RETRACTED ARTICLE: Cadherin 6 is activated by Epstein–Barr virus LMP1 to mediate EMT and metastasis as an interplay node of multiple pathways in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy, which is notorious among head-and-neck cancers with its metastatic feature. Epstein–Barr virus (EBV) infection plays a fundamental role in NPC development with the mechanism is not well understood. Here we demonstrate that EBV oncoprotein LMP1 drives EMT and metastasis of NPC by reactivating the adhesion molecule, cadherin 6 (CDH6), which normally occurs in embryogenesis with unknown role in NPC. CDH6 was found to be upregulated in LMP1-positive NPC tissues, and was identified as a target of the epithelium-specific miR-203. LMP1-activated NF-κB transcriptionally repressed the miR-203 expression by binding to the promoter region of miR-203 gene. CDH6 activation in turn induced EMT and promoted metastasis in NPC. CDH6 depletion, NF-κB inhibitor and miR-203 overexpression were able to impair the EMT effects. The miR-203 downregulation in NPC tissues was strongly associated with metastasis clinically. The CDH6 activator, Runt-related transcription factor 2 (RUNX2), was also activated by EBV in the event. For both CDH6 and RUNX2 are components at TGF-β downstream, CDH6 became a node protein for the interplay of multiple signalings including NF-κB and TGF-β. Therefore, the switch-on of miR-203 was important for nasopharyngeal epithelial cells to maintain normal phenotype. This study demonstrates that EBV has evolved sophisticated strategies by driving epithelial cells to obtain malignant features, particularly in NPC metastasis, providing novel biomarkers for the therapy and prognosis of EBV-associated NPC.

Epstein–Barr Virus Infection of Oral Squamous Cells

“…In the present study, EBV infection induced mesenchymal phenotypes, migration, and invasion of infected cells (Figures 6 and 7). In other EBV-associated epithelial cancers, the activation of EMT was mediated by transcriptional regulators of EMT, such as ZEB1, SNAIL, and TWIST, which was followed by the induction of mesenchymal markers and the suppression of epithelial markers through the activation of cell signaling pathways, such as NF-κB, mTOR, Syk, and PI3K/Akt pathways [43][44][45][46][47][48][49][50][51]. Activation of transcriptional regulators of EMT was followed by down-regulation of epithelial markers and up-regulation of mesenchymal markers in SCC25 EBV cells.…”

Identification and Verification of the Molecular Mechanisms and Prognostic Values of the Cadherin Gene Family in Gastric Cancer

“…It was therefore suggested that CDH6 may be involved in the regulation of PSMA-related prostate cancer metastasis mechanisms [35]. While Goeppert et al found that CDH6 serves as a tumor suppressor gene in cholangiocarcinoma in that its expression is signi cantly lower in cholangiocarcinoma tumor tissue and that the prognosis of cholangiocarcinoma patients with low expression of CDH6 is poor [36], Zuo et al found that it is signi cantly up-regulated in nasopharyngeal carcinoma (NPC) tumor tissue and can promote NPC metastasis by inducing EMT [37]. Gugnoni et al found that CDH6 in papillary thyroid cancers (PTC) can be used as a pro-metastatic gene and serves as a biomarker in PTC cases with high invasive ability [38].…”

Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma

“…Furthermore, LMP1 could also downregulate the tumor suppressor miR-204 to enhance the activity of Cdc42, which mediates cellular invasive properties such as focal complex formation, integrin localization, and MMP expression [ 46 ]. A recent study also demonstrated that through the suppression of miR-203 in an NF-κB-dependent manner, LMP1 can induce activation of cadherin 6 (CDH6) to act as the synergic node of multiple pathways to promote EMT [ 47 ]. Runt-related transcription factor 2 (RUNX2) can also be upregulated by LMP1 in similar manner, and high levels of CDH6 and RUNX2 have been identified in NPC tissues from patients with bone metastasis [ 47 ].…”