Discovery of drug resistant genes in hepatocellular carcinoma cells (HCCs)

• Main Authors: Tzu Ching Kuo, 郭子靖
• Other Authors: C. K. Chao
• Format: Others
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/s33q3y

博士 === 長庚大學 === 生物醫學研究所 === 100 === The development of hepatocellular carcinoma (HCC) in humans is associated with various alterations in oncogenic and tumor suppressor genes. To data, survival rate of HCC patients that accept clinical therapy is still very low in the world. The major reason is the high chemoresistance leading to no efficient therapeutic method for HCC patients. However, the molecular mechanism of tumorigenesis and chemoresistance of HCC is still unclear. In order to validate the correlation between gene expression and prognosis of HCC patients, we analyzed the gene expression profile of HCC patients with poor prognosis that is verified by using complementary DNA microarrays from National Cancer Institute/National Institutes of Health of America. Using gene expression profile to search genes overexpressed and correlated with poor prognosis that may be play a role in established chemoresistance of HCC. In addition, 80% HCC patients in the world who carried hepatitis B virus (HBV) genome and many previous studies have reported that HBx, a viral protein from HBV, increases chemoresistant ability of HCC. In this study, we found that hepatoma up-regulated protein (HURP) is overexpressed in HCC patients and at higher level in HCC patients with poor prognosis compared with HCC patients with well prognosis. Interesting, we observed that expression of HURP could be regulated by HBx in hepatoma cells and HBx-transgenic mice and involed in HBx-mediated chemoresistance of HCC. HURP has been identified as an oncogene and overexpression of HURP induces malignant transformation in normal cells. However, the oncogenic function of HURP is still unknown. Here, we observed that overexpressed HURP could promote protein degradation of tumor suppressor p53 and enhance proliferation and against DNA damage-induced apoptosis in this HURP-p53 manner. Finally, we also found that sorafenib, a tyrosin kinase inhibitor, could downregulate HURP to enhance the cytotoxity of microtubule-target drug, i.e. taxol. This combined treatment could increase chemosensitivity of HCC and reduced chemotherapeutic drug-induced side effects.