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Yuan L, Zhong L, Krummenacher C, Zhao Q, Zhang X. Epstein-Barr virus-mediated immune evasion in tumor promotion. Trends Immunol 2025; 46:386-402. [PMID: 40240193 DOI: 10.1016/j.it.2025.03.007] [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: 10/31/2024] [Revised: 03/12/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025]
Abstract
Epstein-Barr virus (EBV) was the first DNA virus identified to be tightly associated with multiple human tumors. It promotes malignant progression of tumors - including related lymphomas, nasopharyngeal carcinoma, and gastric adenocarcinoma - in part by evading surveillance and attack by the host immune system. In this article we review the main molecular mechanisms by which EBV-encoded proteins and RNAs interact with key molecules of the host immune system to inhibit Toll-like receptor (TLR)-nuclear factor κB (NF-κB), retinoic acid-inducible gene I (RIG-I), and interferon (IFN) signaling pathways, affect antigen presentation, prevent the cytotoxic effects of CD8+ effector cells, regulate the tumor microenvironment (TME) and cell metastasis and invasion, and inhibit cell apoptosis. These interactions not only contribute to the persistence of the virus but also provide potential targets for developing new immunotherapy strategies.
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Affiliation(s)
- Lie Yuan
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Ling Zhong
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Claude Krummenacher
- Department of Biological and Biomedical Sciences, Rowan University, Glassboro, NJ, USA.
| | - Qinjian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, China.
| | - Xiao Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, China.
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2
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Huang X, Tang Y. Unveiling the complex double-edged sword role of exosomes in nasopharyngeal carcinoma. PeerJ 2025; 13:e18783. [PMID: 39822977 PMCID: PMC11737332 DOI: 10.7717/peerj.18783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/09/2024] [Indexed: 01/19/2025] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelium of the nasopharynx. Given its late diagnosis, NPC raises serious considerations in Southeast Asia. In addition to resistance to conventional treatment that combines chemotherapy and radiation, NPC has high rates of metastasis and frequent recurrence. Exosomes are small membrane vesicles at the nanoscale that transport physiologically active compounds from their source cell and have a crucial function in signal transmission and intercellular message exchange. The exosomes detected in the tissues of NPC patients have recently emerged as a potential non-invasive liquid biopsy biomarker that plays a role in controlling the tumor pathophysiology. Here, we take a look back at what we know so far about the complex double-edged sword role of exosomes in NPC. Exosomes could serve as biomarkers and therapeutic agents, as well as the molecular mechanisms by which they promote cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance, and chemotherapy resistance in NPC. Furthermore, we go over some of the difficulties and restrictions associated with exosome use. It is anticipated that this article would provide the reference for the apply of exosomes in clinical practice.
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Affiliation(s)
- Xueyan Huang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Yuedi Tang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, China
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3
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Ge J, Liu Y, Chen P, Zeng Z, Li G, Xiong W, Yi M, Xiang B. FOXA1 enhances antitumor immunity via repressing interferon-induced PD-L1 expression in nasopharyngeal carcinoma. J Immunother Cancer 2024; 12:e010091. [PMID: 39542656 PMCID: PMC11575282 DOI: 10.1136/jitc-2024-010091] [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] [Accepted: 10/23/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a distinct subtype of head and neck cancer which is prevalent in south of China and southeastern of Asia. Consistent activation of interferon (IFN) signaling, and impairment of T cell mediated antitumor immunity is frequent in NPC. Forkhead box A1 (FOXA1) is one of the earliest discovered pioneer factors, which can open up compact chromatin structures to facilitate the binding of other proteins to chromatin. METHODS By using RNA sequencing, it was discovered that FOXA1 suppresses the activation of the interferon signaling pathway and the expression of the related interferon-responsive genes in NPC cells. The effect of FOXA1 on programmed death-ligand 1 (PD-L1) expression in C666-1 and HK1 cells under conditions with or without IFN-γ was detected through quantitative PCR (qPCR), western blot, and flow cytometry. After co-culturing T cells with IFN-γ-treated NPC cells in vitro, apoptosis of CD8+ T cells and the expression of cytotoxic cytokines were assessed by flow cytometry. The cytotoxic effects of T cells on tumor cells in nude mice were measured by tumorigenesis in nude mice and adoptive T cell therapy. The effects of IFN-γ on the expression and nuclear localization of STAT1, as well as the colocalization of FOXA1 with STAT1 were detected by immunofluorescence, qPCR, western blot, and co-immunoprecipitation experiments. RESULTS In this study, we reported that loss of FOXA1, a pioneer factor downregulated in NPC, results in activation of IFN signaling