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miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway.

Authors
  • Tang, ZiBo1
  • Chen, WeiFeng1
  • Xu, Yan1
  • Lin, Xian1
  • Liu, Xiong2
  • Li, YongHao1
  • Liu, YiYi1
  • Luo, ZhiJian1
  • Liu, Zhen3
  • Fang, WeiYi1
  • Zhao, MengYang1, 4
  • 1 Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315 Guangzhou, China. , (China)
  • 2 Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China. , (China)
  • 3 Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, 511436 Guangzhou, China. , (China)
  • 4 Department of Oncology, The People's Hospital of Zhengzhou University, 450003 Zhengzhou, China. , (China)
Type
Published Article
Journal
Molecular Therapy — Nucleic Acids
Publisher
Elsevier
Publication Date
Dec 04, 2020
Volume
22
Pages
557–571
Identifiers
DOI: 10.1016/j.omtn.2020.09.021
PMID: 33230457
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia. In a previous study, Epstein-Barr virus (EBV)-miR-BART22 induces tumor metastasis and stemness and is significantly involved in NPC progression. In the present study, we observed that miR-4721 is induced by EBV-miR-BART22 through phosphatidylinositol 3-kinase (PI3K)/AKT/c-JUN/Sp1 signaling to promote its transcription. In a subsequent study, we observed that miR-4721 serves as a potential oncogenic factor promoting NPC cell cycle progression and cell proliferation in vitro and in vivo. Mechanism analysis indicated that miR-4721 directly targetes GSK3β and reduces its expression, which therefore elevates β-catenin intra-nuclear aggregation and activates its downstream cell cycle factors, including CCND1 and c-MYC. In clinical samples, miR-4721 and GSK3β are respectively observed to be upregulated and downregulated in NPC progression. Elevated expression of miR-4721 is positively associated with clinical progression and poor prognosis. Our study first demonstrated that miR-4721 as an oncogene is induced by EBV-miR-BART22 via modulating PI3K/AKT/c-JUN/Sp1 signaling to target GSK3β, which thus activates the WNT/β-catenin-stimulated cell cycle signal and enhances the tumorigenic capacity in NPC. miR-4721 may be a potential biomarker or therapeutic target in NPC treatment in the future. © 2020 The Authors.

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