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Hsu CL, Chang YS, Li HP. Molecular diagnosis of nasopharyngeal carcinoma: Past and future. Biomed J 2025; 48:100748. [PMID: 38796105 PMCID: PMC11772973 DOI: 10.1016/j.bj.2024.100748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/01/2024] [Accepted: 05/12/2024] [Indexed: 05/28/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from the nasopharynx epithelial cells and has been linked with Epstein-Barr virus (EBV) infection, dietary habits, environmental and genetic factors. It is a common malignancy in Southeast Asia, especially with gender preference among men. Due to its non-specific symptoms, NPC is often diagnosed at a late stage. Thus, the molecular diagnosis of NPC plays a crucial role in early detection, treatment selection, disease monitoring, and prognosis prediction. This review aims to provide a summary of the current state and the latest emerging molecular diagnostic techniques for NPC, including EBV-related biomarkers, gene mutations, liquid biopsy, and DNA methylation. Challenges and potential future directions of NPC molecular diagnosis will be discussed.
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Affiliation(s)
- Cheng-Lung Hsu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Sun Chang
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-Pai Li
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
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Yee TM, Wang LW. Metabolic Reprogramming in Epstein-Barr Virus Associated Diseases. J Med Virol 2025; 97:e70197. [PMID: 39895469 DOI: 10.1002/jmv.70197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 01/10/2025] [Indexed: 02/04/2025]
Abstract
Epstein-Barr virus (EBV) is the first human cancer-causing viral pathogen to be discovered; it has been epidemiologically associated with a wide range of diseases, including cancers, autoimmunity, and hyperinflammatory disorders. Its evolutionary success is underpinned by coordinated expression of viral transcription factors (EBV nuclear antigens), signaling proteins (EBV latent membrane proteins), and noncoding RNAs, which orchestrate cell transformation, immune evasion, and dissemination. Each of those activities entails significant metabolic rewiring, which is achieved by viral subversion of key host metabolic regulators such as the mammalian target of rapamycin (mTOR), MYC, and hypoxia-inducible factor (HIF). In this review, we systemically discuss how EBV-encoded factors regulate metabolism to achieve viral persistence and propagation, as well as potential research questions and directions in EBV-driven metabolism.
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Affiliation(s)
- Tiffany Melanie Yee
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Liang Wei Wang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
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Chen Y, Zhang Y, Duo S, Liu W, Luo B. Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma. Virus Genes 2024; 60:347-356. [PMID: 38739247 DOI: 10.1007/s11262-024-02071-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 04/06/2024] [Indexed: 05/14/2024]
Abstract
O-Glycan synthesis enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) is closely related to the occurrence and development of various cancers. However, the regulatory mechanism and function of GCNT3 in nasopharyngeal carcinoma (NPC) are still poorly understood. This study aims to explore the regulatory mechanism of EBV-encoded latent membrane protein 2A (LMP2A) on GCNT3 and the biological role of GCNT3 in NPC. The results show that LMP2A can activate GCNT3 through the mTORC1 pathway, and there is a positive feedback between the mTORC1 and GCNT3. GCNT3 regulates EMT progression by forming a complex with ZEB1 to promote cell migration. GCNT3 can also promote cell proliferation. These findings indicate that targeting the LMP2A-mTORC1-GCNT3 axis may represent a novel therapeutic target in NPC.
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Affiliation(s)
- Yijing Chen
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Central Hospital of Zibo, Zibo, China
| | - Shi Duo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China.
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China.
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Gómez-de Castro C, Santos-Juanes R, Nuñez-Gómez B, Fernández-Vega I, Vivanco B, Fernández-Velasco A, Reyes-García S, Carrero-Martín J, García-Pedrero JM, Rodrigo JP, González-Vela MDC, Santos-Juanes J, Galache C. Low-Level Expression of p-S6 Is Associated with Nodal Metastasis in Patients with Head and Neck Cutaneous Squamous Cell Carcinoma. Int J Mol Sci 2024; 25:4304. [PMID: 38673889 PMCID: PMC11049968 DOI: 10.3390/ijms25084304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan-Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51-4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.
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Affiliation(s)
- Celia Gómez-de Castro
- Grider, Grupo de Investigación en Dermatología, Universidad de Oviedo, 33006 Oviedo, Spain; (C.G.-d.C.); (B.V.); (A.F.-V.); (C.G.)
- Dermatology Division, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (S.R.-G.); (J.C.-M.)
| | - Raquel Santos-Juanes
- Dermatology Area, Department of Medicine, University of Oviedo, 33006 Oviedo, Spain; (R.S.-J.); (B.N.-G.)
| | - Borja Nuñez-Gómez
- Dermatology Area, Department of Medicine, University of Oviedo, 33006 Oviedo, Spain; (R.S.-J.); (B.N.-G.)
| | - Iván Fernández-Vega
- Department of Pathology, Hospital Universitario Central de Asturias, Biobank of the Principality of Asturias (BioPA), 33011 Oviedo, Spain;
- Department of Pathology, University of Oviedo, 33006 Oviedo, Spain
| | - Blanca Vivanco
- Grider, Grupo de Investigación en Dermatología, Universidad de Oviedo, 33006 Oviedo, Spain; (C.G.-d.C.); (B.V.); (A.F.-V.); (C.G.)
- Department of Pathology, Hospital Universitario Central de Asturias, Biobank of the Principality of Asturias (BioPA), 33011 Oviedo, Spain;
- Department of Pathology, University of Oviedo, 33006 Oviedo, Spain
| | - Adela Fernández-Velasco
- Grider, Grupo de Investigación en Dermatología, Universidad de Oviedo, 33006 Oviedo, Spain; (C.G.-d.C.); (B.V.); (A.F.-V.); (C.G.)
- Department of Pathology, Hospital Universitario Central de Asturias, Biobank of the Principality of Asturias (BioPA), 33011 Oviedo, Spain;
- Department of Pathology, University of Oviedo, 33006 Oviedo, Spain
| | - Sebastián Reyes-García
- Dermatology Division, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (S.R.-G.); (J.C.-M.)
| | - Jimena Carrero-Martín
- Dermatology Division, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (S.R.-G.); (J.C.-M.)
| | - Juana M. García-Pedrero
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain; (J.M.G.-P.); (J.P.R.)
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33006 Oviedo, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan P. Rodrigo
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain; (J.M.G.-P.); (J.P.R.)
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33006 Oviedo, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Otolaryngology-Head and Neck Surgery, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | | | - Jorge Santos-Juanes
- Grider, Grupo de Investigación en Dermatología, Universidad de Oviedo, 33006 Oviedo, Spain; (C.G.-d.C.); (B.V.); (A.F.-V.); (C.G.)
- Dermatology Division, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (S.R.-G.); (J.C.-M.)
- Dermatology Area, Department of Medicine, University of Oviedo, 33006 Oviedo, Spain; (R.S.-J.); (B.N.-G.)
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain; (J.M.G.-P.); (J.P.R.)
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33006 Oviedo, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Cristina Galache
- Grider, Grupo de Investigación en Dermatología, Universidad de Oviedo, 33006 Oviedo, Spain; (C.G.-d.C.); (B.V.); (A.F.-V.); (C.G.)
- Dermatology Division, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (S.R.-G.); (J.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain; (J.M.G.-P.); (J.P.R.)
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33006 Oviedo, Spain
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Cao J, Zeng K, Chen Q, Yang T, Lu F, Lin C, Zhan J, Ma W, Zhou T, Huang Y, Luo F, Zhao H. PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3β and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma. Cell Death Dis 2024; 15:237. [PMID: 38555280 PMCID: PMC10981756 DOI: 10.1038/s41419-024-06615-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/10/2024] [Accepted: 03/15/2024] [Indexed: 04/02/2024]
Abstract
End-stage nasopharyngeal carcinoma (NPC) has unsatisfactory survival. The limited benefit of chemotherapy and the scarcity of targeted drugs are major challenges in NPC. New approaches to treat late-stage NPC are urgently required. In this study, we explored whether the dual PI3K/mTOR inhibitor, PQR309, exerted a favorable antineoplastic effect and sensitized the response to gemcitabine in NPC. We observed that PI3K expression was positive and elevated in 14 NPC cell lines compared with that in normal nasopharygeal cell lines. Patients with NPC with higher PI3K levels displayed poorer prognosis. We subsequently showed that PQR309 alone effectively decreased the viability, invasiveness, and migratory capability of NPC cells and neoplasm development in mice xenograft models, and dose-dependently induced apoptosis. More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3β and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC.
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Affiliation(s)
- Jiaxin Cao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Kangmei Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Qun Chen
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Ting Yang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Feiteng Lu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Chaozhuo Lin
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Jianhua Zhan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Wenjuan Ma
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Ting Zhou
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Yan Huang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Fan Luo
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
| | - Hongyun Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
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Zhou F, Wang W, Xu R, Liu L, Lin T, He L, Tang L, Wang X, He Y. Unraveling the mechanism of Yiqi Jiedu formula against nasopharyngeal carcinoma: An investigation integrating network pharmacology, serum pharmacochemistry, and metabolomics. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117343. [PMID: 37879509 DOI: 10.1016/j.jep.2023.117343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/13/2023] [Accepted: 10/22/2023] [Indexed: 10/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yiqi Jiedu formula (YQJDF), rooted in the traditional Chinese medicinal principle of "tonifying qi and detoxifying", is remarkably efficacious in the clinical treatment of nasopharyngeal carcinoma (NPC). Previous studies have shed light on some of its anti-NPC effects and mechanisms, but the responsible pharmacological substances and their precise mechanisms of action remain unclear. AIM OF THE STUDY The purpose of this study was to identify components of YQJDF that entered the bloodstream and to investigate their mechanisms of action against NPC through network pharmacology and serum metabolomics. MATERIAL AND METHODS Components of YQJDF in serum were identified using liquid chromatography-tandem mass spectrometry. With these serum species as the focus of our research, network pharmacology analysis was used to identify active compounds and target genes that might mediate the efficacy of YQJDF in the treatment of NPC. Following establishment of an NPC xenograft model in nude mice, a non-targeted metabolomics approach was adopted to identify significant serum metabolites and metabolic pathways influenced by YQJDF. RESULTS Thirty-six components of YQJDF were identified, primarily consisting of alkaloids, phenylpropanoids, and flavonoids. Notably, pathways such as PI3K/AKT, factors associated with Epstein-Barr virus infection, IL-17 signaling, and lipid metabolism, were highlighted as potential therapeutic targets of YQJDF during NPC treatment. Additionally, our findings suggested that YQJDF modified the metabolism of arginine and proline in the serum of mice bearing nasopharyngeal tumor grafts. CONCLUSIONS This study identified the primary active components of YQJDF, highlighting its holistic role in the treatment of NPC through multiple targets and pathways. Furthermore, our findings provided a roadmap for future research into the mechanism of YQJDF in the therapy of NPC, setting the stage for its clinical application.
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Affiliation(s)
- Fangliang Zhou
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Wen Wang
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Runshi Xu
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Liu Liu
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Ting Lin
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Key Lab for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Lan He
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China; The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China
| | - Le Tang
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Xianwen Wang
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China; The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China.
| | - Yingchun He
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China.
