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The MRVI1-AS1/ATF3 signaling loop sensitizes nasopharyngeal cancer cells to paclitaxel by regulating the Hippo–TAZ pathway

Oncogene volume 38, pages 6065–6081 (2019)Cite this article

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Abstract

Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo–TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo–TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.

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Funding

This work was supported by the National Natural Science Foundation of China (81874137), the Outstanding Youth Foundation of Hunan Province (2018JJ1047), the Huxiang Young Talent Project (2016RS3022), the Innovation-Driven Project of Central South University (2017CX012), the Fundamental Research Funds for the Central Universities of Central South University, Grant/Award Number: 2018zzts955, and the New Xiangya Talent Projects of the Third Xiangya Hospital of Central South University (20150201, JY201710).

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Authors and Affiliations

  1. Department of Oncology, Third Xiangya Hospital of Central South University, 410013, Changsha, People’s Republic of China

    Yuxing Zhu, Mengqing Xiao, Liang Xiang, Lian Gong, Yanni Ma & Ke Cao

  2. Department of Respiration, The Second People’s Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, 410000, People’s Republic of China

    Dong He

  3. Institute of Reproductive and Stem Cell Engineering, Central South University, 410083, Changsha, Hunan, People’s Republic of China

    Hao Bo

  4. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, People’s Republic of China

    Zexian Liu

  5. Department of Plastic Surgery, Third Xiangya Hospital, Central South University, 410013, Changsha, Hunan, People’s Republic of China

    Jianda Zhou & Yan Liu

  6. Department of Gastroenterology, Third Xiangya Hospital of Central South University, 410013, Changsha, People’s Republic of China

    Xiaoming Liu

  7. Cancer Research Institute and Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, 410078, Changsha, People’s Republic of China

    Yanhong Zhou, Ming Zhou & Wei Xiong

  8. School of Public Health, Central South University, 410078, Changsha, Hunan, People’s Republic of China

    Fei Yang

  9. Center for Medical Experiments, Third Xiangya Hospital, Central South University, 410013, Changsha, People’s Republic of China

    Xiaowei Xing

  10. Yan’an Affiliated Hospital of Kunming Medical University, 650051, Kunming, People’s Republic of China

    Ruhong Li

  11. Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, 410013, Changsha, Hunan, People’s Republic of China

    Wei Li

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  1. Yuxing Zhu
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Zhu, Y., He, D., Bo, H. et al. The MRVI1-AS1/ATF3 signaling loop sensitizes nasopharyngeal cancer cells to paclitaxel by regulating the Hippo–TAZ pathway. Oncogene 38, 6065–6081 (2019). https://doi.org/10.1038/s41388-019-0858-7

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