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Epstein-Barr virus encoded latent membrane protein 1 regulates mTOR signaling pathway genes which predict poor prognosis of nasopharyngeal carcinoma.

ABSTRACT: BACKGROUND: The oncoprotein Epstain-Barr Virus (EBV)-encoded latent membrane protein1 (LMP1) modulates the pathological effects of the NF-kappaB, AP-1 and JAK/STAT pathways in nasopharyngeal carcinoma (NPC). METHODS: Microarray analysis was performed on the NPC cell line HONE1 stably transfected with a LMP1-expression plasmid or an empty vector. Based on assigned pathways analyzed using the KEGG database, the mTOR signaling pathway was selected for verification by quantitative RT-PCR. Western blot, RNA interference and immunofluorescence were used to determine the relationship between LMP1 and mTOR signing pathway genes, and their clinical significance to NPC. RESULTS: Our studies revealed that overexpression of LMP1 upregulated the mTOR signaling pathway, possibly through phosphorylation of AKT/mTOR/P70S6K/4EBP1 in the NPC cell lines HONE1 and 6-10B. Knockdown of LMP1 reduced expression of p-mTOR and p-4EBP1 in EBV-positive NPC cell line C666-1. In addition, LMP1 expression closely correlated with expression of p-mTOR, p-P70S6K and p-4EBP1 in NPC tumors. Expression of p-P70S6K, p-4EBP1 and LMP1, but not p-mTOR, significantly correlated with overall survival of NPC patients. However, only LMP1 was an independent prognostic factor. CONCLUSIONS: These results suggest that the mTOR signaling pathway is regulated by LMP1 expression in NPC. LMP1 and the genes in the mTOR pathway such as p-P70S6K and p-4EBP1 may be potential prognostic biomarkers.

SUBMITTER: Chen J

PROVIDER: S-EPMC2861642 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Epstein-Barr virus encoded latent membrane protein 1 regulates mTOR signaling pathway genes which predict poor prognosis of nasopharyngeal carcinoma.

Chen Jing J Hu Chun-Fang CF Hou Jing-Hui JH Shao Qiong Q Yan Li-Xu LX Zhu Xiao-Feng XF Zeng Yi-Xin YX Shao Jian-Yong JY

Journal of translational medicine 20100326

<h4>Background</h4>The oncoprotein Epstain-Barr Virus (EBV)-encoded latent membrane protein1 (LMP1) modulates the pathological effects of the NF-kappaB, AP-1 and JAK/STAT pathways in nasopharyngeal carcinoma (NPC).<h4>Methods</h4>Microarray analysis was performed on the NPC cell line HONE1 stably transfected with a LMP1-expression plasmid or an empty vector. Based on assigned pathways analyzed using the KEGG database, the mTOR signaling pathway was selected for verification by quantitative RT-PC ...[more]

PMID: 20338061

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Project description:BACKGROUND:EBV-encoded latent membrane protein 1 (EBV-LMP1) is an important oncogenic protein for nasopharyngeal carcinoma (NPC) and has been shown to engage a plethora of signaling pathways. Correspondingly, an LMP1-targeted DNAzyme was found to inhibit the growth of NPC cells both in vivo and in vitro by suppressing cell proliferation and inducing apoptosis. However, it remains unknown whether an LMP1-targeted DNAzyme would affect the vasculature of NPC. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been applied in the clinical trials of anti-angiogenic drugs for more than ten years, and Ktrans has been recommended as a primary endpoint. Therefore, the objective of the current study was to use DCE-MRI to longitudinally study the effect of an EBV-LMP1-targeted DNAzyme on the vasculature of patients with NPC. METHODS:Twenty-four patients were randomly divided into two groups: a combined treatment group (radiotherapy?+?LMP1-targeted DNAzyme) and a radiotherapy alone group (radiotherapy?+?normal saline). DCE-MRI scans were conducted 1?~?2 days before radiotherapy (Pre-RT), during radiotherapy (RT 50 Gy), upon completion of radiotherapy (RT 70 Gy), and three months after radiotherapy (3 months post-RT). Parameters of vascular permeability and intra- and extravascular volumes were subsequently obtained (e.g., Ktrans, kep, ve) using nordicICE software. RESULTS:Both Ktrans and kep values for NPC tumor tissues decreased for both groups after treatment. Moreover, a statistically significant difference in Ktrans values at the pre-therapy and post-therapy timepoints emerged earlier for the combined treatment group (RT 50 Gy, P =0.045) compared to the radiotherapy alone group (3 months post-RT, P = 0.032). For the kep values, the downward trend observed for both the combined treatment group and the radiotherapy alone group were similar. In contrast, ve values for all of the tumor tissues increased following therapy. CONCLUSIONS:The EBV-LMP1-targeted DNAzyme that was tested was found to accelerate the decline of Ktrans values for patients with NPC. Correspondingly, the LMP1-targeted DNAzyme treatments were found to affect the angiogenesis and microvascular permeability of NPC. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01449942. Registered 6 October 2011.

Dataset Information

Epstein-Barr virus encoded latent membrane protein 1 regulates mTOR signaling pathway genes which predict poor prognosis of nasopharyngeal carcinoma.

Publications

Epstein-Barr virus encoded latent membrane protein 1 regulates mTOR signaling pathway genes which predict poor prognosis of nasopharyngeal carcinoma.

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