Hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1α/CXCR4 pathway in non-small cell lung carcinoma cells
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Qing Gu1,2,3,*, Yan He1,2,*, Jianfeng Ji4,*, Yifan Yao1,2, Wenhao Shen1,2, Jialin Luo3, Wei Zhu1,2, Han Cao1,2, Yangyang Geng1,2, Jing Xu1,2, Shuyu Zhang1,2, Jianping Cao1,2 and Wei-Qun Ding5
1 School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China
2 Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou, China
3 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
4 Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, China
5 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, United States
* These authors contributed equally to this work
Shuyu Zhang, email:
Jianping Cao, email:
Keywords: non-small cell lung cancer (NSCLC), ionizing radiation, reactive oxygen species (ROS), CXCR4, invasiveness
Received: November 22, 2014 Accepted: February 18, 2015 Published: March 12, 2015
Radiotherapy is an important procedure for the treatment of inoperable non-small cell lung cancer (NSCLC). However, recent evidence has shown that irradiation can promote the invasion and metastasis of several types of cancer, and the underlying mechanisms are not fully understood. This study aimed to investigate the molecular mechanism by which radiation enhances the invasiveness of NSCLC cells. We found that after irradiation, hypoxia-inducible factor 1α (HIF-1α) was increased and translocated into the nucleus, where it bound to the hypoxia response element (HRE) in the CXCR4 promoter and promoted the transcription of CXCR4. Furthermore, reactive oxygen species (ROS) also plays a role in the radiation-induced expression of CXCR4. Our results revealed that 2 Gy X-ray irradiation promoted the metastasis and invasiveness of H1299, A549 and H460 cells, which were significantly enhanced by SDF-1α treatment. Blocking the SDF-1α/CXCR4 interaction could suppress the radiation-induced invasiveness of NSCLC cells. The PI3K/pAkt and MAPK/pERK1/2 pathways were found to be involved in radiation-induced matrix metalloproteinase (MMP) expression. In vivo, irradiation promoted the colonization of H1299 cells in the liver and lung, which was mediated by CXCR4. Altogether, our findings have elucidated the underlying mechanisms of the irradiation-enhanced invasiveness of NSCLC cells.
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