in NPC cells. Repression of FOXA1 facilitates IFN-γ induced PD-L1 expression, whereas overexpression of FOXA1 exerts the opposite effect. Mechanistically, FOXA1 interacts with STAT1 and inhibits IRF1 expression and binding to PD-L1 promoter on IFN-γ treatment. Co-culture with FOXA1-silenced NPC cells promotes apoptosis of in vitro activated tumor-specific CD8+T cells and reduces the expression of cytotoxic effector molecules. Furthermore, overexpression of FOXA1 increases the therapeutic efficacy of PD-L1 antibody (atezolizumab) against NPC in nude mice receiving adoptive T-cell therapy. CONCLUSIONS We demonstrated that FOXA1 prevents tumor immune evasion by inhibiting IFN-γ induced PD-L1 expression in NPC cells. Our research findings provide new insights into the immunotherapeutic biomarkers and targets for NPC, which is important for the clinical application of programmed cell death protein-1/PD-L1 antibodies in NPC.
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Affiliation(s)
- Junshang Ge
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, China
| | - Ying Liu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, China
| | - Pan Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, China
| | - Mei Yi
- Department of Dermotology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, China
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Bayat M, Golestani S, Motlaghzadeh S, Bannazadeh Baghi H, Lalehzadeh A, Sadri Nahand J. War or peace: Viruses and metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189179. [PMID: 39299491 DOI: 10.1016/j.bbcan.2024.189179] [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: 06/10/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 09/22/2024]
Abstract
Metastasis, the dissemination of malignant cells from a primary tumor to secondary sites, poses a catastrophic burden to cancer treatment and is the predominant cause of mortality in cancer patients. Metastasis as one of the main aspects of cancer progression could be strongly under the influence of viral infections. In fact, viruses have been central to modern cancer research and are associated with a great number of cancer cases. Viral-encoded elements are involved in modulating essential pathways or specific targets that are implicated in different stages of metastasis. Considering the continuous emergence of new viruses and the establishment of their contribution to cancer progression, the warfare between viruses and cancer appears to be endless. Here we aimed to review the critical mechanism and pathways involved in cancer metastasis and the influence of viral machinery and various routes that viruses adopt to manipulate those pathways for their benefit.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahin Golestani
- Department of ophthalmology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Motlaghzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aidin Lalehzadeh
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Gao S, Chen Z, Wu X, Wang L, Bu T, Li L, Li X, Yun D, Sun F, Cheng CY. Perfluorooctane sulfonate-induced Sertoli cell injury through c-Jun N-terminal kinase: a study by RNA-Seq. Am J Physiol Cell Physiol 2024; 327:C291-C309. [PMID: 38826136 DOI: 10.1152/ajpcell.00212.2024] [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: 04/01/2024] [Revised: 05/14/2024] [Accepted: 05/27/2024] [Indexed: 06/04/2024]
Abstract
Per- and polyfluoroalkyl substances (PFASs) are a family of "forever chemicals" including perfluorooctane sulfonate (PFOS). These toxic chemicals do not break down in the environment or in our bodies. In the human body, PFOS and perfluoroctanoic acid (PFOA) have a half-life (T1/2) of about 4-5 yr so low daily consumption of these chemicals can accumulate in the human body to a harmful level over a long period. Although the use of PFOS in consumer products was banned in the United States in 2022/2023, this forever chemical remains detectable in our tap water and food products. Every American tested has a high level of PFAS in their blood (https://cleanwater.org/pfas-forever-chemicals). In this report, we used a Sertoli cell blood-testis barrier (BTB) model with primary Sertoli cells cultured in vitro with an established functional tight junction (TJ)-permeability barrier that mimicked the BTB in vivo. Treatment of Sertoli cells with PFOS was found to perturb the TJ-barrier, which was the result of cytoskeletal disruption across the cell cytoplasm, disrupting actin and microtubule polymerization. These changes thus affected the proper localization of BTB-associated proteins at the BTB. Using RNA-Seq transcriptome profiling, bioinformatics analysis, and pertinent biochemical and cell biology techniques, it was discovered that PFOS -induced Sertoli cell toxicity through the c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase, SAPK) and its phosphorylated/active form p-JNK signaling pathway. More importantly, KB-R7943 mesylate (KB), a JNK/p-JNK activator, was capable of blocking PFOS-induced Sertoli cell injury, supporting the notion that PFOS-induced cell injury can possibly be therapeutically managed.NEW & NOTEWORTHY PFOS induces Sertoli cell injury, including disruption of the 1) blood-testis barrier function and 2) cytoskeletal organization, which, in turn, impedes male reproductive function. These changes are mediated by JNK/p-JNK signaling pathway. However, the use of KB-R7943, a JNK/p-JNK activator was capable of blocking PFOS-induced Sertoli cell injury, supporting the possibility of therapeutically managing PFOS-induced reproductive dysfunction.
