Apicidin-Resistant HA22T Hepatocellular Carcinoma Cells strongly activated the Wnt/β-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-beta activity by phosphorylation and this promoted beta-catenin nuclear localization. Our previous study indicated that beta-catenin mRNA level was significantly higher in tumor areas than in non-tumor ones, especially in late pathologic stage tumors. However, beta-catenin inhibition resulted in significantly suppressed migration and invasion ability of HA22T cells. Thus, Wnt/beta-catenin pathway over-activation might be involved in metastatic enhancement of apicidin-resistant HA22T cell metastasis. Apicidin-resistant (AR) HA22T cells showed higher beta-catenin nuclear accumulation and significantly decreased GSK-3-beta protein level, in relation to parental cells. Results also indicated that AR cells increased abundantly in Tbx3, a downstream target of Wnt/beta-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/beta-catenin pathway and induced, MMP-2 expression via IGF-IR/PI3K/Akt signaling further enhancing cell the metastatic effects.