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Abou Harb M, Meckes DG, Sun L. Epstein-Barr virus LMP1 enhances levels of large extracellular vesicle-associated PD-L1. J Virol 2023; 97:e0021923. [PMID: 37702487 PMCID: PMC10617501 DOI: 10.1128/jvi.00219-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 06/13/2023] [Indexed: 09/14/2023] Open
Abstract
IMPORTANCE A growing body of evidence has supported the notion that viruses utilize EVs and associated pathways to incorporate viral products. This allows for the evasion of an immune response while enabling viral spread within the host. Given that viral proteins often elicit strong antigenic peptides that are recognized by T cells, the regulation of the PD-L1 pathway through the overexpression of lEV-associated PD-L1 may serve as a strategy for immune evasion by viruses. The discovery that EBV LMP1 increases the secretion of PD-L1 in larger EVs identifies a new potential target for immune blockade therapy in EBV-associated cancers. Our findings may help to clarify the mechanism of LMP1-mediated enhancement of PD-L1 packaging into lEVs and may lead to the identification of more specific targets for treatment. Additionally, the identification of lEV biomarkers that predict a viral origin of disease could allow for more targeted therapies to be developed.
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Affiliation(s)
- Monica Abou Harb
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - David G. Meckes
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Li Sun
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
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Soo Hoo WI, Higa K, McCormick AA. Vaccination against Epstein-Barr Latent Membrane Protein 1 Protects against an Epstein-Barr Virus-Associated B Cell Model of Lymphoma. BIOLOGY 2023; 12:983. [PMID: 37508413 PMCID: PMC10376452 DOI: 10.3390/biology12070983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/26/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023]
Abstract
In this study, we demonstrate that expression of viral latent membrane protein 1 (LMP1) in a mouse B cell line renders the animals responsive to protection from a 38C13-LMP1 tumor challenge with a novel vaccine. The Epstein-Barr virus (EBV) preferentially infects circulating B lymphocytes, has oncogenic potential, and is associated with a wide variety of B cell lymphomas. EBV is ectotrophic to human cells, and currently there are no B cell animal models of EBV-associated lymphoma that can be used to investigate vaccine immunotherapy. Since most EBV-infected human tumor cells express latent membrane protein 1 (LMP1) on their surface, this viral antigen was tested as a potential target for an anticancer vaccine in a mouse model. Here, we describe a new mouse model of LMP1-expressing B cell lymphoma produced with plasmid transduction of 38C13 into mouse B cells. The expression of LMP-1 was confirmed with a western blot analysis and immunocytochemistry. We then designed a novel LMP1 vaccine, by fusing viral antigen LMP1 surface loop epitopes to the surface of a viral antigen carrier, the Tobacco Mosaic virus (TMV). Vaccinated mice produced high titer antibodies against the TMV-LMP1 vaccine; however, cellular responses were at the baseline, as measured with IFNγ ELISpot. Despite this, the vaccine showed significant protection from a 38C13-LMP1 tumor challenge. To provide additional immune targets, we compared TMV-LMP1 peptide immunization with DNA immunization with the full-length LMP1 gene. Anti-LMP1 antibodies were significantly higher in TMV-LMP1-vaccinated mice compared to the DNA-immunized mice, but, as predicted, DNA-vaccinated mice had improved cellular responses using IFNγ ELISpot. Surprisingly, the TMV-LMP1 vaccine provided protection from a 38C13-LMP1 tumor challenge, while the DNA vaccine did not. Thus, we demonstrated that LMP1 expression in a mouse B cell line is responsive to antibody immunotherapy that may be applied to EBV-associated disease.
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Affiliation(s)
- Wesley I Soo Hoo
- College of Pharmacy, Touro University California, 1310 Club Drive, Mare Island, Vallejo, CA 94592, USA
| | - Kaylie Higa
- College of Pharmacy, Touro University California, 1310 Club Drive, Mare Island, Vallejo, CA 94592, USA
| | - Alison A McCormick
- College of Pharmacy, Touro University California, 1310 Club Drive, Mare Island, Vallejo, CA 94592, USA
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Chen Y, He Q, Ma H, Zhang L, Liu F, Han Y. Relationship of PI3K-Akt/mTOR/AMPK signaling pathway genetic mutation with efficacy and prognosis in nasopharyngeal carcinoma. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2022; 47:165-173. [PMID: 35545406 PMCID: PMC10930525 DOI: 10.11817/j.issn.1672-7347.2022.200821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Indexed: 11/03/2022]
Abstract
OBJECTIVES Genetic mutation is one of the important causes for tumor genesis and development, but genetic mutation in nasopharyngeal carcinoma (NPC) has rarely been reported. This study explored the role of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR), and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in the efficacy and prognosis in patients with NPC. METHODS A total of 31 patients with advanced NPC, who came from the Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University/Hunan Provincial Cancer Hospital, were enrolled. All of the exons of 288 genes, introns of 38 genes and promoters or fusion breakpoint regions from the nasopharyngeal biopsy tissues before treatment were detected by the gene sequencing platform Illumina NextSeq CN500. The coding regions of 728 genes were carried out a high-depth sequencing of target region capture, and the 4 variant types of tumor genes (including point mutations, insertion deletions of small fragments, copy number variations, and currently known fusion genes) were detected. All of 31 patients received platinum-based induction chemotherapy combined with concurrent chemoradiotherapy and were followed up for a long time. RESULTS The 3-year regional failure-free survival (RFFS) and disease-free survival (DFS) in patients with PI3K-Akt pathway mutation were significantly lower than those in unmutated patients (χ2=6.647, P<0.05). The 3-year RFFS and DFS in patients with mTOR pathway mutations were significantly lower than those in unmutated patients, and there was significant difference (χ2=5.570, P<0.05). The rate of complete response (CR) in patients with unmutated AMPK pathway was significantly higher than that in patients with mutation at 3 months after treatment (P<0.05), and the 3-year RFFS and DFS in patients with AMPK pathway mutation were significantly lower than those in unmutated patients (χ2=4.553, P<0.05). PI3K-Akt/mTOR/AMPK signaling pathway mutations and pre-treatment EB virus DNA copy numbers were independent prognostic factors for 3-year RFFS and DFS in patients with NPC (both P<0.05). CONCLUSIONS The NPC patients with PI3K-Akt/mTOR/AMPK signaling pathway mutation have poor prognosis, and the detection of PI3K-Akt, mTOR, AMPK driver genes and signaling pathways by next-generation sequencing is expected to provide new idea for basic research and targeted therapy of NPC.
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Affiliation(s)
- Yanzhu Chen
- Second Department of Head and Neck Radiotherapy, Hunan Cancer Hospital; Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
| | - Qian He
- Second Department of Head and Neck Radiotherapy, Hunan Cancer Hospital; Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Hongzhi Ma
- Second Department of Head and Neck Radiotherapy, Hunan Cancer Hospital; Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Lin Zhang
- Second Department of Head and Neck Radiotherapy, Hunan Cancer Hospital; Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Feng Liu
- Second Department of Head and Neck Radiotherapy, Hunan Cancer Hospital; Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
| | - Yaqian Han
- Second Department of Head and Neck Radiotherapy, Hunan Cancer Hospital; Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
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10
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EBV LMP1-activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Properties. J Virol 2022; 96:e0194121. [PMID: 35019715 DOI: 10.1128/jvi.01941-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Epstein-Barr Virus (EBV) is associated with several malignant diseases, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), certain types of lymphomas, and a portion of gastric cancers. Virus-encoded oncoprotein LMP1 induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring CSC characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 co-regulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients. Importance LMP1 endows NPC to gain cancer stem cell characteristics through activating mTORC1 and mTORC2 pathways. The different mTOR pathways are responsible for distinct tumorigenic features. Rapamycin-insensitive mTORC1 is essential for CSC drug resistance. NPC tumor initiation capacity is mainly attributed to mTORC2 signaling. mTORC1 and mTORC2 co-regulate NPC cell migration and invasion. The revelation of the roles of mTOR signaling in NPC CSC establishment has implications for novel therapeutic strategies to treat relapsed and metastatic NPC and achieve durable remission.
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11
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Wang Y, Sun J, Yao N. Correlation of the AKT/mTOR signaling pathway with the clinicopathological features and prognosis of nasopharyngeal carcinoma. Eur J Histochem 2021; 65. [PMID: 34783234 PMCID: PMC8611413 DOI: 10.4081/ejh.2021.3304] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/11/2021] [Indexed: 12/03/2022] Open
Abstract
The primary aim of this study was to examine the correlation of the AKT/mTOR signaling pathway with the clinicopathological features and prognostic significance in nasopharyngeal carcinoma (NPC). The study tissues were collected from 285 patients with NPC and normal mucosal tissues were obtained from 289 individuals with normal nasopharynxes. Immunohistochemical staining was used to detected the expression of the AKT, mTOR, and p70 ribosomal S6 kinase (P70S6K) proteins. Follow-up was performed for between 8 and 60 months. Spearman’s rank correlation analysis was performed to evaluate the correlation of the expression of the AKT, mTOR, and P70S6K proteins in NPC tissues. Kaplan-Meier curves were plotted to show the survival of patients with NPC. A Cox proportional hazards model was used to explore the independent risk factors for prognosis. The expression of the AKT, mTOR, and P70S6K proteins in NPC tissues was higher than that in healthy nasopharyngeal mucosal tissues, and was correlated with T-staging, N-staging, clinical stage, distant metastasis, and differentiation. The positive expression of the AKT, mTOR, and P70S6K proteins was higher in patients with stage III/IV NPC, low differentiation, and metastasis. The survival rates of patients with NPC with AKT-positive, mTOR-positive, and P70S6K-positive expression were considerably lower than those without the expression of these proteins. Distant metastasis and the overexpression of the AKT, mTOR, and P70S6K proteins were independent risk factors for the prognosis of patients with NPC. The results obtained from this study indicated an association between the AKT/mTOR signaling pathway and the progression of NPC. The upregulation of the AKT/mTOR pathway in patients with NPC is a predictor of poor prognosis.
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Affiliation(s)
- Yan Wang
- Department of Radiotherapy, Affiliated Hospital of Nantong University, Nantong.
| | - Jie Sun
- Department of Radiotherapy, Affiliated Hospital of Nantong University, Nantong.
| | - Ninghua Yao
- Department of Radiotherapy, Affiliated Hospital of Nantong University, Nantong.
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12
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Chau HF, Wu Y, Fok WY, Thor W, Cho WCS, Ma P, Lin J, Mak NK, Bünzli JCG, Jiang L, Long NJ, Lung HL, Wong KL. Lanthanide-Based Peptide-Directed Visible/Near-Infrared Imaging and Inhibition of LMP1. JACS AU 2021; 1:1034-1043. [PMID: 34467347 PMCID: PMC8395644 DOI: 10.1021/jacsau.1c00187] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Indexed: 06/13/2023]
Abstract
A lanthanide-based peptide-directed bioprobe LnP19 (Ln = Eu or Yb) is designed as an impressive example of a small molecule-based dual-functional probe for the EBV oncoprotein LMP1. The peptide P19 (Pra-KAhx-K-LDLALK-FWLY-K-IVMSDKW-K-RrRK) is designed to selectively bind to LMP1 by mimicking its TM1 region during oligomerization in lipid rafts while signal transduction is significantly suppressed. Immunofluorescence imaging and Western blotting results reveal that P19 can effectively inactivate the oncogenic cellular pathway nuclear factor κB (NF-κB) and contribute to a selective cytotoxic effect on LMP1-positive cells. By conjugation with cyclen-based europium(III) and ytterbium(III) complexes, EuP19 and YbP19 were constructed to offer visible and near-infrared LMP1-targeted imaging and cancer monitoring. In addition to the ability to target and inhibit LMP1 and to selective inhibit LMP1-positive cells, selective growth inhibition toward the LMP1-positive tumor by LnP19 is also demonstrated.