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Affiliation(s)
- Sheng Gao
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
| | - Zifeng Chen
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
| | - Xiaolong Wu
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Lingling Wang
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
| | - Tiao Bu
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
| | - Linxi Li
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xinyao Li
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
| | - Damin Yun
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
| | - Fei Sun
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
| | - C Yan Cheng
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, People's Republic of China
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ZHAO XUHUI, HUANG XIAOMIN, DANG CHUNYAN, WANG XIA, QI YUJIAO, LI HONGLING. The Epstein-Barr virus-miRNA-BART6-5p regulates TGF-β/SMAD4 pathway to induce glycolysis and enhance proliferation and metastasis of gastric cancer cells. Oncol Res 2024; 32:999-1009. [PMID: 38686046 PMCID: PMC11055990 DOI: 10.32604/or.2024.046679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/26/2023] [Indexed: 05/02/2024] Open
Abstract
Background EBV-miR-BARTs exhibit significant relevance in epithelial tumors, particularly in EBV-associated gastric and nasopharyngeal cancers. However, their specific mechanisms in the initiation and progression of gastric cancer remain insufficiently explored. Material and Methods Initially, EBV-miRNA-BART6-5p and its target gene SMAD4 expression were assessed in EBV-associated gastric cancer tissues and cell lines. Subsequent transfection induced overexpression of EBV-miRNA-BART6-5p in AGS and MKN-45, and downregulation in EBV-positive cells (SUN-719). The subsequent evaluation aimed to observe their impact on gastric cancer cell proliferation, migration, and glycolytic processes, with the TGF-β/SMAD4 signaling pathway value clarified using a TGF-β inhibitor. Results EBV-miRNA-BART6-5p exhibits pronounced upregulation in EBV-associated gastric cancer tissues and EBV-positive cells, while its target gene SMAD4 demonstrates downregulated expression. Upregulation of it can promote the proliferation and migration of gastric cancer cells. Additionally, We found EBV-miRNA-BART6-5p promotes glycolysis of gastric cancer cells. Inhibition of the TGF-β/SMAD4 signaling pathway resulted in suppressed proliferation and migration of gastric cancer cells, concomitant with a diminished glycolytic capacity. Conclusion In this study, we found that EBV-miRNA-BART6-5p can target SMAD4, effectively increasing glycolysis in gastric cancer cells by regulating the TGF-β/SMAD4 signaling pathway, thereby enhancing the proliferation and metastasis of gastric cancer cells. Our findings may offer new insights into the metabolic aspects of gastric cancer.
