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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00939

EBV-miR-BART7-3p imposes stemness in nasopharyngeal carcinoma cells by suppressing SMAD7

Longmei Cai1, Yufei Long1,  Tuotuo Chong1,  Chi M. Tsang2, Xiaohan Zhou3, Yanling Lin3, Yuxiang /chen1, Jianguo Wang1,  Tengteng Ding1,  Xiaoming Lyu1,  William C. Cho4* and  Xin Li1*
  • 1Shenzhen Hospital, Southern Medical University, China
  • 2Li Ka Shing Faculty of Medicine, University of Hong Kong, China
  • 3Nanfang Hospital, Southern Medical University, China
  • 4Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong

Cancer stem-like cells, possessing "stemness" properties, play crucial roles in progression, metastasis, and drug resistance in various cancers. Viral microRNAs (such as EBV-miR-BART7-3p), as exogenous regulators, have been discovered to regulate malignant progression of nasopharyngeal carcinoma (NPC) before, suggesting a possible role of viral microRNAs in imposing stemness. In this study, we found that EBV-miR-BART7-3p indeed induce stemness of NPC cells. We firstly observed that EBV-miR-BART7-3p increased the percentage of side population cells, the development of tumor spheres, and the expression level of stemness markers in vitro. This viral microRNA also enhanced stem-like or caner-initiating properties of NPC cells in vivo. Secondly, we identified SMAD7 as a novel target gene of EBV-miR-BART7-3p in addition to PTEN gene we previously reported; this viral microRNA suppressed SMAD7, led to activation of TGF-β signaling, and eventually enhanced the stemness of NPC cells. Silencing of SMAD7 resembled the effects generated by EBV-miR-BART7-3p in NPC cells. After reconstitution of SMAD7, EBV-miR-BART7-3p-expressing cells underwent a phenotypic reversion. EBV-positive NPC cells were used to enable experimental validation. Finally, we further discovered that EBV-miR-BART7-3p increased chemo-resistance of NPC in vitro and in vivo, supporting that EBV-miR-BART7-3 resulted in increased stemness of NPC cells and lead to higher drug resistance and cancer recurrence. Overall, this study displays a novel mechanism underlying viral microRNA-associated stemness of NPC cells. This viral microRNA and its associated cellular genes may be potential therapeutic targets for restraining chemo-resistance and cancer recurrence of NPC.

Keywords: EBV-miR-BART7-3p, microRNA, nasopharyngeal carcinoma, SMAD7, Stemness

Received: 02 Apr 2019; Accepted: 05 Sep 2019.

Copyright: © 2019 Cai, Long, Chong, Tsang, Zhou, Lin, /chen, Wang, Ding, Lyu, Cho and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. William C. Cho, Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, williamcscho@gmail.com
Prof. Xin Li, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong Province, China, xinli268@gmail.com