EBV-miR-BART10-3p facilitates epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma by targeting BTRC

Abstract

Epstein-Barr virus (EBV) infection is closely associated with tumorigenesis and development of nasopharyngeal carcinoma (NPC), but the underlying molecular mechanisms remain poorly understood. It has been recently reported that EBV encodes 44 mature miRNAs, some of which were found to promote tumor development by targeting virus-infected host genes or self-viral genes. However, few targets of EBV encoded-miRNAs that are related to NPC development have been identified to date. In this study, we revealed that in NPC cells, EBV-miR-BART10-3p directly targets BTRC gene that encodes βTrCP (beta-transducin repeat containing E3 ubiquitin protein ligase). We found that EBV-miR-BART10-3p expression in clinical samples from a cohort of 106 NPC patients negatively correlated with BTRC expression levels. Over-expression of EBV-miR-BART10-3p and down-regulation of BTRC were associated with poor prognosis in NPC patients. EBV-miR-BART10-3p promoted the invasion and migration cabilities of NPC cells through the targeting of BTRC and regulation of the expression of the downstream substrates β-catenin and Snail. As a result, EBV-miR-BART10-3p facilitated epithelial-mesenchymal transition of NPC. Our study presents an unreported mechanism underlying EBV infection in NPC carcinogenesis, and provides a potential novel biomarker for NPC diagnosis, treatment and prognosis.

Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers

“…Further experiments showed that the increase in cell motility and invasiveness by EBV miR-BART9 was indeed associated with several mesenchymal EMT properties, namely, E-cadherin downregulation, induction of β-catenin signaling, expression of vimentin and MMPs, and spindle-cell morphology [80]. Essentially the same properties reported for EBV miR-BART9 were found for viral miR-BART10-3p, which expression was directly associated with patient poor survival in a series of 106 NPCs [81]. …”

Overexpression long non-coding RNA LINC00673 is associated with poor prognosis and promotes invasion and metastasis in tongue squamous cell carcinoma

“…For gene knockdown, cells were seed in six-well plates to confluency and transfected siRNAs by using Lipofectamine RNAiMAX Reagent (Invitrogen) in OptiMEM medium (Invitrogen) [58–61]. Two sequences of LINC00673 targeting siRNAs were: 5′-CCAGTTGTC CTTGACTGCATGGTTT-3′; and 5′-AGGGAACCACAGGATTCCATGTGAT-3′.…”

Role of tumor microenvironment in tumorigenesis

“…Many assays have respectively demonstrated ECM components, including collagens 245-247, laminins 248, fibronectins 249, proteoglycans 250, and hyaluronans 251, 252 in a specific organization 225. In vitro, one three-dimensional (3D) model indicated that ECM heterogeneity is crucial for controlling collective cell invasive behaviors and determining metastasis efficiency 253-262. Because of the complexity of ECM heterogeneity in vivo, its influence on collective cell behavior has been described but not quantified 253.…”