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Affiliation(s)
- XUHUI ZHAO
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, 730000, China
- Department of Oncology, Gansu People’s Hospital, Lanzhou, 730000, China
| | - XIAOMIN HUANG
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, 730000, China
| | - CHUNYAN DANG
- Department of Oncology, Gansu People’s Hospital, Lanzhou, 730000, China
| | - XIA WANG
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, 730000, China
| | - YUJIAO QI
- The Clinical Medical College, Ningxia Medical University, Ningxia, 750004, China
| | - HONGLING LI
- Department of Oncology, Gansu People’s Hospital, Lanzhou, 730000, China
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Chakraborty C, Bhattacharya M, Lee SS. Regulatory role of miRNAs in the human immune and inflammatory response during the infection of SARS-CoV-2 and other respiratory viruses: A comprehensive review. Rev Med Virol 2024; 34:e2526. [PMID: 38446531 DOI: 10.1002/rmv.2526] [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: 01/16/2024] [Revised: 02/11/2024] [Accepted: 02/22/2024] [Indexed: 03/07/2024]
Abstract
miRNAs are single-stranded ncRNAs that act as regulators of different human body processes. Several miRNAs have been noted to control the human immune and inflammatory response during severe acute respiratory infection syndrome (SARS-CoV-2) infection. Similarly, many miRNAs were upregulated and downregulated during different respiratory virus infections. Here, an attempt has been made to capture the regulatory role of miRNAs in the human immune and inflammatory response during the infection of SARS-CoV-2 and other respiratory viruses. Firstly, the role of miRNAs has been depicted in the human immune and inflammatory response during the infection of SARS-CoV-2. In this direction, several significant points have been discussed about SARS-CoV-2 infection, such as the role of miRNAs in human innate immune response; miRNAs and its regulation of granulocytes; the role of miRNAs in macrophage activation and polarisation; miRNAs and neutrophil extracellular trap formation; miRNA-related inflammatory response; and miRNAs association in adaptive immunity. Secondly, the miRNAs landscape has been depicted during human respiratory virus infections such as human coronavirus, respiratory syncytial virus, influenza virus, rhinovirus, and human metapneumovirus. The article will provide more understanding of the miRNA-controlled mechanism of the immune and inflammatory response during COVID-19, which will help more therapeutics discoveries to fight against the future pandemic.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal, India
| | | | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopaedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Gangwon-do, Republic of Korea
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Rismanbaf A. Improving targeted small molecule drugs to overcome chemotherapy resistance. Cancer Rep (Hoboken) 2024; 7:e1945. [PMID: 37994401 PMCID: PMC10809209 DOI: 10.1002/cnr2.1945] [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: 07/15/2023] [Revised: 10/25/2023] [Accepted: 11/12/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Conventional cancer treatments face the challenge of therapeutic resistance, which causes poor treatment outcomes. The use of combination therapies can improve treatment results in patients and is one of the solutions to overcome this challenge. Chemotherapy is one of the conventional treatments that, due to the non-targeted and lack of specificity in targeting cancer cells, can cause serious complications in the short and long-term for patients by damaging healthy cells. Also, the employment of a wide range of strategies for chemotherapy resistance by cancer cells, metastasis, and cancer recurrence create serious problems to achieve the desired results of chemotherapy. Accordingly, targeted therapies can be used as a combination treatment with chemotherapy to both cause less damage to healthy cells, which as a result, they reduce the side effects of chemotherapy, and by targeting the factors that cause therapeutic challenges, can improve the results of chemotherapy in patients. RECENT FINDINGS Small molecules are one of the main targeted therapies that can be used for diverse targets in cancer treatment due to their penetration ability and characteristics. However, small molecules in cancer treatment are facing obstacles that a better understanding of cancer biology, as well as the mechanisms and factors involved in chemotherapy resistance, can lead to the improvement of this type of major targeted therapy. CONCLUSION In this review article, at first, the challenges that lead to not achieving the desired results in chemotherapy and how cancer cells can be resistant to chemotherapy are examined, and at the end, research areas are suggested that more focusing on them, can lead to the improvement of the results of using targeted small molecules as an adjunctive treatment for chemotherapy in the conditions of chemotherapy resistance and metastasis of cancer cells.
