Apicidin-resistant HA22T Hepatocellular Carcinoma Cells Extraordinarily Activate the Metastatic and EMT Effects Individually via IGF-IR/PI3K/Akt and Ikkαβ/NF-κB Signaling Pathways

• Main Authors: Li-Hao Cheng, 鄭力豪
• Other Authors: Chih-Yang Huang
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/19628793895204417980

碩士 === 中國醫藥大學 === 基礎醫學研究所碩士班 === 99 === Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Chemoresistance is the major problem affecting HCC therapy, the solution of HCC Chemoresistant is the most important issue today. Our previous research indicated that β-catenin play a key role in metastasis in HA22T Hepatocellular cell line and HCC patients. Apicidin is a novel HDAC inhibitor derived from a fungal metabolite, and it’s treatment resistant in HCC remains to be elucidated. To establish a stable liver cancer cell lines chronically resistant to apicidin, HA22T cells were exposed to gradually increasing concentrations of apicidin. We observed that Apicidin-resistant (AR) HA22T cells were highly increased in β-catenin nuclear accumulation and significantly decreased in GSK-3-β protein level than HA22T cells, results also showed that AR cells abundantly increased in Tbx3, a downstream target of the Wnt pathway which implicated in liver tumorigenesis metastasis. In addition, the epithelial-mesenchymal transition (EMT) determining factor, matrix metalloproteinase (MMP)-2 was also highly up-regulated in AR cells. Moreover, we identified the extraordinarily up-regulation of MMP-2 and Wnt signaling pathway, individually via IGF-IR/PI3K/Akt and Ikkαβ/NF-κB pathway. Therefore, our results suggest that AR cells highly potentiate the aggressive behavior of EMT and metastasis effect, and further suggest that β-catenin and MMP-2 gene knockdown or nature herbal extraction candidates might overcome apicidin drug resistance. Our finding might lead to develop the novel therapeutic strategies, and improve the overall survival rate of Chemoresistant HCC patients.