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Affiliation(s)
- Ho-Fai Chau
- Department
of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Yue Wu
- Department
of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Wan-Yiu Fok
- Department
of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Waygen Thor
- Department
of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - William Chi-Shing Cho
- Department
of Clinical Oncology, Queen Elizabeth Hospital,
Kowloon, Hong Kong SAR, China
| | - Ping’an Ma
- State
Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
| | - Jun Lin
- State
Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
| | - Nai-Ki Mak
- Department
of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Jean-Claude G. Bünzli
- Department
of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
- ISIC, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland
| | - Lijun Jiang
- Department
of Applied Biological and Chemical Technology, Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Nicholas J. Long
- Department
of Chemistry, Imperial College London, Molecular Sciences Research Hub,
White City Campus, Wood Lane, London W12 0BZ, United Kingdom
| | - Hong Lok Lung
- Department
of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Ka-Leung Wong
- Department
of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
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13
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Cirone M. Cancer cells dysregulate PI3K/AKT/mTOR pathway activation to ensure their survival and proliferation: mimicking them is a smart strategy of gammaherpesviruses. Crit Rev Biochem Mol Biol 2021; 56:500-509. [PMID: 34130564 DOI: 10.1080/10409238.2021.1934811] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The serine/threonine kinase mammalian target of rapamycin (mTOR) is the catalytic subunit of two complexes, mTORC1 and mTORC2, which have common and distinct subunits that mediate separate and overlapping functions. mTORC1 is activated by plenty of nutrients, and the two complexes can be activated by PI3K signaling. mTORC2 acts as an upstream regulator of AKT, and mTORC1 acts as a downstream effector. mTOR signaling integrates both intracellular and extracellular signals, acting as a key regulator of cellular metabolism, growth, and survival. A dysregulated activation of mTOR, as result of PI3K pathway or mTOR regulatory protein mutations or even due to the presence of cellular or viral oncogenes, is a common finding in cancer and represents a central mechanism in cancerogenesis. In the final part of this review, we will focus on the PI3K/AKT/mTOR activation by the human gammaherpesviruses EBV and KSHV that hijack this pathway to promote their-mediated oncogenic transformation and pathologies.
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Affiliation(s)
- Mara Cirone
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
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14
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Sadri Nahand J, Rabiei N, Fathazam R, Taghizadieh M, Ebrahimi MS, Mahjoubin-Tehran M, Bannazadeh Baghi H, Khatami A, Abbasi-Kolli M, Mirzaei HR, Rahimian N, Darvish M, Mirzaei H. Oncogenic viruses and chemoresistance: What do we know? Pharmacol Res 2021; 170:105730. [PMID: 34119621 DOI: 10.1016/j.phrs.2021.105730] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
Chemoresistance is often referred to as a major leading reason for cancer therapy failure, causing cancer relapse and further metastasis. As a result, an urgent need has been raised to reach a full comprehension of chemoresistance-associated molecular pathways, thereby designing new therapy methods. Many of metastatic tumor masses are found to be related with a viral cause. Although combined therapy is perceived as the model role therapy in such cases, chemoresistant features, which is more common in viral carcinogenesis, often get into way of this kind of therapy, minimizing the chance of survival. Some investigations indicate that the infecting virus dominates other leading factors, i.e., genetic alternations and tumor microenvironment, in development of cancer cell chemoresistance. Herein, we have gathered the available evidence on the mechanisms under which oncogenic viruses cause drug-resistance in chemotherapy.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Ebrahimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - AliReza Khatami
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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15
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Lo AKF, Dawson CW, Lung HL, Wong KL, Young LS. The Role of EBV-Encoded LMP1 in the NPC Tumor Microenvironment: From Function to Therapy. Front Oncol 2021; 11:640207. [PMID: 33718235 PMCID: PMC7947715 DOI: 10.3389/fonc.2021.640207] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 01/21/2021] [Indexed: 12/19/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. It is also characterized by heavy infiltration with non-malignant leucocytes. The EBV-encoded latent membrane protein 1 (LMP1) is believed to play an important role in NPC pathogenesis by virtue of its ability to activate multiple cell signaling pathways which collectively promote cell proliferation and survival, angiogenesis, invasiveness, and aerobic glycolysis. LMP1 also affects cell-cell interactions, antigen presentation, and cytokine and chemokine production. Here, we discuss how LMP1 modulates local immune responses that contribute to the establishment of the NPC tumor microenvironment. We also discuss strategies for targeting the LMP1 protein as a novel therapy for EBV-driven malignancies.
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Affiliation(s)
| | | | - Hong Lok Lung
- Department of Biology, Hong Kong Baptist University, Hong Kong, China
| | - Ka-Leung Wong
- Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| | - Lawrence S. Young
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
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16
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Kang Y, He W, Ren C, Qiao J, Guo Q, Hu J, Xu H, Jiang X, Wang L. Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma. Signal Transduct Target Ther 2020; 5:245. [PMID: 33093441 PMCID: PMC7582884 DOI: 10.1038/s41392-020-00340-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 09/12/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck region which mainly distributes in southern China and Southeast Asia and has a crucial association with the Epstein-Barr virus. Based on epidemiological data, both incidence and mortality of NPC have significantly declined in recent decades grounded on the improvement of living standard and medical level in an endemic region, in particular, with the clinical use of individualized chemotherapy and intensity-modulated radiotherapy (IMRT) which profoundly contributes to the cure rate of NPC patients. To tackle the challenges including local recurrence and distant metastasis in the current NPC treatment, we discussed the implication of using targeted therapy against critical molecules in various signal pathways, and how they synergize with chemoradiotherapy in the NPC treatment. Combination treatment including targeted therapy and IMRT or concurrent chemoradiotherapy is presumably to be future options, which may reduce radiation or chemotherapy toxicities and open new avenues for the improvement of the expected functional outcome for patients with advanced NPC.
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Affiliation(s)
- Yuanbo Kang
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Weihan He
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Caiping Ren
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China.
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
| | - Jincheng Qiao
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Qiuyong Guo
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Jingyu Hu
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Hongjuan Xu
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Xingjun Jiang
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Lei Wang
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China.
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
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17
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Li SB, Liu YY, Yuan L, Ji MF, Zhang A, Li HY, Tang LQ, Fang SG, Zhang H, Xing S, Li MZ, Zhong Q, Lin SJ, Liu WL, Huang P, Zeng YX, Zheng YM, Ling ZQ, Sui JH, Zeng MS. Autocrine INSL5 promotes tumor progression and glycolysis via activation of STAT5 signaling. EMBO Mol Med 2020; 12:e12050. [PMID: 32657028 PMCID: PMC7507000 DOI: 10.15252/emmm.202012050] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 06/15/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Metabolic reprogramming plays important roles in development and progression of nasopharyngeal carcinoma (NPC), but the underlying mechanism has not been completely defined. In this work, we found INSL5 was elevated in NPC tumor tissue and the plasma of NPC patients. Plasma INSL5 could serve as a novel diagnostic marker for NPC, especially for serum VCA-IgA-negative patients. Moreover, higher plasma INSL5 level was associated with poor disease outcome. Functionally, INSL5 overexpression increased, whereas knockdown of its receptor GPCR142 or inhibition of INSL5 reduced cell proliferation, colony formation, and cell invasion in vitro and tumorigenicity in vivo. Mechanistically, INSL5 enhanced phosphorylation and nuclear translocation of STAT5 and promoted glycolytic gene expression, leading to induced glycolysis in cancer cells. Pharmaceutical inhibition of glycolysis by 2-DG or blockade of INSL5 by a neutralizing antibody reversed INSL5-induced proliferation and invasion, indicating that INSL5 can be a potential therapeutic target in NPC. In conclusion, INSL5 enhances NPC progression by regulating cancer cell metabolic reprogramming and is a potential diagnostic and prognostic marker as well as a therapeutic target for NPC.
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Affiliation(s)
- Shi-Bing Li
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan-Yan Liu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Yuan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ming-Fang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan, China
| | - Ao Zhang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hui-Yu Li
- National Institute of Biological Sciences, Beijing, China
| | - Lin-Quan Tang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuo-Gui Fang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hua Zhang
- School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shan Xing
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Man-Zhi Li
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qian Zhong
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shao-Jun Lin
- Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, China
| | - Wan-Li Liu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Peng Huang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yi-Xin Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu-Ming Zheng
- Department of Clinical Laboratory, Wuzhou Red Cross Hospital, Wuzhou, China
| | | | - Jian-Hua Sui
- National Institute of Biological Sciences, Beijing, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Richardo T, Prattapong P, Ngernsombat C, Wisetyaningsih N, Iizasa H, Yoshiyama H, Janvilisri T. Epstein-Barr Virus Mediated Signaling in Nasopharyngeal Carcinoma Carcinogenesis. Cancers (Basel) 2020; 12:2441. [PMID: 32872147 PMCID: PMC7565514 DOI: 10.3390/cancers12092441] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 12/14/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most common tumors occurring in China and Southeast Asia. Etiology of NPC seems to be complex and involves many determinants, one of which is Epstein-Barr virus (EBV) infection. Although evidence demonstrates that EBV infection plays a key role in NPC carcinogenesis, the exact relationship between EBV and dysregulation of signaling pathways in NPC needs to be clarified. This review focuses on the interplay between EBV and NPC cells and the corresponding signaling pathways, which are modulated by EBV oncoproteins and non-coding RNAs. These altered signaling pathways could be critical for the initiation and progression of NPC.
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Affiliation(s)
- Timmy Richardo
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany;
- Department of Biomedicine, Indonesia International Institute for Life Science (i3L), Jakarta 13210, Indonesia;
- Department of Microbiology, Shimane University, Izumo 693-8501, Japan; (H.I.); (H.Y.)
| | - Pongphol Prattapong
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (P.P.); (C.N.)
| | - Chawalit Ngernsombat
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (P.P.); (C.N.)
| | - Nurulfitri Wisetyaningsih
- Department of Biomedicine, Indonesia International Institute for Life Science (i3L), Jakarta 13210, Indonesia;
| | - Hisashi Iizasa
- Department of Microbiology, Shimane University, Izumo 693-8501, Japan; (H.I.); (H.Y.)
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University, Izumo 693-8501, Japan; (H.I.); (H.Y.)
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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Wu Z, Jia J, Xu X, Xu M, Peng G, Ma J, Jiang X, Yao J, Yao K, Li L, Tang H. Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling. PLoS Pathog 2020; 16:e1008568. [PMID: 32516328 PMCID: PMC7282626 DOI: 10.1371/journal.ppat.1008568] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 04/22/2020] [Indexed: 12/13/2022] Open
Abstract
Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus worldwide. However, whether and how HHV-6 infection influences the metabolic machinery of the host cell to provide the energy and biosynthetic resources for virus propagation remains unknown. In this study, we identified that HHV-6A infection promotes glucose metabolism in infected T cells, resulting in elevated glycolytic activity with an increase of glucose uptake, glucose consumption and lactate secretion. Furthermore, we explored the mechanisms involved in HHV-6A-mediated glycolytic activation in the infected T cells. We found increased expressions of the key glucose transporters and glycolytic enzymes in HHV-6A-infected T cells. In addition, HHV-6A infection dramatically activated AKT-mTORC1 signaling in the infected T cells and pharmacological inhibition of mTORC1 blocked HHV-6A-mediated glycolytic activation. We also found that direct inhibition of glycolysis by 2-Deoxy-D-glucose (2-DG) or inhibition of mTORC1 activity in HHV-6A-infected T cells effectively reduced HHV-6 DNA replication, protein synthesis and virion production. These results not only reveal the mechanism of how HHV-6 infection affects host cell metabolism, but also suggest that targeting the metabolic pathway could be a new avenue for HHV-6 therapy.