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Affiliation(s)
- Amirhossein Rismanbaf
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical SciencesIslamic Azad UniversityTehranIran
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Chen Y, Lin T, Tang L, He L, He Y. MiRNA signatures in nasopharyngeal carcinoma: molecular mechanisms and therapeutic perspectives. Am J Cancer Res 2023; 13:5805-5824. [PMID: 38187072 PMCID: PMC10767356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 10/10/2023] [Indexed: 01/09/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a prevalent cancerous tumor that affects the head and neck region. Recent studies have provided compelling evidence indicating the significant involvement of microRNAs (miRNAs) in the development and progression of NPC. This review aims to present a comprehensive summary of the current knowledge regarding miRNA signatures in NPC, encompassing their expression patterns, molecular mechanisms, and potential therapeutic implications. Initially, the article outlines the aberrant expression of miRNAs in NPC and elucidates their roles in tumor initiation, invasion, and metastasis. Subsequently, the underlying molecular mechanisms of miRNA-mediated regulation of NPC-associated signaling pathways are discussed. Additionally, the review highlights the potential clinical applications of miRNAs as diagnostic and prognostic biomarkers, as well as their therapeutic potential in NPC treatment. In conclusion, this review underscores the critical involvement of miRNAs in NPC pathogenesis and underscores their promise as novel therapeutic targets for combating this devastating disease.
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Affiliation(s)
- Yan Chen
- School of Medicine, Hunan University of Chinese MedicineChangsha, Hunan, China
| | - Ting Lin
- 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 MedicineChangsha 410208, China
- Hunan Provincial Key Lab for The Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Hunan University of Chinese MedicineChangsha 410208, China
| | - Le Tang
- School of Medicine, Hunan University of Chinese MedicineChangsha, Hunan, 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 MedicineChangsha 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 MedicineChangsha 410208, China
- The First Affiliated Hospital of Hunan University of Chinese MedicineChangsha, Hunan, China
| | - Yingchun He
- School of Medicine, Hunan University of Chinese MedicineChangsha, Hunan, 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 MedicineChangsha 410208, China
- Hunan Provincial Key Lab for The Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Hunan University of Chinese MedicineChangsha 410208, China
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Yang G, Zhou J, Guo Z, Fan L, Chen B, Zhang D, Wen H. miR-26b Targets CEP135 Gene to Regulate Nasopharyngeal Carcinoma Proliferation and Migration by NF-κB Pathway. Mol Biotechnol 2023; 65:1857-1868. [PMID: 36820950 PMCID: PMC10518290 DOI: 10.1007/s12033-023-00691-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023]
Abstract
To screen microRNAs (miRNAs) and analyze their role in the nasopharyngeal carcinoma (NPC) development through differential analysis and cytological validation of the nasopharyngeal carcinoma dataset. The Gene Expression Omnibus (GEO) database of NPC-related data were utilized to screen for differential miRNAs, downstream target genes and relevant pathways, and the relationships among them were verified by luciferase reporter assay and cell co-culture. To analyze the function of miRNAs and downstream target genes, a series of mimics, inhibitors or Small interfering RNAs (siRNAs) targeting the downstream target genes were transfected into NPC cells or normal epithelial cells by cell transfection techniques. Cell Counting Kit-8 (CCK8), Transwell, Enzyme-linked immunosorbent assay (ELISA) apoptosis, and western blotting were adopted to determine the changes in cell activity, invasiveness, and apoptosis after differential miRNA and target gene overexpression or downregulation. Differential analysis of miRNA dataset showed that the expression of miR-26b was significantly downregulated in NPC, in agreement with the validation results of nasopharyngeal carcinoma cell lines. And downregulation of miR-26b expression in normal nasopharyngeal epithelial cells transformed the cells to tumors. CEP135 was identified as the miR-26b downstream target gene by mRNA dataset analysis, and a luciferase reporter test revealed a direct targeting link between the two. Upregulation of CEP135 levels in nasopharyngeal cancer cell lines increased cell activity, accelerated cell migration, and inhibited apoptosis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that CEP135 exerted the above effects on cells via the NF-κB pathway, and co-culture with NF-κB pathway blockers reversed cell biological behavior to the level of the control group. MiR-26b downregulation leads to CEP135 overexpression and NF-κB pathway activation in NPC, which enhances proliferation, migration, and prevents apoptosis of nasopharyngeal carcinoma cells. Therefore, the study further clarifies the biological behavior mechanism of NPC and suggests new therapeutic options for NPC.
