Hsieh Cheng-Hong, Cheng Li-Hao, Hsu Hsi-Hsien, Ho Tsung-Jung, Tu Chuan-Chou, Lin Yueh-Min, Chen Ming-Cheng, Tsai Fuu-Jen, Hsieh You-Liang, Huang Chih-Yang
Department of Health and Nutritional Biotechnology, Asia University.
Biosci Biotechnol Biochem. 2013;77(12):2397-404. doi: 10.1271/bbb.130503. Epub 2013 Dec 7.
The IGF-IR/PI3K/Akt signaling pathway inhibited GSK3-β activity by phosphorylation and this promoted β-catenin nuclear localization. Our previous study indicated that β-catenin mRNA level was significantly higher in tumor areas than in non-tumor ones, especially in late pathologic stage tumors. However, β-catenin inhibition resulted in significantly suppressed migration and invasion ability of HA22T cells. Thus, Wnt/β-catenin pathway over-activation might be involved in metastatic enhancement of apicidin-resistant HA22T cell metastasis. Apicidin-resistant (AR) HA22T cells showed higher β-catenin nuclear accumulation and significantly decreased GSK-3-β protein level, in relation to parental cells. Results also indicated that AR cells increased abundantly in Tbx3, a downstream target of Wnt/β-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/β-catenin pathway and induced, MMP-2 expression via IGF-IR/PI3K/Akt signaling further enhancing cell the metastatic effects.
IGF-IR/PI3K/Akt信号通路通过磷酸化抑制GSK3-β活性，这促进了β-连环蛋白的核定位。我们之前的研究表明，β-连环蛋白mRNA水平在肿瘤区域显著高于非肿瘤区域，尤其是在病理晚期肿瘤中。然而，β-连环蛋白的抑制导致HA22T细胞的迁移和侵袭能力显著受到抑制。因此，Wnt/β-连环蛋白通路的过度激活可能参与了耐阿皮西丁的HA22T细胞转移的转移增强。与亲代细胞相比，耐阿皮西丁（AR）的HA22T细胞显示出更高的β-连环蛋白核积累和显著降低的GSK-3-β蛋白水平。结果还表明，AR细胞中Wnt/β-连环蛋白的下游靶点Tbx3大量增加，而Tbx3与肝癌有关。AR细胞还抑制了促进MMP-2激活的MEK/ERK/PEA3通路。但是，LY294002和AG1024完全逆转了耐阿皮西丁的作用。总之，耐阿皮西丁的HA22T细胞激活了Wnt/β-连环蛋白通路，并通过IGF-IR/PI3K/Akt信号诱导MMP-2表达，进一步增强了细胞的转移作用。
