SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target.
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ABSTRACT:
SUBMITTER: Emanuel O
PROVIDER: S-EPMC8508244 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionThe role of podoplanin (PDPN) in nasopharyngeal carcinoma (NPC) is still unknown. The aims of this study were to investigate the expression and role of PDPN in NPC cells.Materials and methodsImmunofluorescence staining and functional tests were used to determine the effects of PDPN knockdown by siRNA in TW01 NPC cells. Microarray analysis was conducted to identify genes regulated by PDPN. The molecular mechanism of PDPN on NPC cells was further determined by Ingenuity Pathways Analysis (IPA).ResultsPDPN was expressed in most TW01 NPC cells. PDPN knockdown by siRNA decreased NPC cell proliferation, migration, and invasion. The microarray data showed 63 upregulated genes and 12 downregulated genes following PDPN knockdown. The top 5 most upregulated genes analyzed by IPA were IFI27, IFI44L, IFI6, OAS1, and TRIM22, and the most relevant pathway was the interferon signaling pathway.ConclusionsTo the best of our knowledge, this is the first report to show that knocking down PDPN leads to suppression of NPC cell proliferation, migration, and invasion. Our results suggest that PDPN may serve as a potential chemotherapeutic target for NPC treatment in the future.
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Project description:Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Project description:Sphingosine kinase 1 (SPHK1) has been shown to be involved in the progression of various types of human cancers. We previously demonstrated that SPHK1 is overexpressed and associated with clinical stage, locoregional recurrence, distant metastasis and poor prognosis in nasopharyngeal carcinoma (NPC). However, the biological roles involving SPHK1 and its potential usefulness as a therapeutic target in NPC remain unknown. In this study, Blocking SPHK1 using siRNA or FTY720 (a SPHK1 inhibitor) significantly reduced proliferation and migration and increased cell cycle arrest and apoptosis in NPC cells. FTY720 also decreased SPHK1 activity, and overexpressing SPHK1 abrogated the FTY720-induced effects on cell viability. In addition, FTY720 sensitized NPC cells to radiotherapy by inhibiting SPHK1 activity in vitro and in vivo. Furthermore, high SPHK1 expression was associated with increased Ki-67 and p-Akt and decreased caspase-3 expression in human NPC specimens. These data suggest that SPHK1 might be a potential therapeutic target for NPC.
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Project description:Nasopharyngeal carcinoma (NPC) is one of the Epstein-Barr virus (EBV)-associated malignancies. NPC is highly metastatic compared to other head and neck carcinomas, and evidence has shown that the metastatic features of NPC are involved in EBV infection. The prognosis of advanced cases, especially those with distant metastasis, is still poor despite advancements in molecular research and its application to clinical settings. Thus, further advancement in basic and clinical research that may lead to novel therapeutic modalities is needed. Farnesylation is a lipid modification in the C-terminus of proteins. It enables proteins to attach to the lipid bilayer structure of cellular membranes. Farnesylation was initially identified as a key process of membrane association and activation of the RAS oncoprotein. Farnesylation is thus expected to be an ideal therapeutic target in anti-RAS therapy. Additionally, more and more molecular evidence has been reported, showing that proteins other than RAS are also farnesylated and have significant roles in cancer progression. However, although several clinical trials have been conducted in cancers with high rates of ras gene mutation, such as pancreatic carcinomas, the results were less favorable than anticipated. In contrast, favorable outcomes were reported in the results of a phase II trial on head and neck carcinoma. In this review, we provide an overview of the molecular pathogenesis of NPC in terms of the process of farnesylation and discuss the potential of anti-farnesylation therapy in the treatment of NPC.