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Affiliation(s)
- Guangrun Yang
- Department of Radiotherapy, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar City, China
| | - Jiafu Zhou
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Zhong Guo
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Lixia Fan
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Bowen Chen
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Dapeng Zhang
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Haitao Wen
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China.
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Diggins NL, Hancock MH. Viral miRNA regulation of host gene expression. Semin Cell Dev Biol 2023; 146:2-19. [PMID: 36463091 PMCID: PMC10101914 DOI: 10.1016/j.semcdb.2022.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
Viruses have evolved a multitude of mechanisms to combat barriers to productive infection in the host cell. Virally-encoded miRNAs are one such means to regulate host gene expression in ways that benefit the virus lifecycle. miRNAs are small non-coding RNAs that regulate protein expression but do not trigger the adaptive immune response, making them powerful tools encoded by viruses to regulate cellular processes. Diverse viruses encode for miRNAs but little sequence homology exists between miRNAs of different viral species. Despite this, common cellular pathways are targeted for regulation, including apoptosis, immune evasion, cell growth and differentiation. Herein we will highlight the viruses that encode miRNAs and provide mechanistic insight into how viral miRNAs aid in lytic and latent infection by targeting common cellular processes. We also highlight how viral miRNAs can mimic host cell miRNAs as well as how viral miRNAs have evolved to regulate host miRNA expression. These studies dispel the myth that viral miRNAs are subtle regulators of gene expression, and highlight the critical importance of viral miRNAs to the virus lifecycle.
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Affiliation(s)
- Nicole L Diggins
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA
| | - Meaghan H Hancock
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA.
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12
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Ding T, Zhang Y, Ren Z, Cong Y, Long J, Peng M, Faleti OD, Yang Y, Li X, Lyu X. EBV-Associated Hub Genes as Potential Biomarkers for Predicting the Prognosis of Nasopharyngeal Carcinoma. Viruses 2023; 15:1915. [PMID: 37766321 PMCID: PMC10537168 DOI: 10.3390/v15091915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
This study aimed to develop a model using Epstein-Barr virus (EBV)-associated hub genes in order to predict the prognosis of nasopharyngeal carcinoma (NPC). Differential expression analysis, univariate regression analysis, and machine learning were performed in three microarray datasets (GSE2371, GSE12452, and GSE102349) collected from the GEO database. Three hundred and sixty-six EBV-DEGs were identified, 25 of which were found to be significantly associated with NPC prognosis. These 25 genes were used to classify NPC into two subtypes, and six genes (C16orf54, CD27, CD53, CRIP1, RARRES3, and TBC1D10C) were found to be hub genes in NPC related to immune infiltration and cell cycle regulation. It was shown that these genes could be used to predict the prognosis of NPC, with functions related to tumor proliferation and immune infiltration, making them potential therapeutic targets. The findings of this study could aid in the development of screening and prognostic methods for NPC based on EBV-related features.
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Affiliation(s)
- Tengteng Ding
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre (CIRC), Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China; (T.D.); (Y.Z.); (Y.C.); (M.P.)
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
| | - Yuanbin Zhang
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre (CIRC), Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China; (T.D.); (Y.Z.); (Y.C.); (M.P.)
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
| | - Zhixuan Ren
- Department of Radiation Oncology, Huadong Hospital, Fudan University, Shanghai 200040, China;
| | - Ying Cong
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre (CIRC), Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China; (T.D.); (Y.Z.); (Y.C.); (M.P.)
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
| | - Jingyi Long
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Manli Peng
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre (CIRC), Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China; (T.D.); (Y.Z.); (Y.C.); (M.P.)
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
| | - Oluwasijibomi Damola Faleti
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Yinggui Yang
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre (CIRC), Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China; (T.D.); (Y.Z.); (Y.C.); (M.P.)
- Department of Urology, Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China
| | - Xin Li
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre (CIRC), Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China; (T.D.); (Y.Z.); (Y.C.); (M.P.)
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
| | - Xiaoming Lyu
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; (J.L.); (O.D.F.)
