Epstein-Barr Virus miR-BART17-5p Promotes Migration and Anchorage-Independent Growth by Targeting Kruppel-Like Factor 2 in Gastric Cancer

Abstract

Epstein-Barr virus (EBV) infects more than 90% of the global population and is associated with a variety of tumors including nasopharyngeal carcinoma, Hodgkin lymphoma, natural killer/T lymphoma, and gastric carcinoma. In EBV-associated gastric cancer (EBVaGC), highly expressed EBV BamHI A rightward transcripts (BART) miRNAs may contribute to tumorigenesis with limited viral antigens. Despite previous studies on the targets of BART miRNAs, the functions of all 44 BART miRNAs have not been fully clarified. Here, we used RNA sequencing data from the Cancer Genome Atlas to find genes with decreased expression in EBVaGC. Furthermore, we used AGS cells infected with EBV to determine whether expression was reduced by BART miRNA. We showed that the expression of Kruppel-like factor 2 (KLF2) is lower in AGS-EBV cells than in the AGS control. Using bioinformatics analysis, four BART miRNAs were selected to check whether they suppress KLF2 expression. We found that only miR-BART17-5p directly down-regulated KLF2 and promoted gastric carcinoma cell migration and anchorage-independent growth. Our data suggest that KLF2 functions as a tumor suppressor in EBVaGC and that miR-BART17-5p may be a valuable target for effective EBVaGC treatment.

EBV-Positive Gastric Cancer: Current Knowledge and Future Perspectives

“…For instance, miR-BART5 upregulates p53 with PUMA as the target, promoting the survival of host cells ( 71 , 72 ); miR-BART3-5p targets DICE1 tumor suppressor, and promotes the growth and transformation of cancer cells ( 73 ); miR-BART9 specifically inhibits E-cadherin to induce a mesenchymal-like phenotype ( 74 , 75 ); miR-BART9, -11, and -12 downregulates Bim expression ( 76 ); EBV-miR-BART4-5p has an antiapoptotic role that regulates Bid expression in EBV-associated gastric carcinoma ( 77 ); EBV-miR-BART20-5p regulates cell proliferation and apoptosis by targeting BAD ( 78 ); and miR-BART16 abrogates the production of IFN-stimulated genes in response to IFN-α stimulation and inhibits the antiproliferative effect of IFN-α in latently infected cells ( 79 ). Modulation of expression of LMP2A by newly identified EBV-encoded miRNAs, miR-BART22 ( 80 ) and miR-BART17-5p, promotes migration and anchorage-independent growth by targeting kruppel-like factor 2 in gastric cancer ( 81 , 82 ). EBV-miR-BART15-3p targets the anti-apoptotic TAX1BP1 and NLRP3 genes in cancer cells, thus increasing apoptosis ( Table 2 ) ( 84 – 86 ).…”

Epstein-Barr virus BART microRNAs in EBV- associated Hodgkin lymphoma and gastric cancer

“…miR-BART17-5p is expressed in gastric cancer tissue [59,60] and in EBV+ gastric cancer cell lines [60]. High miR-BART17-5p serum levels were found in NPC patients in association with progression and recurrence of the tumor [68][69][70].…”

“…In NPC, LMP1 is the main target of miR-BART17-5p [71]. However, since LMP1 expression is abrogated in EBV-positive gastric cancer, the main effect of miR-BART17-5p occurs on the transcription factor Kruppel-like factor 2 (KLF2) [59]. KLF2 negatively regulates energy metabolism of tumor cells and inflammation; thus, miRBART action on KLF2 positively favors gastric cancer cell migration and anchorage-independent growth.…”

“…miR-BART5-5p also targets TP53, and thus promotes cell survival [74]. Of interest, it also directly targets PIAS3, an inhibitor of the activated pSTAT3 protein [59]. pSTAT3 migrates to the nucleus where it induces the transcription of several genes in gastric cancer.…”

Special Issue: Epstein–Barr–Virus–Associated Cancers

“…This Special Issue assembles eleven papers, comprising seven research articles, two reviews, and two brief reports, which collectively provide novel information on the mechanisms of oncogenesis [ 2 , 3 , 4 , 5 , 6 ] and viral replication [ 7 , 8 , 9 , 10 ], as well as applications for diagnosis [ 11 , 12 ].…”