Apicidin-resistant HA22T hepatocellular carcinoma cells strongly activated the Wnt/ß-catenin signaling pathway and MMP-2 expression via the IGF-IR/PI3K/Akt signaling pathway enhancing cell metastatic effect.

The IGF-IR/PI3K/Akt signaling pathway inhibited GSK3-ß activity by phosphorylation and this promoted ß-catenin nuclear localization. Our previous study indicated that ß-catenin mRNA level was significantly higher in tumor areas than in non-tumor ones, especially in late pathologic stage tumors. However, ß-catenin inhibition resulted in significantly suppressed migration and invasion ability of HA22T cells. Thus, Wnt/ß-catenin pathway over-activation might be involved in metastatic enhancement of apicidin-resistant HA22T cell metastasis. Apicidin-resistant (AR) HA22T cells showed higher ß-catenin nuclear accumulation and significantly decreased GSK-3-ß protein level, in relation to parental cells. Results also indicated that AR cells increased abundantly in Tbx3, a downstream target of Wnt/ß-catenin that it is implicated in liver cancer. AR cells also inhibited the MEK/ERK/PEA3 pathway which promoted MMP-2 activation. But, apicidin-resistant effect was totally reversed by LY294002 and AG1024. In conclusion, Apicidin-R HA22T cells activated the Wnt/ß-catenin pathway and induced, MMP-2 expression via IGF-IR/PI3K/Akt signaling further enhancing cell the metastatic effects.