Apoptosis is normally considered a barrier for carcinogenesis because of its roles in getting rid of unwanted or damaged cells. However recent discoveries in our laboratory suggest that we need to re-examine the roles of apoptosis, especially those of apoptotic caspases, in carcinogenesis. In this project, we will examine the hypothesis that non-lethal caspase 3 or 7 activation induces genomic instability to facilitate radiation and other stress-induced carcinogenesis. Our hypothesis is a bold one that goes against the current paradigm. It will have wide-ranging implications since many endogenous and external stimuli could activate apoptotic caspases. Examples of such stimuli include exposure to ionizing radiation, UV, chemicals, and oncogene expression (e.g., myc). A facilitative role for caspases in carcinogenesis would provide exciting new insights into how those diverse environmental insults cause cancer. We will use a variety of in vitro and in vivo models, in combination with state-of-the-art molecular technologies, to examine the roles of caspases 3&7 in radiation- and other stress-induced genetic instability and carcinogenesis. We expect our studies to provide a comprehensive evaluation of the roles of caspases 3&7 in promoting carcinogenesis through inducing genetic instability. Upon completion of the project, we hope we can gain significant insights into the roles of apoptotic caspases in carcinogenesis. Such insights may provide novel targets for future cancer prevention strategies.
In this project, we propose to examine a novel hypothesis that caspases 3&7 promote genetic instability to facilitate radiation-, chemical-, and oncogene-induced carcinogenesis. Understanding such a mechanism will lead to better prevention strategies for cancer. Therefore, our study is highly relevant to public health.
|Liu, Xinjian; Zhou, Min; Mei, Ling et al. (2016) Key roles of necroptotic factors in promoting tumor growth. Oncotarget 7:22219-33|
|Li, Fang; Liu, Xinjian; Sampson, John H et al. (2016) Rapid Reprogramming of Primary Human Astrocytes into Potent Tumor-Initiating Cells with Defined Genetic Factors. Cancer Res 76:5143-50|
|Liu, Xinjian; He, Yujun; Li, Fang et al. (2015) Caspase-3 promotes genetic instability and carcinogenesis. Mol Cell 58:284-96|
|Liu, XinJian; Huang, Qian; Li, Fang et al. (2014) Enhancing the efficiency of direct reprogramming of human primary fibroblasts into dopaminergic neuron-like cells through p53 suppression. Sci China Life Sci 57:867-75|