ACTIVATING TRANSCRIPTION FACTOR 4 INCREASE CHEMORESISTANCE OF HUMAN HEPATOCELLULAR CARCINOMA
Objectives: Activating Transcription Factor 4 (ATF4) , a member of the ATF/CREB transcription factor family, is overexpressed in various tumor tissues. Hepatocellular carcinoma (HCC), with high mortality, is the fifth most malignant tumor in worldwide and difficult to cure. Currently, the major treatment for HCC is hepatectomy and chemotherapy and HCC shows a higher resistance to chemotherapy. So to identify the molecule used for targeting therapies will greately benefite to clinical practice. The effects of ATF4 on drug resistance in HCC are still unknown, so we assume that ATF4 may be a potential therapeutic target in HCC treatment. We can use RNA interference both in vitro and in vivo and ATF4 overexpression technology to study the effect of ATF4 on the cisplatin resistance in HCC. Materials and Methods: Firstly, this experiment used immunohistochemistry to detect the expression of ATF4 in 67 HCC tissues and 10 normal samples from the tissue microarray. Secondly, we set up the overexpression and slience of ATF4 stable cell lines, and tested the cisplatin cytotoxicity and cisplatininduced apoptosis of these cell lines by WST-1 and flow cytometry .We further investigated the biosynthesis of glutathione in the ATF4 knockdown cells. Finally, we detected the role of ATF4 on chemoresistance to cisplatin in HCC xenograft transplantation models by using the TUNEL assay. Results: We found that ATF4 was overexpressed in about 50.7％ percent HCC tissues. Knockdown of ATF4 increased the cisplatin cytotoxicity in in Vitro and in Vivo HCC models, while overexpression of this molecule significantly decreased the sensitivity of HCC cell lines to cisplatin. hi addition, we found that the synthesis of glutathione reduced in knockdown of ATF4 HCC cells. Conclusions: We demonstrated that ATF4 can increase cisplatin resistance of human HCC, and it maybe a promising protein target for anti-HCC drug developing.
ATF4 hepatocellular carcinoma chemotherapy cisplatin
Zhuhong Zhang Na Li Dan Lv Rong Xiang Yaping Tian Chenghu Liu Jing Yin Chunyan Zhang Ning Liang Nan Bai Antao Chang Yanhua Liu Zongjin Li Xiaoyue Tan
Department of Immunology The school of Medicine, Nankai University, Tianjin, 300071, China Departmen Department of Immunology The school of Medicine, Nankai University, Tianjin, 300071, China Department of Clinical Biochemistry, Chinese PLA General Hospital, Beijing, 100853, China
国际会议
亚太地区国际肿瘤生物学和医学学术会议、全国肿瘤标志学术大会、第六届中国中青年肿瘤专家论坛
上海
英文
147-162
2011-10-13（万方平台首次上网日期，不代表论文的发表时间）