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Affiliation(s)
- Zhisheng Wu
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Junli Jia
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Xianyi Xu
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Mengyuan Xu
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Guangyong Peng
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America
| | - Jingjing Ma
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Xuefeng Jiang
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Jialin Yao
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Kun Yao
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
| | - Lingyun Li
- Department of Medical Genetics, Nanjing Medical University, Nanjing, P. R. China
- * E-mail: (LL); (HT)
| | - Huamin Tang
- Department of Immunology, Nanjing Medical University, Nanjing, P. R. China
- Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing, P. R. China
- * E-mail: (LL); (HT)
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20
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Wu RWK, Chu ESM, Yow CMN. Evaluation of the effect of 5-aminolevulinic acid hexyl ester (H-ALA) PDT on EBV LMP1 protein expression in human nasopharyngeal cells. Photodiagnosis Photodyn Ther 2020; 30:101801. [PMID: 32360854 DOI: 10.1016/j.pdpdt.2020.101801] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/21/2020] [Accepted: 04/24/2020] [Indexed: 01/10/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is of high prevalence in Hong Kong and southern China. The pathogenesis of NPC is closely associated with Epstein-Barr virus (EBV) infection via regulation of viral oncoprotein latent membrane protein 1 (LMP1). The conventional treatment for NPC is chemo-radiotherapy, but the prognosis remains poor for advanced stage, recurrent and metastatic NPC. Photodynamic therapy (PDT) is a therapeutic approach to combat tumors. PDT effectiveness depends on the interaction of photosensitizers, light and molecular oxygen. 5- aminolevulinic acid hexyl derivative (H-ALA) is one of the photosensitizers derived from 5-ALA. H-ALA with improved lipophilic properties by adding a long lipophilic chain (hexyl group) to 5-ALA, resulted in better penetration into cell cytoplasm. In this study, the effect of H-ALA-PDT on NPC cells (EBV positive C666-1 and EBV negative CNE2) was investigated. The H-ALA mediated cellular uptake and cytotoxicity was revealed via flow cytometry analysis and MTT assay respectively. H-ALA PDT mediated protein modulation was analysed by western blot analysis. Our finding reported that the cellular uptake of H-ALA in C666-1 and CNE2 cells was in a time dependent manner. H-ALA PDT was effective to C666-1 and CNE2 cells. EBV LMP1 proteins was expressed in C666-1 cells only and its expression was responsive to H-ALA PDT in a dose dependent manner. This work revealed the potential of H-ALA PDT as a treatment regiment for EBV positive NPC cells. Understanding the mechanism of H-ALA mediated PDT could develop improved strategies for the treatment of NPC.
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Affiliation(s)
- R W K Wu
- School of Medical and Health Sciences, Tung Wah College, Hong Kong Special Administrative Region; Medical Laboratory Science, Department of Health Technology & Informatics, Hong Kong Polytechnic University, Hong Kong Special Administrative Region.
| | - E S M Chu
- School of Medical and Health Sciences, Tung Wah College, Hong Kong Special Administrative Region
| | - C M N Yow
- Medical Laboratory Science, Department of Health Technology & Informatics, Hong Kong Polytechnic University, Hong Kong Special Administrative Region
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21
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Mai S, Xiao R, Shi L, Zhou X, Yang T, Zhang M, Weng N, Zhao X, Wang R, Liu J, Sun R, Qin H, Wang H. MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma. Cell Death Dis 2019; 10:819. [PMID: 31659158 PMCID: PMC6817863 DOI: 10.1038/s41419-019-2060-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 09/17/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.
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Affiliation(s)
- ShiJuan Mai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - RuoWen Xiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Lu Shi
- Department of thoracic oncology, the cancer center of the fifth affiliated hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - XiaoMin Zhou
- ZhouKou Hospital of Traditional Chinese Medicine, Zhoukou, 466000, China
| | - Te Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - MeiYin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - NuoQing Weng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - XinGe Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - RuiQi Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ji Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Rui Sun
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - HaiDe Qin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - HuiYun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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22
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Chang L, Huang Z, Li S, Yao Z, Bao H, Wang Z, Li X, Chen X, Huang J, Zhang G. A low dose of AZD8055 enhances radiosensitivity of nasopharyngeal carcinoma cells by activating autophagy and apoptosis. Am J Cancer Res 2019; 9:1922-1937. [PMID: 31598395 PMCID: PMC6780664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/28/2019] [Indexed: 06/10/2023] Open
Abstract
Activation of the PI3K/mTOR pathways is significantly correlated with a poor prognosis in nasopharyngeal carcinoma (NPC). Inhibition of these pathways was reported to be effective in restoring radiosensitivity. In this study, the activity of the novel ATP-competitive, orally bioavailable mTOR inhibitor AZD8055 was found to inhibit the phosphorylated mTOR and NPC cells proliferation. The IC50 doses in CNE1 and CNE2 cell lines were 60 and 100 nanomolar, respectively. AZD8055 significantly enhanced the inhibitions of cell growth and colony formation induced by irradiation (P < 0.05 for all). AZD8055 at the IC50 doses prolonged G2/M arrest (P < 0.05) and promoted the apoptosis (P < 0.01) induced by irradiation and autophagy in NPC cells. Blocking autophagy weaken the cell growth inhibition and decreased apoptosis induced by AZD8055 combined with irradiation. Treatment with AZD8055 at 5, 10 and 20 mg/kg/d significantly enhanced NPC cell radiosensitivity in vivo and significantly induced apoptosis and autophagy in tumor tissues, Neither 5 nor 20 mg/kg/d AZD8055 induced significantly pro-apoptosis bax expressions in mouse livers and kidneys. 5 mg/kg/d produced good radiosensitivity but had little impact on body weight. We concluded that AZD8055 was a promising candidate radiosensitizer for NPC.
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Affiliation(s)
- Lihong Chang
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Zizhen Huang
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Shuaixiang Li
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Zhouzhou Yao
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Hongwei Bao
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Zhiyuan Wang
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Xia Li
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Xiaohong Chen
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Jiancong Huang
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
| | - Gehua Zhang
- Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital, Sun Yat-sen University NO. 600 Tianhe Road, Guangzhou 510630, China
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23
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Zhang S, Hu B, Lv X, Chen S, Liu W, Shao Z. The Prognostic Role of Ribosomal Protein S6 Kinase 1 Pathway in Patients With Solid Tumors: A Meta-Analysis. Front Oncol 2019; 9:390. [PMID: 31139572 PMCID: PMC6527894 DOI: 10.3389/fonc.2019.00390] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 04/26/2019] [Indexed: 12/26/2022] Open
Abstract
Background: Recent studies supported the predictive role of ribosomal protein S6 kinase 1 (S6K1), phosphorylated S6K1 (p-S6K1), and phosphorylated ribosomal protein S6 (p-S6) for the outcome of cancer patients. However, inconsistent results were acquired across different researches. To comprehensively and quantitatively elucidate their prognostic significance in solid malignancies, the current meta-analysis was carried out utilizing the results of clinical studies. Methods: We conducted the literature retrieval by searching PubMed, Web of Science, EMBASE, and Cochrane library to identify eligible publications. Data were collected from included articles to calculate pooled overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), and progression-free survival (PFS). Hazard ratios (HRs) with 95% confidence intervals (CIs) served as appropriate parameters to assess prognostic significance. Results: Forty-four original studies were included, of which 7 studies were analyzed for S6K1, 24 for p-S6K1, and 16 for p-S6. The overexpression of p-S6K1 was significantly associated with poorer prognosis of solid tumor patients in OS (HR = 1.706, 95%CI: 1.369–2.125, p < 0.001), DFS (HR = 1.665, 95%CI: 1.002–2.768, p = 0.049). However, prognostic role of p-S6K1 in RFS and PFS was not found. The result also revealed that S6K1 and p-S6 were significantly associated with reduced OS (HR = 1.691, 95%CI: 1.306–2.189, p < 0.001; HR = 2.019, 95%CI: 1.775–2.296, p < 0.001, respectively). Conclusions: The present meta-analysis demonstrated that elevated expression of S6K1, p-S6K1, or p-S6 might indicate worse prognosis of patients with solid tumors, and supported a promising clinical test to predict solid tumor prognosis based on the level of S6K1 pathway.
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Affiliation(s)
- Shuo Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binwu Hu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Songfeng Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weijian Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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24
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Zheng GD, Hu PJ, Chao YX, Zhou Y, Yang XJ, Chen BZ, Yu XY, Cai Y. Nobiletin induces growth inhibition and apoptosis in human nasopharyngeal carcinoma C666-1 cells through regulating PARP-2/SIRT1/AMPK signaling pathway. Food Sci Nutr 2019; 7:1104-1112. [PMID: 30918653 PMCID: PMC6418462 DOI: 10.1002/fsn3.953] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 12/29/2018] [Accepted: 01/06/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND/AIM Nobiletin, a major polymethoxyflavones (PMFs) from citri reticulatae pericarpium (CRP), can inhibit several forms of cancer proliferation. However, the effects of nobiletin on nasopharyngeal carcinoma (NPC) C666-1 cells remain largely unknown. MATERIALS AND METHODS Cell counting kit 8 (CCK8) assay was used to measure cell vitality. Flow cytometry was performed to measure the apoptosis rate. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were applied to determine the expression of mRNA and protein, respectively. RESULTS We showed that the proliferation rate of C666-1 cells was inhibited and the apoptosis rate was raised after treating with nobiletin. Moreover, nobiletin inhibited the expression of poly(ADP-ribose)polymerase-2 (PARP-2), and the tumor suppression effect of nobiletin on C666-1 is associated with PARP-2-dependent pathway. CONCLUSION We demonstrated for the first time that nobiletin inhibited the growth of C666-1 cells, which may be relative to its regulation on PARP-2/SIRT1/AMPK signaling pathway. Our result implied that nobiletin may serve as a strategy to treat nasopharyngeal carcinoma.
