title: EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN.
abstract: The epithelial-mesenchymal transition (EMT) is crucial to cancer progression and metastasis. Although multiple cellular miRNAs have been identified to regulate the EMT and metastasis in cancers, the role of viral miRNAs in cancer progression remains largely unknown. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy typically characterized by its early metastasis. In the present study, we have discovered the involvement of a viral miRNA, EBV-miR-BART7-3p, in the EMT and metastasis of NPC cells. Initially, we observed that EBV-miR-BART7-3p was highly expressed in NPC and positively correlated with lymph node metastasis and clinical stage of NPC. Subsequently, we demonstrated that EBV-miR-BART7-3p enhanced cell migration/invasion in vitro, cancer metastasis in vivo, and particularly the EMT characterized by loss of epithelial markers and gain of mesenchymal features in NPC cells. Furthermore, mechanistic studies disclosed that EBV-miR-BART7-3p targeted a major human tumor suppressor PTEN, modulating PI3K/Akt/GSK-3β signaling and eventually leading to the high expression and nuclear accumulation of Snail and β-catenin, which favor EMT. Knockdown of PTEN could phenocopy the effect of EBV-miR-BART7-3p, whereas re-expression of PTEN resulted in a phenotypic reversion. Moreover, these findings were supported by an observation of an EBV-positive cell model in which silencing of endogenous EBV-miR-BART7-3p partially attenuated cell migration/invasion and altered EMT protein expression pattern via reverting PI3K/Akt, Snail and β-catenin expression. Thus, this study suggests a novel mechanism by which EBV-miR-BART7-3p modulates the EMT and metastasis of NPC cells, and a clinical implication of EBV-miR-BART7-3p as a potential biomarker or therapeutic target.
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: L-M
authors.initials: LM
authors.lastname: Cai
authors.affiliation: 1] Cancer Research Institute, Southern Medical University, Guangzhou, China [2] Department of Laboratory Medicine, the Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: X-M
authors.initials: XM
authors.lastname: Lyu
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: W-R
authors.initials: WR
authors.lastname: Luo
authors.affiliation: Department of ENT, 463 Hospital of the Chinese PLA, Shenyang, China.
authors.forename: X-F
authors.initials: XF
authors.lastname: Cui
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Y-F
authors.initials: YF
authors.lastname: Ye
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: C-C
authors.initials: CC
authors.lastname: Yuan
authors.affiliation: School of Chinese Traditional Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Q-X
authors.initials: QX
authors.lastname: Peng
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: D-H
authors.initials: DH
authors.lastname: Wu
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou, China.
authors.forename: T-F
authors.initials: TF
authors.lastname: Liu
authors.affiliation: Infectious Diseases and Immunogenetics Section, DTM, Clinical Center, the National Institutes of Health, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.affiliation: Infectious Diseases and Immunogenetics Section, DTM, Clinical Center, the National Institutes of Health, Bethesda, MD, USA.
authors.forename: F-M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: K-T
authors.initials: KT
authors.lastname: Yao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Fang
authors.affiliation: School of Chinese Traditional Medicine, Southern Medical University, Guangzhou, China.
authors.forename: H-B
authors.initials: HB
authors.lastname: Cai
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
mesh_terms: D002277:Carcinoma; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D012334:RNA, Neoplasm; D012367:RNA, Viral; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human