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Project description:Epstein-Barr virus (EBV) was the first oncogenic virus identified in humans. It is primarily associated with multiple lymphoid and epithelial cancers, including nasopharyngeal carcinoma (NPC). However, its association with ferroptosis and its role in cancer therapy resistance have not been fully elucidated. Here, we show that EBV infection reduces the sensitivity of NPC cells to ferroptosis by activating the p62-Keap1-NRF2 signaling pathway in conjunction with upregulation of SLC7A11 and GPX4 expression. Knockdown of endogenous GPX4 or blockade of GPX4 using a specific inhibitor enhanced the chemosensitivity of EBV-infected NPC cells. Functional studies revealed that GPX4 knockdown suppresses the proliferation and colony formation of NPC cells. Mechanistically, GPX4 interacts with the TAK1-TAB1/TAB3 complex, regulates TAK1 kinase activity, and further activates downstream MAPK-JNK and NFκB pathways. High GPX4 expression is correlated with poor clinical outcomes in patients with NPC and other cancer types. Taken together, our findings suggest that EBV infection has important effects on redox homeostasis, revealing a previously unappreciated role for GPX4 in tumor progression. This novel mechanism provides a potential new target for the treatment of EBV-related tumors.
| S-EPMC9346003 | biostudies-literature
Project description:Virus-associated malignancies are potential targets for immunotherapeutic vaccines aiming to stimulate T-cell responses against viral antigens expressed in tumor cells. Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma, a high-incidence tumor in southern China, expresses a limited set of EBV proteins, including the nuclear antigen EBNA1, an abundant source of HLA class II-restricted CD4(+) T-cell epitopes, and the latent membrane protein LMP2, a source of subdominant CD8(+) T-cell epitopes presented by HLA class I alleles common in the Chinese population. We used appropriately modified gene sequences from a Chinese EBV strain to generate a modified vaccinia virus Ankara recombinant, MVA-EL, expressing the CD4 epitope-rich C-terminal domain of EBNA1 fused to full-length LMP2. The endogenously expressed fusion protein EL is efficiently processed via the HLA class I pathway, and MVA-EL-infected dendritic cells selectively reactivate LMP2-specific CD8(+) memory T-cell responses from immune donors in vitro. Surprisingly, endogenously expressed EL also directly accesses the HLA class II presentation pathway and, unlike endogenously expressed EBNA1 itself, efficiently reactivates CD4(+) memory T-cell responses in vitro. This unscheduled access to the HLA class II pathway is coincident with EL-mediated redirection of the EBNA1 domain from its native nuclear location to dense cytoplasmic patches. Given its immunogenicity to both CD4(+) and CD8(+) T cells, MVA-EL has potential as a therapeutic vaccine in the context of nasopharyngeal carcinoma.
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Project description:Tumor metastasis is a complex phenomenon that is the culmination of effects of numerous cellular factors. We have shown that the Epstein-Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1), is capable of inducing a wide range of such factors in cell culture, expression of which is also elevated in the LMP1-expressing tumor, nasopharyngeal carcinoma (NPC), a highly invasive neoplasm. Recently, the membrane crosslinker protein, ezrin, has been implicated in tumor cell metastasis and malignant progression. In this study, we evaluated the possible role of LMP1 and ezrin in the pathophysiology of NPC. We show that C-terminal phosphorylation of ezrin is increased by the expression of LMP1 in nasopharyngeal (NP) cells through a protein kinase C (PKC) pathway. LMP1 enhances the organization of a ternary complex of CD44, ezrin and F-actin, which is a prerequisite for ezrin phosphorylation. In NPC tissues, the expression of phosphoezrin and LMP1 is directly correlated. Silencing of endogenously expressed ezrin suppresses LMP1-induced cell motility and invasiveness. Moreover, the inhibition of ezrin phosphorylation by PKC inhibitor suppresses migration and invasion of NP cells. These data show that the phosphorylation of ezrin and its recruitment to the cell membrane linked to F-actin and CD44 is a process required for LMP1-stimulated cell motility and invasion of NP cells.