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Affiliation(s)
- Guo Dong Zheng
- Key Laboratory of Molecular Target & Clinical PharmacologyState Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China
| | - Ping Jun Hu
- Key Laboratory of Molecular Target & Clinical PharmacologyState Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China
| | - Ying Xin Chao
- Key Laboratory of Molecular Target & Clinical PharmacologyState Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China
| | - Ying Zhou
- Key Laboratory of Molecular Target & Clinical PharmacologyState Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China
| | - Xiu Juan Yang
- Key Laboratory of Molecular Target & Clinical PharmacologyState Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China
| | - Bai Zhong Chen
- Guangdong Xinbaotang Biological Technology Co, LtdJiangmenChina
| | - Xi Yong Yu
- Key Laboratory of Molecular Target & Clinical PharmacologyState Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China
| | - Yi Cai
- Key Laboratory of Molecular Target & Clinical PharmacologyState Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China
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25
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Xiang T, Lin YX, Ma W, Zhang HJ, Chen KM, He GP, Zhang X, Xu M, Feng QS, Chen MY, Zeng MS, Zeng YX, Feng L. Vasculogenic mimicry formation in EBV-associated epithelial malignancies. Nat Commun 2018; 9:5009. [PMID: 30479336 PMCID: PMC6258759 DOI: 10.1038/s41467-018-07308-5] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 10/22/2018] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated epithelial cancers, including nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancers, termed EBVaGC, represent 80% of all EBV-related malignancies. However, the exact role of EBV in epithelial cancers remains elusive. Here, we report that EBV functions in vasculogenic mimicry (VM). Epithelial cancer cells infected with EBV develop tumor vascular networks that correlate with tumor growth, which is different from endothelial-derived angiogenic vessels and is VEGF-independent. Mechanistically, activation of the PI3K/AKT/mTOR/HIF-1α signaling cascade, which is partly mediated by LMP2A, is responsible for EBV-induced VM formation. Both xenografts and clinical samples of NPC and EBVaGC exhibit VM histologically, which are correlated with AKT and HIF-1α activation. Furthermore, although anti-VEGF monotherapy shows limited effects, potent synergistic antitumor activities are achieved by combination therapy with VEGF and HIF-1α-targeted agents. Our findings suggest that EBV creates plasticity in epithelial cells to express endothelial phenotype and provides a novel EBV-targeted antitumor strategy. EBV latent infection contributes to the pathogenesis of epithelial malignancies by inducing angiogenesis. Here, the authors show EBV promotes vasculogenic mimicry in EBV associated epithelial cancers via AKT/HIF-1α pathway and combination therapy of HIF-1α and VEGF reduces tumour growth.
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Affiliation(s)
- Tong Xiang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.,Department of Oncology, No. 421 Hospital of PLA, 510318, Guangzhou, China
| | - Yu-Xin Lin
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Wenlong Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Hao-Jiong Zhang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Ke-Ming Chen
- Department of Pathology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Gui-Ping He
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Xiao Zhang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Miao Xu
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Qi-Sheng Feng
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Ming-Yuan Chen
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Mu-Sheng Zeng
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Yi-Xin Zeng
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
| | - Lin Feng
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
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26
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Tetraspanin CD63 Bridges Autophagic and Endosomal Processes To Regulate Exosomal Secretion and Intracellular Signaling of Epstein-Barr Virus LMP1. J Virol 2018; 92:JVI.01969-17. [PMID: 29212935 DOI: 10.1128/jvi.01969-17] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 11/30/2017] [Indexed: 12/19/2022] Open
Abstract
The tetraspanin protein CD63 has been recently described as a key factor in extracellular vesicle (EV) production and endosomal cargo sorting. In the context of Epstein-Barr virus (EBV) infection, CD63 is required for the efficient packaging of the major viral oncoprotein latent membrane protein 1 (LMP1) into exosomes and other EV populations and acts as a negative regulator of LMP1 intracellular signaling. Accumulating evidence has also pointed to intersections of the endosomal and autophagy pathways in maintaining cellular secretory processes and as sites for viral assembly and replication. Indeed, LMP1 can activate the mammalian target of rapamycin (mTOR) pathway to suppress host cell autophagy and facilitate cell growth and proliferation. Despite the growing recognition of cross talk between endosomes and autophagosomes and its relevance to viral infection, little is understood about the molecular mechanisms governing endosomal and autophagy convergence. Here, we demonstrate that CD63-dependent vesicle protein secretion directly opposes intracellular signaling activation downstream of LMP1, including mTOR-associated proteins. Conversely, disruption of normal autolysosomal processes increases LMP1 secretion and dampens signal transduction by the viral protein. Increases in mTOR activation following CD63 knockout are coincident with the development of serum-dependent autophagic vacuoles that are acidified in the presence of high LMP1 levels. Altogether, these findings suggest a key role of CD63 in regulating the interactions between endosomal and autophagy processes and limiting cellular signaling activity in both noninfected and virally infected cells.IMPORTANCE The close connection between extracellular vesicles and viruses is becoming rapidly and more widely appreciated. EBV, a human gamma herpesvirus that contributes to the progression of a multitude of lymphomas and carcinomas in immunocompromised or genetically susceptible populations, packages its major oncoprotein, LMP1, into vesicles for secretion. We have recently described a role of the host cell protein CD63 in regulating intracellular signaling of the viral oncoprotein by shuttling LMP1 into exosomes. Here, we provide strong evidence of the utility of CD63-dependent EVs in regulating global intracellular signaling, including mTOR activation by LMP1. We also demonstrate a key role of CD63 in coordinating endosomal and autophagic processes to regulate LMP1 levels within the cell. Overall, this study offers new insights into the complex intersection of cellular secretory and degradative mechanisms and the implications of these processes in viral replication.
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Meta-analysis of the prognostic value of p-4EBP1 in human malignancies. Oncotarget 2017; 9:2761-2769. [PMID: 29416809 PMCID: PMC5788677 DOI: 10.18632/oncotarget.23031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 09/20/2017] [Indexed: 01/16/2023] Open
Abstract
Phosphorylated 4E-binding protein 1 (p-4EBP1) is the inactivated form of 4EBP1, which is a downstream mediator in the mTOR signaling pathway and a vital factor in the synthesis of some oncogenic proteins. This meta-analysis was conducted to assess the predicative value of p-4EBP1 expression in human malignancies. The PubMed and Embase databases were carefully searched. Articles comparing the prognostic worthiness of different p-4EBP1 levels in human malignancies were collected for pooled analyses and methodologically appraised using the Newcastle-Ottawa Scale (NOS). A total of 39 retrospective cohorts with an overall sample size of 3,980 were selected. Patients with lower p-4EBP1 expression had better 3-year (P < 0.00001), 5-year (P < 0.00001), and 10-year (P = 0.03) overall survival and better 3-year (P < 0.0001) and 5-year (P = 0.0005) disease-free survival. Subgroup analyses confirmed the unfavorable prognosis associated with p-4EBP1 overexpression. These findings were further validated by sensitivity analyses. Harbord and Peters tests revealed no publication bias within the included studies. It thus appears higher expression of p-4EBP1 indicates a poor prognosis in human malignancies.
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Qin L, Li X, Lin Z, Li H, Mo Y, Su F, Mo W, Yang Z. EBV-LMP1 regulating AKT/mTOR signaling pathway and WWOX in nasopharyngeal carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:8619-8625. [PMID: 31966718 PMCID: PMC6965410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 03/15/2017] [Indexed: 06/10/2023]
Abstract
Our previous studies found the expression of tumor suppressor gene WWOX was reduced in nasopharyngeal carcinoma (NPC), and WWOX expression gradually declined with the progress and lymph node metastasis in patients. These suggested that WWOX was related with the development of NPC. AKT/mTOR signaling pathway was considered the primary pathway of cancer cell survival. AKT/mTOR pathway and WWOX had been found to be closely related. NPC was closely related to infection of Epstein-Barr virus (EBV). The study mainly used oncogene LMP1 of EBV as a starting point to explore whether LMP1 regulated the AKT/mTOR signaling pathway and WWOX gene. Western blot and qPCR were used to detect the expression of AKT/mTOR pathway (AKT, p-AKT, p70S6K and p-p70S6K) and WWOX in nasopharyngeal carcinoma cell lines CNE1 and CNE1-LMP1, and accessed relationship of LMP1 with AKT/mTOR and WWOX. Research of correlation between LMP1 and WWOX gene expression suggested that in CNE1-LMP1 cells, WWOX gene and protein levels were decreased compared with CNE1 cells (P=0.025, P=0.042, respectively). The difference was statistically significant, and suggested that LMP1 expression correlated with WWOX. Research of correlation between LMP1 and AKT/mTOR signaling pathway demonstrated that when cell line CNE1-LMP1 was compared with CNE1 in AKT/mTOR pathway key protein of AKT, p-AKT, p70S6K and p-p70S6K expression, P values were 0.075, 0.008, 0.124, 0.034, respectively, and expression of p-AKT, p-p70S6K in CNE1-LMP1 were higher than CNE1, which were significantly different from each other. It suggested AKT/mTOR pathway was regulated by LMP1. WWOX gene and AKT/mTOR signaling pathway were regulated by the EBV-LMP1 oncogene.
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Affiliation(s)
- Lingyan Qin
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
| | - Xiaohong Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
| | - Zhongyuan Lin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
| | - Hongtao Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
| | - Yingxi Mo
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
| | - Fang Su
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
| | - Wuning Mo
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
| | - Zheng Yang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi, People’s Republic of China
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de Vicente JC, Peña I, Rodrigo JP, Rodríguez-Santamarta T, Lequerica-Fernández P, Suárez-Fernández L, Allonca E, García-Pedrero JM. Phosphorylated ribosomal protein S6 correlation with p21 expression and inverse association with tumor size in oral squamous cell carcinoma. Head Neck 2017; 39:1876-1887. [PMID: 28675642 DOI: 10.1002/hed.24854] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 03/01/2017] [Accepted: 05/01/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate the clinical relevance of phosphorylated ribosomal protein S6 (p-S6), a surrogate marker of mammalian target of rapamycin (mTOR) activation, and p21 in a series of 125 patients with oral squamous cell carcinomas (OSCCs). METHODS Immunohistochemical analysis was performed to ascertain the phosphorylation status of p-S6 at Ser235/236 and Ser240/244, p21, and p53 protein expression. RESULTS Expression of phosphorylated S6 protein on either serine 235/236 or serine 240/244 was detected in 83% and 88% tumors, respectively, and both of them were inversely and significantly correlated with the tumor size and local infiltration. Positive p21 expression was found in 91.5% of the cases, and was inversely correlated with tumor size. In OSCC, p21 expression correlates with p-S6 levels, a surrogate marker of mTOR activation, independently of p53 status. CONCLUSION Expression of both p21 and p-S6 was found to inversely associate with tumor size but not survival outcomes in patients with OSCC.
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Affiliation(s)
- Juan C de Vicente
- Department of Oral and Maxillofacial Surgery, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain.,Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Hospital Universitario Central de Asturias, Oviedo, Asturias, CIBERONC ISCIII Spain
| | - Ignacio Peña
- Department of Oral and Maxillofacial Surgery, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain
| | - Juan P Rodrigo
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain.,Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Hospital Universitario Central de Asturias, Oviedo, Asturias, CIBERONC ISCIII Spain
| | - Tania Rodríguez-Santamarta
- Department of Oral and Maxillofacial Surgery, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain
| | | | - Laura Suárez-Fernández
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain
| | - Eva Allonca
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain
| | - Juana M García-Pedrero
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain.,Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Hospital Universitario Central de Asturias, Oviedo, Asturias, CIBERONC ISCIII Spain
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Zhang H, Wang J, Yu D, Liu Y, Xue K, Zhao X. Role of Epstein-Barr Virus in the Development of Nasopharyngeal Carcinoma. Open Med (Wars) 2017; 12:171-176. [PMID: 28730175 PMCID: PMC5471915 DOI: 10.1515/med-2017-0025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 03/14/2017] [Indexed: 12/12/2022] Open
Abstract
Southern China experiences larger extent of total cancer pathologies, of which nasopharyngeal carcinoma has the highest incidence under otorhinolaryngeal malignant carcinomas. Risk factor of nasopharyngeal carcinoma varies from hereditary causes to virus infection, among which Epstein-Barr virus (EBV) infection is the mostly investigated. The study into mechanism of EBV in occurrence, development and prognosis of nasopharyngeal carcinoma has been studied for several decades. The pathophysiology in making of EBV into a cancerogen includes proteins as latent membrane protein 1 (LMPs) and nucleic acids as micro-RNAs. In this paper, we reviewed till date studies focusing on relationship between EBV and nasopharyngeal carcinoma.
