Research Papers:

Epstein-Barr virus stably confers an invasive phenotype to epithelial cells through reprogramming of the WNT pathway

Christine E. Birdwell, Kanchanjunga Prasai, Samantha Dykes, Yali Jia, Tawsha G.C. Munroe, Malgorzata Bienkowska-Haba and Rona S. Scott _

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Oncotarget. 2018; 9:10417-10435. https://doi.org/10.18632/oncotarget.23824

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Christine E. Birdwell1,2,4, Kanchanjunga Prasai1, Samantha Dykes1,2,3, Yali Jia1, Tawsha G.C. Munroe1, Malgorzata Bienkowska-Haba1,2 and Rona S. Scott1,2

1Department of Microbiology and Immunology, Louisiana State University Health Science Center-Shreveport, Shreveport, LA 71130, USA

2Feist-Weiller Cancer Center, Shreveport, LA 71130, USA

3Radiation Oncology Department, University of Florida, Gainesville, FL 32610, USA

4Current address: Department of Microbial Pathogenesis and Immunology, Texas A & M University, College Station, TX 77843, USA

Correspondence to:

Rona S. Scott, email: [email protected]

Keywords: Epstein-Barr virus; epigenetics; WNT; LEF1; invasion

Received: December 15, 2016     Accepted: December 18, 2017     Published: January 02, 2018


Epstein-Barr virus (EBV)-associated carcinomas, such as nasopharyngeal carcinoma (NPC), exhibit an undifferentiated and metastatic phenotype. To determine viral contributions involved in the invasive phenotype of EBV-associated carcinomas, EBV-infected human telomerase-immortalized normal oral keratinocytes (NOK) were investigated. EBV-infected NOK were previously shown to undergo epigenetic reprogramming involving CpG island hypermethylation and delayed responsiveness to differentiation. Here, we show that EBV-infected NOK acquired an invasive phenotype that was epigenetically retained after viral loss. The transcription factor lymphoid enhancer factor 1 (LEF1) and the secreted ligand WNT5A, expressed in NPC, were increased in EBV-infected NOK with sustained expression for more than 20 passages after viral loss. Increased LEF1 levels involved four LEF1 variants, and EBV-infected NOK showed a lack of responsiveness to β-catenin activation. Although forced expression of WNT5A and LEF1 enhanced the invasiveness of parental NOK, LEF1 knockdown reversed the invasive phenotype of EBV-infected NOK in the presence of WNT5A. Viral reprogramming of LEF1 and WNT5A was observed several passages after EBV infection, suggesting that LEF1 and WNT5A may provide a selective advantage to virally-infected cells. Our findings suggest that EBV epigenetically reprogrammed epithelial cells with features of basal, wound healing keratinocytes, with LEF1 contributing to the metastatic phenotype of EBV-associated carcinomas.

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