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Project description:Epstein-Barr virus (EBV) was the first tumor virus in humans. Nasopharyngeal carcinoma (NPC) accounts for approximately 60% of the 200,000 new tumor cases caused by EBV infection worldwide each year. NPC has an insidious onset and is highly malignant, with more than 70% of patients having intermediate to advanced disease at the time of initial diagnosis, and is strongly implicated in epithelial cancers as well as malignant lymphoid and natural killer/T cell lymphomas. Over 90% of patients with confirmed undifferentiated NPC are infected with EBV. In recent decades, much progress has been made in understanding the molecular mechanisms of NPC and developing therapeutic approaches. Radiotherapy and chemotherapy are the main treatment options for NPC; however, they have a limited efficacy in patients with locally advanced or distant metastatic tumors. Tumor immunotherapy, including vaccination, adoptive cell therapy, and immune checkpoint blockade, represents a promising therapeutic approach for NPC. Significant breakthroughs have recently been made in the application of immunotherapy for patients with recurrent or metastatic NPC (RM-NPC), indicating a broad prospect for NPC immunotherapy. Here, we review important research findings regarding immunotherapy for NPC patients and provide insights for future research.
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Project description:Nasopharyngeal carcinoma (NPC) is a rare cancer of the nasopharyngeal mucosa with a specific geographic predisposition. NPC is often associated with Epstein-Barr Virus (EBV) infection and as a result contains many characteristic biomarkers. Treatment of locally-contained NPC is generally achieved through use of radiotherapy (RT), as part of a multimodality treatment regimen. Induction chemotherapy followed by concurrent RT and platinum-based chemotherapy regimen has emerged as the definitive treatment of choice for locoregionally-advanced NPC. Recently, immunotherapy is finding a role in the treatment of recurrent or metastatic NPC. Immune checkpoint blockade therapies targeted against the programmed death-1 (PD-1) receptor have demonstrated efficacy in early phase clinical trials, with ongoing phase III trials in effect. Biomarkers for treatment efficacy remain an ongoing area of investigation, with important prognostic implications on the horizon.
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Project description:BackgroundNonviral vectors are attractively used for gene therapy owing to their distinctive advantages. Our previous study has demonstrated that transfer of human IFN? gene into nasopharyngeal carcinoma (NPC) by using a novel nonviral vector, minicircle (mc), under the control of cytomegalovirus (CMV) promoter was effective to inhibit tumor growth. However, therapies based on CMV promoter cannot express the targeted genes in cancer tissues. Previous studies indicated that the development of human NPC was closely associated with Epstein-Barr virus (EBV) and demonstrated the transcriptional enhancer function of oriP when bound by EBV protein. Therefore, the present study is to explore the targeted gene expression and the anti-tumor effect of a novel tumor-specific gene therapeutic system (mc-oriP-IFN?) in which the transgene expression was under the transcriptional regulation of oriP promoter.Methodology/principal findingsDual-luciferase reporter assay and ELISA were used to assess the expression of luciferase and IFN?. WST assay was used to assess the cell proliferation. RT-PCR was used to detect the mRNA level of EBNA1. RNAi was used to knockdown the expression of EBNA1. NPC xenograft models in nude mice were used to investigate the targeted antitumor efficacy of mc-oriP-IFN?. Immunohistochemistry was used to detect the expression and the activity of the IFN? in tumor sections. Our results demonstrated that mc-oriP vectors mediated comparable gene expression and anti-proliferative effect in the EBV-positive NPC cell line C666-1 compared to mc-CMV vectors. Furthermore, mc-oriP vectors exhibited much lower killing effects on EBV-negative cell lines compared to mc-CMV vectors. The targeted expression of mc-oriP vectors was inhibited by EBNA1-siRNA in C666-1. This selective expression was corroborated in EBV-positive and -negative tumor models.Conclusions/significanceThis study demonstrates the feasibility of mc-oriP-IFN? as a safe and highly effective targeted gene therapeutic system for the treatment of EBV positive NPC.
| S-EPMC3088667 | biostudies-literature