title: Epstein-Barr virus-encoded latent membrane protein 2A promotes the epithelial-mesenchymal transition in nasopharyngeal carcinoma via metastatic tumor antigen 1 and mechanistic target of rapamycin signaling induction.
abstract: Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) promotes the epithelial-mesenchymal transition (EMT) of nasopharyngeal carcinoma (NPC), thereby increasing tumor invasion. Recently, the dysregulation of metastatic tumor antigen 1 (MTA1) was found to enhance tumor metastasis in a variety of cancers. A molecular connection between these two proteins has been proposed but not firmly established. In this study, we reported the overexpression of MTA1 in 29/60 (48.3%) NPC patients, and the overexpression of MTA1 significantly correlated with tumor metastasis. The overexpression of MTA1 promoted EMT via the Wnt1 pathway and β-catenin activation. We demonstrated that LMP2A reinforces the expression of MTA1 via the mechanistic target of rapamycin (mTOR) pathway to promote EMT in NPC. Furthermore, by knocking down 4EBP1 in combination with the new mTOR inhibitor INK-128 treatment, we discovered that LMP2A expression activates the 4EBP1-eIF4E axis and increases the expression of MTA1 at the translational level partially independent of c-myc. These findings provided novel insights into the correlation between the LMP2A and MTA1 proteins and reveal a novel function of the 4EBP1-eIF4E axis in EMT of nasopharyngeal carcinoma. Importance: Prevention of the recurrence and metastasis of NPC is critical to achieving a successful NPC treatment. As we all know, EMT has a vital role in metastasis of malignancies. LMP2A, an oncoprotein of Epstein-Barr virus, a well-known NPC activator, induces EMT and has been proved to exert a promoting effect in tumor metastasis. Our study demonstrated that LMP2A could induce EMT by activating MTA1 at the translational level via activating mTOR signaling and the 4EBP1-eIF4E axis. Taken together, our findings bridge the gap between the NPC-specific cell surface molecule and the final phenotype of the NPC cells. Additionally, our findings indicate that LMP2A and mTOR will serve as targets for NPC therapy in the future.
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wan
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Tang
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China chenyun@njmu.edu.cn sunbc@njmu.edu.cn.
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, China chenyun@njmu.edu.cn sunbc@njmu.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D012097:Repressor Proteins / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D015534:Trans-Activators; D014763:Viral Matrix Proteins / Q000502:physiology*
chemical_list: D017931:DNA Primers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D014763:Viral Matrix Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D006655:Histone Deacetylases
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