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Affiliation(s)
- Hui Zhang
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun130041, China
| | - Jing Wang
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun130041, China
| | - Dan Yu
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun130041, China
| | - Yan Liu
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun130041, China
| | - Kai Xue
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun130041, China
| | - Xue Zhao
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun130041, China
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Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways. J Virol 2017; 91:JVI.02168-16. [PMID: 28053105 DOI: 10.1128/jvi.02168-16] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/22/2016] [Indexed: 12/27/2022] Open
Abstract
Accumulating evidence indicates that oncogenic viral protein plays a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a transmembrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-κB is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-κB signaling to mediate aerobic glycolysis. NF-κB activation is involved in the LMP1-induced upregulation of glucose transporter 1 (Glut-1) transcription and growth of nasopharyngeal carcinoma (NPC) cells. Blocking the activity of mTORC1 signaling effectively suppressed LMP1-induced NF-κB activation and Glut-1 transcription. Interfering NF-κB signaling had no effect on mTORC1 activity but effectively altered Glut-1 transcription. Luciferase promoter assay of Glut-1 also confirmed that the Glut-1 gene is a direct target gene of NF-κB signaling. Furthermore, we demonstrated that C-terminal activating region 2 (CTAR2) of LMP1 is the key domain involved in mTORC1 activation, mainly through IKKβ-mediated phosphorylation of TSC2 at Ser939 Depletion of Glut-1 effectively led to suppression of aerobic glycolysis, inhibition of cell proliferation, colony formation, and attenuation of tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial (NPE) cells. These findings suggest that targeting the signaling axis of mTORC1/NF-κB/Glut-1 represents a novel therapeutic target against NPC.IMPORTANCE Aerobic glycolysis is one of the hallmarks of cancer, including NPC. Recent studies suggest a role for LMP1 in mediating aerobic glycolysis. LMP1 expression is common in NPC. The delineation of essential signaling pathways induced by LMP1 in aerobic glycolysis contributes to the understanding of NPC pathogenesis. This study provides evidence that LMP1 upregulates Glut-1 transcription to control aerobic glycolysis and tumorigenic growth of NPC cells through mTORC1/NF-κB signaling. Our results reveal novel therapeutic targets against the mTORC1/NF-κB/Glut-1 signaling axis in the treatment of EBV-infected NPC.
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EBV Infection and Glucose Metabolism in Nasopharyngeal Carcinoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1018:75-90. [DOI: 10.1007/978-981-10-5765-6_6] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Huang L, Yang M, Yuan Y, Li X, Kuang E. Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation. Antiviral Res 2016; 138:68-78. [PMID: 27939840 DOI: 10.1016/j.antiviral.2016.12.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 11/30/2016] [Accepted: 12/05/2016] [Indexed: 12/31/2022]
Abstract
Infection with the oncogenic γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause several severe malignancies in humans. Inhibition of the lytic replication of EBV and KSHV eliminates the reservoir of persistent infection and transmission, consequently preventing the occurrence of diseases from the sources of infection. Antiviral drugs are limited in controlling these viral infectious diseases. Here, we demonstrate that niclosamide, an old anthelmintic drug, inhibits mTOR activation during EBV lytic replication. Consequently, niclosamide effectively suppresses EBV lytic gene expression, viral DNA lytic replication and virion production in EBV-infected lymphoma cells and epithelial cells. Niclosamide exhibits cytotoxicity toward lymphoma cells and induces irreversible cell cycle arrest in lytically EBV-infected cells. The ectopic overexpression of mTOR reverses the inhibition of niclosamide in EBV lytic replication. Similarly, niclosamide inhibits KSHV lytic replication. Thus, we conclude that niclosamide is a promising candidate for chemotherapy against the acute occurrence and transmission of infectious diseases of oncogenic γ-herpesviruses.
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Affiliation(s)
- Lu Huang
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Mengtian Yang
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Yan Yuan
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiaojuan Li
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
| | - Ersheng Kuang
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China.
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Chen YP, Zhang WN, Chen L, Tang LL, Mao YP, Li WF, Liu X, Zhou GQ, Sun Y, Kang TB, Zeng MS, Liu N, Ma J. Effect of latent membrane protein 1 expression on overall survival in Epstein-Barr virus-associated cancers: a literature-based meta-analysis. Oncotarget 2016; 6:29311-23. [PMID: 26336130 PMCID: PMC4745728 DOI: 10.18632/oncotarget.4906] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 08/07/2015] [Indexed: 01/11/2023] Open
Abstract
Latent membrane protein 1 (LMP1) is identified as the main transforming oncoprotein of Epstein-Barr virus (EBV). LMP1 is frequently expressed in a variety of EBV-associated cancers, including nasopharyngeal carcinoma (NPC), non-Hodgkin lymphoma (NHL), Hodgkin disease (HD), and gastric cancer (GC). However, due to conflicting results, the prognostic value of LMP1 expression on clinical outcomes in EBV-associated cancers remains unclear. We performed a meta-analysis on 32 studies with a total of 3752 patients to explore the association between LMP1 expression and overall survival (OS) in EBV-associated cancers. Overall, LMP1 expression was significantly associated with poorer OS (hazard ratio, HR = 1.51, 95% confidence interval, CI, 1.13–2.03), irrespective of cancer type. Further analyses showed that LMP1 expression correlated with poorer OS in NPC (HR = 2.48, 95% CI, 1.77–3.47) and NHL patients (HR = 1.83, 95% CI, 1.07–3.15), but not in HD patients (HR = 0.98, 95% CI, 0.60–1.62) or GC patients (HR = 0.70, 95% CI, 0.44–1.12). Subgroup analyses indicated that the age and geographical factors seemed to have an effect on the clinical outcomes of HD patients with positive LMP1 expression. In conclusion, LMP1 expression can be used as a prognostic biomarker in NPC, NHL, and certain HD patients. This data suggests that novel therapies targeting LMP1 may improve clinical outcomes for EBV-associated cancer patients.
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Affiliation(s)
- Yu-Pei Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Wen-Na Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Lei Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Ling-Long Tang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Yan-Ping Mao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Wen-Fei Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Xu Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Guan-Qun Zhou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Ying Sun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Tie-Bang Kang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Mu-Sheng Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Na Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Jun Ma
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
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Adi-Kusumo F, Wiraya A. Mathematical modeling of the cells repair regulations in Nasopharyngeal carcinoma. Math Biosci 2016; 277:108-16. [PMID: 27140528 DOI: 10.1016/j.mbs.2016.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 04/11/2016] [Accepted: 04/24/2016] [Indexed: 11/28/2022]
Abstract
Nasopharyngeal Carcinoma (NPC) is a malignant cancer which is caused by the activation of Epstein-Barr Virus (EBV) via some external factors. In the cells repair regulations, the p53 gene mutation can be used as the early indication of the NPC growth. The NPC growth is due to the DNA damage accumulation caused by the EBV infection. In this paper we construct the cells repair regulations model to characterize the NPC growth. The model is a 15 dimensional of first order ODE system and consists the proteins and enzymes reactions. We do some numerical simulations to show the inactivation of the phosphorylated and acetylated p53, and the chromosomal instability of p53 gene, which can be used as the earlier stage detection of NPC.
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Affiliation(s)
- Fajar Adi-Kusumo
- Department of Mathematics, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Indonesia.
| | - Ario Wiraya
- Department of Mathematics, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Indonesia.
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Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis. Oncogene 2016; 35:4675-88. [DOI: 10.1038/onc.2015.515] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 12/11/2015] [Accepted: 12/11/2015] [Indexed: 01/17/2023]
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WANG KEFENG, YANG HANG, JIANG WENQI, LI SU, CAI YUCHEN. Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells. Int J Mol Med 2015; 36:1556-62. [PMID: 26499488 PMCID: PMC4678157 DOI: 10.3892/ijmm.2015.2378] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 10/05/2015] [Indexed: 01/07/2023] Open
Abstract
There are numerous studies that demonstrate the anti-neoplastic activity of phosphatidylinositol 3-kinase (PI3K) inhibitors and the mechanisms of inducing autophagy in cancer cells. The new anticancer drug puquitinib mesylate (XC-302) is a molecular-targeted drug, which suppresses the activity of PI3K directly. However, it remains unclear whether XC‑302 can develop an antitumor effect by inducing autophagy in nasopharyngeal cancer cells. The MTT assay was used to study the anti-proliferative effects of XC-302. Subsequently, autophagy was determined by monodansylcadaverine (MDC) staining, punctate localization of green fluorescent protein (GFP)-light chain 3 (LC3), LC3 protein blotting and electron microscopy. The expression levels of beclin 1, p62, protein kinase B (AKT), phospho (p)‑AKT, mechanistic target of rapamycin (mTOR) and p‑mTOR in XC-302‑induced autophagy were detected. Autophagy inhibition was assayed by 3-methyladenine (3‑MA) or small interfering RNA (siRNA) silencing of beclin 1. XC-302 inhibited the viability of CNE‑2 in a dose-dependent manner and the IC50 of 72 h was 5.2 µmol/l. After cells were exposed to XC-302 for 24 h, MDC-labeled autophagolysosomes were evident in CNE-2 cells by fluorescence microscope. Autophagosomes and autolysosomes were identified by transmission electron microscopy. Following transfection with GFP‑LC3, XC-302 induced a significant accumulation of GFP‑LC3, as monitored by a confocal microscope, which was reduced by 3-MA. XC-302 induced the formation of LC3‑II, increased beclin 1 levels and decreased the expression of p62. Additionally, the expression levels of p‑AKT and p‑mTOR were reduced with the elevation of XC-302. Knockdown of beclin 1 with siRNA or co-treatment with 3-MA enhanced significantly the survival of CNE-2 and promoted the ability of clone formation. XC-302 also induced apoptosis in CNE-2, and when autophagy was inhibited by 3-MA, the apoptosis rate was decreased. The present data provides the evidence that XC-302 can induce autophagy in CNE-2, which promotes the program of cell death and inhibits the PI3K/AKT/mTOR signaling pathway. Furthermore, XC-302 also promoted apoptosis in CNE-2 cells, which could be reduced when autophagy was suppressed, meaning that autophagy may interact with apoptosis to induce cell death.
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Affiliation(s)
| | | | | | - SU LI
- Correspondence to: Professor Yu-Chen Cai or Professor Su Li, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651E Dongfeng Ave, Guangzhou, Guangdong 510060, P.R. China, E-mail: , E-mail:
| | - YU-CHEN CAI
- Correspondence to: Professor Yu-Chen Cai or Professor Su Li, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651E Dongfeng Ave, Guangzhou, Guangdong 510060, P.R. China, E-mail: , E-mail:
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de Souza APD, de Freitas DN, Antuntes Fernandes KE, D'Avila da Cunha M, Antunes Fernandes JL, Benetti Gassen R, Fazolo T, Pinto LA, Scotta M, Mattiello R, Pitrez PM, Bonorino C, Stein RT. Respiratory syncytial virus induces phosphorylation of mTOR at ser2448 in CD8 T cells from nasal washes of infected infants. Clin Exp Immunol 2015; 183:248-57. [PMID: 26437614 DOI: 10.1111/cei.12720] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2015] [Indexed: 12/12/2022] Open
Abstract
Respiratory syncytial virus (RSV)-specific CD8(+) T cell responses do not protect against reinfection. Activation of mammalian target of rapamycin (mTOR) impairs memory CD8(+) T cell differentiation. Our hypothesis was that RSV inhibits the formation of CD8(+) T cells memory responses through mTOR activation. To explore this, human and mouse T cells were used. RSV induced mTOR phosphorylation at Ser2448 in CD8 T cells. mTOR activation by RSV was completely inhibited using rapamycin. RSV-infected children presented higher mTOR gene expression on nasal washes comparing to children infected with metapneumovirus and rhinovirus. In addition, RSV-infected infants presented a higher frequency of CD8(+) pmTORser2448(+) T cells in nasal washes compared to RSV-negative infants. Rapamycin treatment increased the frequency of mouse CD8 RSV-M282-90 pentamer-positive T cells and the frequency of RSV-specific memory T cells precursors. These data demonstrate that RSV is activating mTOR directly in CD8 T cells, indicating a role for mTOR during the course of RSV infection.
