaling transduction, that regulated the cross-talk between PI3K/Akt and Wnt/ß-catenin signaling pathways, sustaining PI3K/GSK-3ß/ß-catenin signal activation in CRC. Therefore, these findings not only reveal a mechanism that promotes aggressiveness and progression in CRC, but also provide insight into novel molecular targets for antitumor therapy in CRCs.