title: miR-504 mediated down-regulation of nuclear respiratory factor 1 leads to radio-resistance in nasopharyngeal carcinoma.
abstract: 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.
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zheyu
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Pi
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Wuzhong
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Metabolism Endocrinology Research Institute, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Hu
authors.affiliation: Metabolism Endocrinology Research Institute, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Jingchen
authors.initials: J
authors.lastname: Lu
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Lanbo
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Live Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Live Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.|Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Lunquan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.|Molecular Imaging Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002277:Carcinoma; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D009243:NAD / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D009367:Neoplasm Staging; D051266:Nuclear Respiratory Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C550379:MIRN504 microRNA, human; D035683:MicroRNAs; D051266:Nuclear Respiratory Factor 1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009243:NAD; D000255:Adenosine Triphosphate
keywords: biomarker; miR-504; nasopharyngeal carcinoma (NPC); nuclear respiratory factor 1 (NRF1); radio-resistance