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Affiliation(s)
- A P Duarte de Souza
- Laboratório De Imunologia Clínica E Experimental, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - D Nascimento de Freitas
- Laboratório De Imunologia Clínica E Experimental, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - K E Antuntes Fernandes
- Laboratório De Imunologia Clínica E Experimental, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - M D'Avila da Cunha
- Laboratório De Imunologia Clínica E Experimental, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - J L Antunes Fernandes
- Laboratório De Imunologia Clínica E Experimental, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - R Benetti Gassen
- Laboratório De Imunologia Clínica E Experimental, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - T Fazolo
- Laboratório De Imunologia Clínica E Experimental, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - L A Pinto
- Laboratório De Respirologia Pediátrica, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - M Scotta
- Laboratório De Respirologia Pediátrica, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - R Mattiello
- Laboratório De Respirologia Pediátrica, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - P M Pitrez
- Laboratório De Respirologia Pediátrica, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - C Bonorino
- Laboratorio De Imunologia Celular E Molecular, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - R T Stein
- Laboratório De Respirologia Pediátrica, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil.,Instituto De Pesquisas Biomédicas, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
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Li S, Wang L, He X, Xie Y, Zhang Z. Identification and analysis of the promoter region of the STGC3 gene. Arch Med Sci 2015; 11:1095-100. [PMID: 26528355 PMCID: PMC4624735 DOI: 10.5114/aoms.2015.49213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 12/18/2012] [Accepted: 03/21/2013] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck. The STGC3 gene is related to development of nasopharyngeal cancer. The aim of this study is to explore the promoter region of the STGC3 gene. MATERIAL AND METHODS The bioinformatic technique was applied to predict its promoter region and construct the gene promoter region luciferase for the gene vector and transfection of the human embryonic kidney epithelial 293T cell line, human nasopharyngeal carcinoma CNE2 cell line and immortalized nasopharyngeal epithelial NP69 cell line. The recombinant plasmid pGL3-en283, pGL3-en281, pGL3-en571, empty plasmid pGL3-control, negative control pGL3-enhance and internal control of marine intestine luciferase expression vector pRL-SV40 were transfected into NP69 cells, 293T cells and CNE2 cells. Dual luciferase activity detection showed luciferase luminescence values and marine intestine luciferase luminescence values. Relative luciferase activity (RLA) in each cell was calculated. RESULTS We observed strong promoter activity of plasmid pGL3-en283, pGL3-en281 and pGL3-en571 in NP69, 293T and CNE2 cells compared with the negative control pGL3-enhance plasmid. Among them, pGL3-en281 showed the strongest promoter activity, and these three kinds of recombinant plasmids showed stronger promoter activity in 293T cells than in CNE2 cells. CONCLUSIONS The pGL3-en281 plasmid showed stronger promoter activity than pGL3-en571 in the three cells, indicating that -11048 bp to -653 bp might be the core promoter region.
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Affiliation(s)
- Suyun Li
- Cancer Research Institute of the University of South China, Hengyang, China
| | - Lili Wang
- Cancer Research Institute of the University of South China, Hengyang, China
| | - Xiusheng He
- Cancer Research Institute of the University of South China, Hengyang, China
| | - Yuanjie Xie
- Cancer Research Institute of the University of South China, Hengyang, China
| | - Zhiwei Zhang
- Cancer Research Institute of the University of South China, Hengyang, China
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Ooft ML, Braunius WW, Heus P, Stegeman I, van Diest PJ, Grolman W, Zuur CI, Willems SM. Prognostic significance of the EGFR pathway in nasopharyngeal carcinoma: a systematic review and meta-analysis. Biomark Med 2015; 9:997-1010. [PMID: 26441207 DOI: 10.2217/bmm.15.68] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE To evaluate the prognostic impact of the EGF receptor (EGFR) pathway molecules and assess their clinical usefulness. METHODS We conducted a systematic review. Pubmed and EMBASE were searched January 2014. The prognostic relevance of EGFR, JAK, PI3K, PIK3CA, STAT3, STAT5, PTEN, AKT, mTOR, GRB2, SOS, RAF, RAS, MAPK, ERK, MEK and CCND1 in nasopharyngeal carcinoma was assessed. The outcomes considered were overall survival, disease-free survival and tumor-node-metastasis stage. Twenty-two studies were included. Risk of bias was evaluated. Meta-analysis for which pooled hazard ratios and 95% CIs were calculated. CONCLUSION EGFR overexpression predicts a worse overall survival and disease-free survival in nasopharyngeal carcinoma, but no specific causal pathway molecule could be identified.
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Affiliation(s)
- Marc L Ooft
- Department of Pathology, University Medical Center, Utrecht, The Netherlands
| | - Weibel W Braunius
- Department of Otolaryngology, University Medical Center, Utrecht, The Netherlands
| | - Paulien Heus
- Dutch Cochrane Center, Julius Center for Health Sciences & Primary Care, University Medical Center, Utrecht, The Netherlands
| | - Inge Stegeman
- Department of Otolaryngology, University Medical Center, Utrecht, The Netherlands
| | - Paul J van Diest
- Department of Pathology, University Medical Center, Utrecht, The Netherlands
| | - Wilko Grolman
- Department of Otolaryngology, University Medical Center, Utrecht, The Netherlands
| | - Charlotte I Zuur
- Department of Head & Neck Surgery & Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Stefan M Willems
- Department of Pathology, University Medical Center, Utrecht, The Netherlands
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Liu MT, Chen MK, Huang CC, Huang CY. Prognostic Value of Molecular Markers and Implication for Molecular Targeted Therapies in Nasopharyngeal Carcinoma: An Update in an Era of New Targeted Molecules Development. World J Oncol 2015; 6:243-261. [PMID: 29147412 PMCID: PMC5649942 DOI: 10.14740/wjon610w] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2012] [Indexed: 12/15/2022] Open
Abstract
The aim of the study was to evaluate the prognostic significance of molecular biomarkers which could provide information for more accurate prognostication and development of novel therapeutic strategies for nasopharyngeal carcinoma (NPC). NPC is a unique malignant epithelial carcinoma of head and neck region, with an intimate association with the Epstein-Barr virus (EBV). Currently, the prediction of NPC prognosis is mainly based on the clinical TNM staging; however, NPC patients with the same clinical stage often present different clinical outcomes, suggesting that the TNM stage is insufficient to precisely predict the prognosis of this disease. In this review, we give an overview of the prognostic value of molecular markers in NPC and discuss potential strategies of targeted therapies for treatment of NPC. Molecular biomarkers, which play roles in abnormal proliferation signaling pathways (such as Wnt/β-catenin pathway), intracellular mitogenic signal aberration (such as hypoxia-inducible factor (HIF)-1α), receptor-mediated aberrations (such as vascular endothelial growth factor (VEGF)), tumor suppressors (such as p16 and p27 activity), cell cycle aberrations (such as cyclin D1 and cyclin E), cell adhesion aberrations (such as E-cadherin), apoptosis dysregualtion (such as survivin) and centromere aberration (centromere protein H), are prognostic markers for NPC. Plasma EBV DNA concentrations and EBV-encoded latent membrane proteins are also prognostic markers for NPC. Implication of molecular targeted therapies in NPC was discussed. Such therapies could have potential in combination with different cytotoxic agents to combat and eradicate tumor cells. In order to further improve overall survival for patients with loco-regionally advanced NPC, the development of innovative strategies, including prognostic molecular markers and molecular targeted agents is needed.
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Affiliation(s)
- Mu-Tai Liu
- Department of Radiation Oncology, Changhua Christian Hospital, 135 Nan Shiau Street, Changhua, Taiwan 500, ROC.,Department of Oncology, National Taiwan University Hospital, 7 Chung San South Road, Taipei, Taiwan 100, ROC.,Department of Medicine, Chang Shan Medical University, 110 Section 1, Chien- Kuo N. Road, Taichung, Taiwan 402, ROC.,Department of Radiology, Yuanpei University of Science and Technology, 306 Yuanpei Street, Hsinchu, Taiwan 300, ROC
| | - Mu-Kuan Chen
- Department of Radiology, Yuanpei University of Science and Technology, 306 Yuanpei Street, Hsinchu, Taiwan 300, ROC.,Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, 135 Nan Shiau Street, Changhua, Taiwan 500, ROC
| | - Chia-Chun Huang
- Department of Radiation Oncology, Changhua Christian Hospital, 135 Nan Shiau Street, Changhua, Taiwan 500, ROC
| | - Chao-Yuan Huang
- Department of Oncology, National Taiwan University Hospital, 7 Chung San South Road, Taipei, Taiwan 100, ROC
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Liu T, Sun Q, Li Q, Yang H, Zhang Y, Wang R, Lin X, Xiao D, Yuan Y, Chen L, Wang W. Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. Mol Cancer Ther 2015; 14:429-39. [PMID: 25504751 DOI: 10.1158/1535-7163.mct-14-0548] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual γ-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2-M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC.
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Affiliation(s)
- Tongxin Liu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Quanquan Sun
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Qi Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Hua Yang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yuqin Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Rong Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiaoshan Lin
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Dong Xiao
- Cancer Research Institute, Southern Medical University, Guangzhou, People's Republic of China
| | - Yawei Yuan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Longhua Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
| | - Wei Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
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Allaya N, Khabir A, Sallemi-Boudawara T, Sellami N, Daoud J, Ghorbel A, Frikha M, Gargouri A, Mokdad-Gargouri R, Ayadi W. Over-expression of miR-10b in NPC patients: correlation with LMP1 and Twist1. Tumour Biol 2015; 36:3807-14. [DOI: 10.1007/s13277-014-3022-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 12/26/2014] [Indexed: 12/20/2022] Open
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Activation of Akt/mTOR pathway is associated with poor prognosis of nasopharyngeal carcinoma. PLoS One 2014; 9:e106098. [PMID: 25165983 PMCID: PMC4148345 DOI: 10.1371/journal.pone.0106098] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 07/23/2014] [Indexed: 12/21/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck region, which frequently occurs in Southeast Asia, especially in the south of China. It is known that the mammalian target of rapamycin (mTOR) pathway plays a central role in regulating cellular functions, including proliferation, growth, survival, mobility, and angiogenesis. Aberrant expression of the mTOR signaling pathway molecules has been found in many types of cancer. However, whether the alterations of p-Akt, p-p70S6K and p-4EBP1 protein expression are associated with clinicopathological features and prognostic implications in NPC have not been reported. The purposes of the present study are to investigate the association between the expression of p-Akt, p-p70S6K and p-4EBP1 proteins and clinicopathological features in NPC by immunohistochemistry. The results showed that the positive percentage of p-Akt, p-p70S6K and p-4EBP1 proteins expression in NPC (47.2%, 73.0% and 61.7%, respectively) was significantly higher than that in the non-cancerous nasopharyngeal control tissue (33.3%, 59.1% and 47.0%, respectively). There was a significantly higher positive expression of p-Akt in undifferentiated non-keratinizing nasopharyngeal carcinoma than that in differentiated non-keratinizing nasopharyngeal carcinoma (P = 0.014). Additionally, positive expression of p-p70S6K and p-4EBP1 proteins, and positive expression of either of p-Akt, p-p70S6K and p-4EBP1 were significantly correlated inversely with overall survival rates of NPC patients (P = 0.023, P = 0.033, P = 0.008, respectively). Spearman’s rank correlation test showed that expression of p-Akt in NPC was significantly associated with expression of p-p70S6K (r = 0.263, P<0.001) and p-4EBP1(r = 0.284, P<0.001). Also there was an obviously positive association between expression of p-p70S6K and p-4EBP1 proteins in NPC (r = 0.286, P<0.001). Multivariate Cox regression analysis further identified positive expression of p-4EBP1 and p-p70S6K proteins were the independent poor prognostic factors for NPC (P = 0.043, P = 0.027, respectively). Taken together, high expression of p-p70S6K and p-4EBP1 proteins may act as valuable independent biomarkers to predict a poor prognosis of NPC.
