Head and neck cancer is one of the top five most common forms of malignancy. One of main problems in head and neck cancer treatment is local regional control and frequent recurrence. In this grant application, we propose to examine a hypothesis that may significantly improve the radiotherapy of H&N cancer. The long-term objective of this project is to characterize the status of the so-called """"""""master switches"""""""": hypoxia-inducible factor (HIF) genes, during radiotherapy of head and neck cancer and to exploit such knowledge for potential therapeutic gain. The hypothesis of our project is that HIF-1&2 genes play key roles in determining head and neck (H&N) cancer responses to radiotherapy, and that inhibiting HIF-1&2 activities can enhance the efficacy of H&N cancer radiotherapy. Our project is based on previous studies indicating that hypoxia and both of the HIF-1&2 factors play important roles in determining prognosis of head and neck cancer radiotherapy. In addition, it is based on our new data that indicated HIF factors were activated by radiotherapy independent of hypoxia through the generation of intratumoral nitric oxide, which can stabilize the alpha subunits of the HIF genes. We will conduct experiments to systematically characterize radiation-induced HIF-1 and HIF-2 gene activation in preclinical head and neck cancer models by use of novel molecular imaging and transgenic mouse approaches. Specifically, we will examine the roles of specific nitric oxide synthase genes in radiation-induced HIF-1&2 activation (Specific aim 1). In addition, we will attempt to decipher the molecular mechanism through which nitric oxide mediates radiation-induced HIF-1&2 activation in head and neck cancer radiotherapy (Specific aim 2). Finally, we will evaluate the relative importance of these two factors in head and neck cancer survival after radiotherapy (Specific Aim 3). The proposed studies should provide important insights into the biological mechanisms of radiation-induced activation of the HIF genes and evaluate the efficacy for inhibiting these two factors during head and neck cancer radiotherapy.
This project studies the mechanism of the involvement of the HIF genes in radiotherapy treatment of head and neck cancer. It may provide new insights that allow for the development of new therapeutics that can enhance current head and neck cancer therapy.
|Feng, Xiao; Tian, Ling; Zhang, Zhengxiang et al. (2015) Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis. Oncotarget 6:32353-67|
|Liu, Xinjian; He, Yujun; Li, Fang et al. (2015) Caspase-3 promotes genetic instability and carcinogenesis. Mol Cell 58:284-96|
|Cheng, Jin; Tian, Ling; Ma, Jingjing et al. (2015) Dying tumor cells stimulate proliferation of living tumor cells via caspase-dependent protein kinase CÎ´ activation in pancreatic ductal adenocarcinoma. Mol Oncol 9:105-14|
|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|
|Liu, Chad; Li, Chuan-Yuan; Yuan, Fan (2014) Mathematical modeling of the Phoenix Rising pathway. PLoS Comput Biol 10:e1003461|
|Donato, Anne L; Huang, Qian; Liu, Xinjian et al. (2014) Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy. J Invest Dermatol 134:1686-92|
|Ma, Jingjing; Tian, Ling; Cheng, Jin et al. (2013) Sonic hedgehog signaling pathway supports cancer cell growth during cancer radiotherapy. PLoS One 8:e65032|
|Ng, Wooi-Loon; Huang, Qian; Liu, Xinjian et al. (2013) Molecular mechanisms involved in tumor repopulation after radiotherapy. Transl Cancer Res 2:442-448|
|Zimmerman, Mary A; Huang, Qian; Li, Fang et al. (2013) Cell death-stimulated cell proliferation: a tissue regeneration mechanism usurped by tumors during radiotherapy. Semin Radiat Oncol 23:288-95|
|Kon, Takashi; Zhang, Xiuwu; Huang, Qian et al. (2012) Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA. Transl Cancer Res 1:4-14|
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