肝癌是一種常見的肝臟疾病，在肝癌治療上面臨最主要的問題是化學治療藥物的阻抗，因此如何解決藥物阻抗則是目前肝癌治療上最重要的課題。在我們實驗室先前的研究顯示β-catenin在肝癌轉移扮演極關鍵的角色。Apicidin是由黴菌代謝產物所分離出的新穎組蛋白去乙醯酶抑制劑，在肝癌治療所產生的抗藥性機轉仍持續被研究中。我們首將HA22T細胞處理Apicidin使其產生慢性的藥物阻抗。我們進一步發現，Apicidin藥性阻抗之HA22T肝癌細胞更大量增加了β-catenin核內堆積的現象和抑制GSK3-β的表現量，且更大幅活化和腫瘤轉移高度相關的β-catenin下游基因Tbx3表現。此外上皮間質轉化關鍵蛋白基質金屬蛋白酵素2同樣的在Apicidin藥性阻抗之HA22T肝癌細胞中被大量活化。同時發現Apicidin藥性阻抗之肝癌細胞分別是藉由活化IGF-IR/PI3K/Akt 和Ikkαβ/NF-κB途徑使造成異常地正調控基質金屬蛋白酵素2和β-catenin，進而造成細胞更產生上皮間質轉化和轉移的惡性現象。總和以上結果，我們認為合併使用能專一抑制基質金屬蛋白酵素2和β-catenin的小干擾RNA(siRNA)或天然中草藥，應可開發成為新穎的治療技術，進而得以增加肝癌病患在化學療法過程中所產生藥物阻抗之存活率。
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.