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Zhao Y, Pang TY, Wang Y, Wang S, Kang HX, Ding WB, Yong WW, Bie YH, Cheng XG, Zeng C, Yao YH, Li Q, Hu XR. LMP1 stimulates the transcription of eIF4E to promote the proliferation, migration and invasion of human nasopharyngeal carcinoma. FEBS J 2014; 281:3004-18. [PMID: 24814906 DOI: 10.1111/febs.12838] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 04/04/2014] [Accepted: 05/07/2014] [Indexed: 01/09/2023]
Abstract
Eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting translation initiation factor for many oncogenes. Previous studies have shown eIF4E overexpression in nasopharyngeal carcinoma (NPC). We aimed to study whether viral oncogene latent membrane protein 1 (LMP1) stimulates the transcription of eIF4E to promote NPC malignancy. In NPC cell lines (CNE1 and CNE2), ectopic LMP1 significantly increased the mRNA and protein levels of eIF4E and the transcriptional activity of the eIF4E promoter in a LMP1-plasmid-transfected dose-dependent manner. As a backward experiment, knocking down of LMP1 significantly reduced eIF4E mRNA in B95-8 cells. In the high LMP1 expression condition, knocking down of c-Myc significantly reduced eIF4E mRNA in both NPC and B95-8 cells, and knocking down of eIF4E significantly inhibited the tumor proliferation, migration and invasion promoted by LMP1. The results indicated that LMP1 stimulates the transcription of eIF4E via c-Myc to promote NPC. To the best of our knowledge, this is the first evidence that LMP1 stimulates the transcription of eIF4E. This might be an important cause of the overexpression of eIF4E in NPC and be the novel mechanism by which LMP1 initiates cancer. LMP1-stimulated eIF4E initiates the translation of those oncogenes transcriptionally activated by LMP1 to amplify and pass down the carcinogenesis signals launched by LMP1.
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Affiliation(s)
- Yi Zhao
- Pathology Department, Cancer Institute of Guangdong Medical College, Dongguan, China; Microbiology and Immunology Department, Guangdong Medical College, Dongguan, China
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Sang Y, Wang L, Tang JJ, Zhang MF, Zhang MX, Liu X, Zhang RH, Kang TB, Chen MY. Oncogenic roles of carbonic anhydrase IX in human nasopharyngeal carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:2942-2949. [PMID: 25031713 PMCID: PMC4097237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 05/05/2014] [Indexed: 06/03/2023]
Abstract
Carbonic anhydrase IX (CA IX), a hypoxia-inducible protein in tumors, has been shown to be valuable for the prognosis of nasopharyngeal carcinoma (NPC). However, the function and mechanism of CA IX has been not explored in NPC. Here, we found that CA IX was detected at higher levels in NPC cells and tissues than their corresponding partners. Furthermore, the cell growth, migration and invasion in vitro were altered with shRNA or overexpression of CA IX in NPC cells. More importantly, the metastatic ability of NPC cells stably expressing CA IX was significantly enhanced using the hepatic metastasis model of nude mice in vivo. Finally, the mTOR pathway was indicated to be involved in such effects of CA IX on NPC. This is the first evidence that CA IX may promote the NPC metastasis to potentially be a therapeutic target for NPC, and that the inhibitory molecules of CA IX and/or the mTOR pathway alone or combination with both may be worth to have a clinical trial for the patients with NPC.
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Affiliation(s)
- Yi Sang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Li Wang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Jian-Jun Tang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Mei-Fang Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Meng-Xia Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Xia Liu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Ru-Hua Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Tie-Bang Kang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
| | - Ming-Yuan Chen
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center Guangzhou 510060, China
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Radiosensitization effect of nedaplatin on nasopharyngeal carcinoma cells in different status of Epstein-Barr virus infection. BIOMED RESEARCH INTERNATIONAL 2014; 2014:713674. [PMID: 24900979 PMCID: PMC4036599 DOI: 10.1155/2014/713674] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 04/15/2014] [Indexed: 12/17/2022]
Abstract
This study aims to evaluate the radiosensitization effect of nedaplatin on nasopharyngeal carcinoma (NPC) cell lines with different Epstein-Barr virus (EBV) status. Human NPC cell lines CNE-2 (EBV-negative) and C666 (EBV-positive) were treated with 0-100 μg/mL nedaplatin, and inhibitory effects on cell viability and IC50 were calculated by MTS assay. We assessed changes in radiosensitivity of cells by MTS and colony formation assays, and detected the apoptosis index and changes in cell cycle by flow cytometry. MTS assay showed that nedaplatin caused significant cytotoxicity in CNE-2 and C666 cells in a time- and dose-dependent manner. After 24 h, nedaplatin inhibited growth of CNE-2 and C666 cells with IC50 values of 34.32 and 63.69 μg/mL, respectively. Compared with radiation alone, nedaplatin enhanced the radiation effect on both cell lines. Nedaplatin markedly increased apoptosis and cell cycle arrest in G2/M phase. Nedaplatin radiosensitized human NPC cells CNE-2 and C666, with a significantly greater effect on the former. The mechanisms of radiosensitization include induction of apoptosis and enhancement of cell cycle arrest in G2/M phase.
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Chu JH, Zhao CR, Song ZY, Wang RQ, Qin YZ, Li WB, Qu XJ. 1082-39, an analogue of sorafenib, inhibited human cancer cell growth more potently than sorafenib. Biomed Pharmacother 2014; 68:335-41. [DOI: 10.1016/j.biopha.2014.01.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 01/20/2014] [Indexed: 01/07/2023] Open
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Li S, Wang L, Xie Y, He X, Zhang Z. The 656C and 725C are two important sites in gene STGC3 for its negative regulation on cell growth. BIOTECHNOL BIOTEC EQ 2014; 28:295-300. [PMID: 26019513 PMCID: PMC4434117 DOI: 10.1080/13102818.2014.916499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 12/27/2013] [Indexed: 10/25/2022] Open
Abstract
The aim of this study was to analyze the functional sites of the nasopharyngeal candidate tumour suppressor gene STGC3. Recombinant plasmid pcDNA3.1TM/myc-His B-STGC3 was constructed. Site-directed mutagenesis of pcDNA3.1TM/myc-His B-STGC3 plasmid at sites of C656G, C725T and T913G was induced by the Stratagene mutagenesis method. Recombinant plasmids with point mutations at C656G, C725T and T913G of gene STGC3 were named as STGC3-C656G, STGC3-C725T and STGC3-T913G, respectively. CNE2 cell lines stably expressing wild and mutant STGC3 genes were established. STGC3 expression was detected by Western Blotting and immunocytochemistry. Cell proliferation was analyzed by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue staining. Flow cytometry analysis was used to assess apoptosis of CNE2 cells. Bax protein expression was detected by Western Blotting. Proteins of wild-type and mutant STGC3 genes were expressed in the cytoplasm and nucleus of CNE2 cells. Compared with the control groups, in cells stably expressing wild-type STGC3 and STGC3-T913G genes, cell proliferation was significantly inhibited, whereas levels of apoptosis and Bax protein expression were significantly increased. However, the cell proliferation, apoptosis and Bax protein expression in cells stably expressing STGC3-C656G and STGC3-C725T genes were not significantly different from those in the control groups. Our results suggest that mutations at 656C and 725C, but not 913T, abolished the effects of the wild-type STGC3 gene on CNE2 cells and that the 656C and 725C were important sites in gene STGC3 for its negative regulation on cell growth.
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Affiliation(s)
- Suyun Li
- Cancer Research Institute, University of South China , Hengyang , Hunan , P.R. China
| | - Lili Wang
- Department of Pathology, Daye People's Hospital , Daye , Hunan , P.R. China
| | - Yuanjie Xie
- Cancer Research Institute, University of South China , Hengyang , Hunan , P.R. China
| | - Xiusheng He
- Cancer Research Institute, University of South China , Hengyang , Hunan , P.R. China
| | - Zhiwei Zhang
- Cancer Research Institute, University of South China , Hengyang , Hunan , P.R. China
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You X, Yang YC, Ke X, Hong SL, Hu GH. Fluorescence visualization screening for EBV-LMP1-targeted DNAzymes. Otolaryngol Head Neck Surg 2013; 150:251-8. [PMID: 24323909 DOI: 10.1177/0194599813514514] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVES To develop a novel screening method for DNAzymes targeting the LMP1 carboxy region. STUDY DESIGN To design a method to screen special DNAzymes toward the Epstein-Barr virus (EBV)-associated carcinoma before clinic use. SETTING Key Laboratory of the Ministry of Education-Molecular Biology of Infectious Diseases in Chongqing Medical University. SUBJECTS AND METHODS Four novel 10-23 DNAzymes (DZ509, DZ1037, DZ893, and DZ827) targeting the EBV-LMP1 gene were designed and evaluated by detecting enhanced green fluorescence protein (EGFP) expression of LMP1 mRNA and the protein in the nasopharyngeal carcinoma (NPC) cell line CNE2 transfected with the pEGFP-C1-LMP1c vector. The screened specific DNAzymes were then transfected into NPC cell lines C666-1 while a mutant oligonucleotide mutDZ509 and an antisense oligonucleotide ASODN509 were designed as positive and negative controls. Cell proliferation, cell apoptosis, LMP1 mRNA, and the protein were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, Annexin V-fluorescence isothiocyanate (FITC), reverse transcription polymerase chain reaction (RT-PCR), and Western blots. RESULTS The inhibition rates of fluorescence expression of the DNAzymes DZ509, DZ1037, DZ893, and DZ827 were 91.25%, 65.84%, 49.02%, and 44.56%, respectively. The results were in accordance with the inhibition effects of mRNA and protein expression. The screened DZ509 could effectively knock down endogenous LMP1 expression in C666-1 cells, inhibit cell proliferation, and induce cell apoptosis compared with mutDZ509 and ASODN509. CONCLUSION LMP1 could present a potential target for DNAzymes toward the EBV-associated carcinoma, and the EGFP expression vector could be a visible method for screening special DNAzymes before clinic use.
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Affiliation(s)
- Xi You
- Department of Otolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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