c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma

// Zhi-Gang Liu 1, * , Guanmin Jiang 2, * , Jiao Tang 1, * , Hui Wang 1, * , Guokai Feng 3 , Furong Chen 3 , Ziwei Tu 3 , Guiyun Liu 1 , Yu Zhao 1 , Ming-Jing Peng 4 , Zheng-Wen He 5 , Xiao-Yan Chen 6 , Holly Lindsay 7 , Yun-Fei Xia 3 , Xiao-Nan Li 7 1 Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China 2 Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China 3 State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China 4 Translational Medicine Center, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China 5 Department of Neurosurgery, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China 6 Department of Pathology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China 7 Laboratory of Molecular Neuro-Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston TX, 77030, USA * These authors have contributed equally to this work Correspondence to: Zhi-Gang Liu, email: zhigangliu1983@hotmail.com Keywords: malignant glioma, radioresistance, c-Fos , prognosis Received: January 06, 2016 Accepted: August 22, 2016 Published: September 01, 2016 ABSTRACT c-Fos is a major component of activator protein (AP)-1 complex. It has been implicated in cell differentiation, proliferation, angiogenesis, invasion, and metastasis. To investigate the role of c-Fos in glioma radiosensitivity and to understand the underlying molecular mechanisms, we downregulated c-Fos gene expression by lentivirus-mediated shRNA in glioma cell lines and subsequently analyzed the radiosensitivity, DNA damage repair capacity, and cell cycle distribution. Finally, we explored its prognostic value in 41 malignant glioma patients by immunohistochemistry. Our results showed that silencing c-Fos sensitized glioma cells to radiation by increasing radiation-induced DNA double strand breaks (DSBs), disturbing the DNA damage repair process, promoting G2/M cell cycle arrest, and enhancing apoptosis. c-Fos protein overexpression correlated with poor prognosis in malignant glioma patients treated with standard therapy. Our findings provide new insights into the mechanism of radioresistance in malignant glioma and identify c-Fos as a potentially novel therapeutic target for malignant glioma patients.