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学术报告

　　报告题目：AKT/mTOR signaling during liver cancer development

　　报告人：Xin Chen, Ph.D.

　　Associate Professor

　　Dept. of Bioengineering and Therapeutic Sciences

　　University of California, San Francisco

　　时间：2011年10月28日(星期五)上午9：30

　　地点：生化三层中厅

　　主持人：刘翠苓副教授

Abstract:

　　Hepatocellular carcinoma (HCC), commonly known as liver cancer, is one of leading causes of cancer-related death world-wide. Coordinated activation of Ras/MAPK and AKT/mTOR pathways is frequently observed in human HCC and is associated with poor prognosis. However, how AKT/mTOR signaling contributes to liver cancer pathogenesis, how it cooperates with Ras/MAPK signaling to promote tumor development and what are the key events downstream of AKT/mTOR remain unknown. In our lab, we overexpressed activated from of AKT in mouse liver, and we found that activation of AKT signaling led to increased lipogenesis, hepatocyte proliferation and eventually liver tumor formation in vivo. Co-expression of AKT and RasV12 resulted in a dramatic acceleration of liver tumor development when compared with mice overexpressing AKT alone. Mechanistic studies suggested that accelerated hepatocarcinogenesis driven by AKT/Ras resulted from a strong activation of mTORC1. Furthermore, elevated expression of FOXM1/SKP2 and c-Myc also contributed to rapid tumor growth in AKT/Ras mice, yet via mTORC1-independent mechanisms. To study the signalling events downstream of mTORC1, we treated AKT/Ras mice with Rapamycin which inhibits p-RSP6 without effecting 4EBP1-eIF4E pathway. Rapamycin treatment prevented AKT/Ras induced tumor development, yet the withdrawal of Rapamycin led to rapid re-growth of AKT/Ras tumor cells. Overexpression of 4EBP1A4, the dominant negative form of 4EBP1 which blocks eIF4E medicated CAP dependent translation also efficiently inhibited AKT/Ras tumor growth. Together our experiments suggest that both RPS6 and 4EBP1 pathways are critical mediators of mTORC1 activity, and blocking either one of these downstream pathways is sufficient to inhibit AKT induced liver tumor development in mice.