miR-504 mediated down-regulation of nuclear respiratory factor 1 leads to radio-resistance in nasopharyngeal carcinoma

Luqing Zhao, Min Tang, Zheyu Hu, Bin Yan, Weiwei Pi, Zhi Li, Jing Zhang, Liqin Zhang, Wuzhong Jiang, Guo Li, Yuanzheng Qiu, Fang Hu, Feng Liu, Jingchen Lu, Xue Chen, Lanbo Xiao, Zhijie Xu, Yongguang Tao, Lifang Yang, Ann M. BodeZigang Dong, Jian Zhou, Jia Fan, Lunquan Sun, Ya Cao

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15995-16018
Number of pages24
JournalOncotarget
Volume6
Issue number18
DOIs
StatePublished - 2015

Keywords

  • Biomarker
  • Nasopharyngeal carcinoma (NPC)
  • Nuclear respiratory factor 1 (NRF1)
  • Radio-resistance
  • miR-504

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