miR-504 mediated down-regulation of nuclear respiratory factor 1 leads to radio-resistance in nasopharyngeal carcinoma
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Luqing Zhao1,2,3,4, Min Tang1,2,3,4, Zheyu Hu1,2,3,4, Bin Yan1,2,3,4, Weiwei Pi5,6, Zhi Li5, Jing Zhang6, Liqin Zhang8, Wuzhong Jiang6, Guo Li7, Yuanzheng Qiu7, Fang Hu9, Feng Liu9, Jingchen Lu1,6, Xue Chen1,2,3,4, Lanbo Xiao1,2,3,4, Zhijie Xu1,2,3,4, Yongguang Tao1,2,3,4, Lifang Yang1,2,3,4, Ann M. Bode10, Zigang Dong10, Jian Zhou11, Jia Fan11, Lunquan Sun4,5 and Ya Cao1,2,3,4
1 Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China
2 Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China
3 Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
4 Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China
5 Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
6 Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
7 Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
8 Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
9 Metabolism Endocrinology Research Institute, The Second Xiangya Hospital, Central South University, Changsha, China
10 The Hormel Institute, University of Minnesota, Austin, MN, USA
11 Department of Live Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
Ya Cao, email:
Lunquan Sun, email:
Keywords: miR-504; radio-resistance; nuclear respiratory factor 1 (NRF1); biomarker; nasopharyngeal carcinoma (NPC)
Received: December 30, 2014 Accepted: April 20, 2015 Published: May 14, 2015
microRNAs (miRNAs) are involved in the various processes of DNA damage repair and play crucial roles in regulating response of tumors to radiation therapy. Here, we used nasopharyngeal carcinoma (NPC) radio-resistant cell lines as models and found that the expression of miR-504 was significantly up-regulated. In contrast, the expression of nuclear respiratory factor 1 (NRF1) and other mitochondrial metabolism factors, including mitochondrial transcription factor A (TFAM) and oxidative phosphorylation (OXPHOS) complex III were down-regulated in these cell lines. At the same time, the Seahorse cell mitochondrial stress test results indicated that the mitochondrial respiratory capacity was impaired in NPC radio-resistant cell lines and in a miR-504 over-expressing cell line. We also conducted dual luciferase reporter assays and verified that miR-504 could directly target NRF1. Additionally, miR-504 could down-regulate the expression of TFAM and OXPHOS complexes I, III, and IV and impaired the mitochondrial respiratory function of NPC cells. Furthermore, serum from NPC patients showed that miR-504 was up-regulated during different weeks of radiotherapy and correlated with tumor, lymph nodes and metastasis (TNM) stages and total tumor volume. The radio-therapeutic effect at three months after radiotherapy was evaluated. Results indicated that patients with high expression of miR-504 exhibited a relatively lower therapeutic effect ratio of complete response (CR), but a higher ratio of partial response (PR), compared to patients with low expression of miR-504. Taken together, these results demonstrated that miR-504 affected the radio-resistance of NPC by down-regulating the expression of NRF1 and disturbing mitochondrial respiratory function. Thus, miR-504 might become a promising biomarker of NPC radio-resistance and targeting miR-504 might improve tumor radiation response.
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