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
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13
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Wu Y, Zhang X, Liu C, Li Z, Wen Y, Zheng R, Xu C, Tian J, Wei L, Wang J, Yan Q, Zheng X, Ma J. Epstein-Barr virus microRNA miR-BART2-5p accelerates nasopharyngeal carcinoma metastasis by suppressing RNase Ⅲ endonuclease DICER1. J Biol Chem 2023; 299:105082. [PMID: 37495108 PMCID: PMC10470218 DOI: 10.1016/j.jbc.2023.105082] [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: 01/23/2023] [Revised: 07/08/2023] [Accepted: 07/11/2023] [Indexed: 07/28/2023] Open
Abstract
The development and progression of nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. NPC is usually asymptomatic until it spreads to other sites, and more than 70% of cases are classified as locally advanced disease at diagnosis. EBV-positive nasopharyngeal cancer tissues express only limited viral latent proteins, but express high levels of the EBV-encoded BamHI-A rightward transcript (BART) miRNA molecules. Here, we report that EBV-miRNA-BART2-5p (BART2-5p) promotes NPC cell invasion and metastasis in vivo and in vitro but has no effect on NPC cell proliferation and apoptosis. In addition, BART2-5p altered the mRNA and miRNA expression profiles of NPC cells. The development of human tumors has been reported to be associated with altered miRNAs expression, and overall miRNAs expression is reduced in many types of tumors. We found that BART2-5p downregulated the expression of several miRNAs that could exert oncogenic functions. Mechanistically, BART2-5p directly targets the RNase III endonuclease DICER1, inhibiting its function of cleaving double-stranded stem-loop RNA into short double-stranded RNA, which in turn causes altered expression of a series of key epithelial-mesenchymal transition molecules, and reverting DICER1 expression can rescue this phenotype. Furthermore, analysis from clinical samples showed a negative correlation between BART2-5p and DICER1 expression. According to our study, high expression of BART2-5p in tissues and plasma of patients with NPC is associated with poor prognosis. Our results suggest that, BART2-5p can accelerate NPC metastasis through modulating miRNA profiles which are mediated by DICER1, implying a novel role of EBV miRNAs in the pathogenesis of NPC.
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Affiliation(s)
- Yangge Wu
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Xiaoyue Zhang
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Can Liu
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Zhengshuo Li
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Yuqing Wen
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Run Zheng
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Chenxiao Xu
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Junrui Tian
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Lingyu Wei
- Department of Pathology and Immunology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Jia Wang
- Department of Pathology and Immunology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Qun Yan
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China.
| | - Xiang Zheng
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
| | - Jian Ma
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
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14
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Das P, Pal S, Das N, Chakraborty K, Chatterjee K, Mal S, Choudhuri T. Endogenous PTEN acts as the key determinant for mTOR inhibitor sensitivity by inducing the stress-sensitized PTEN-mediated death axis in KSHV-associated malignant cells. Front Mol Biosci 2023; 10:1062462. [PMID: 37602330 PMCID: PMC10433768 DOI: 10.3389/fmolb.2023.1062462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 04/19/2023] [Indexed: 08/22/2023] Open
Abstract
As a part of viral cancer evolution, KSHV-infected human endothelial cells exert a unique transcriptional program via upregulated mTORC1 signaling. This event makes them sensitive to mTOR inhibitors. Master transcriptional regulator PTEN acts as the prime regulator of mTOR and determining factor for mTOR inhibitory drug resistance and sensitivity. PTEN is post-translationally modified in KSHV-associated cell lines and infected tissues. Our current study is an attempt to understand the functional role of upstream modulator PTEN in determining the sensitivity of mTOR inhibitors against KSHV-infected cells in an in vitro stress-responsive model. Our analysis shows that, despite phosphorylation, endogenous levels of intact PTEN in different KSHV-infected cells compared to normal and non-infected cells are quite high. Genetic overexpression of intact PTEN showed functional integrity of this gene in the infected cells in terms of induction of a synchronized cell death process via cell cycle regulation and mitochondria-mediated apoptosis. PTEN overexpression enhanced the mTOR inhibitory drug activity, the silencing of which hampers the process against KSHV-infected cells. Additionally, we have shown that endogenous PTEN acts as a stress balancer molecule inside KSHV-infected cells and can induce stress-sensitized death program post mTOR inhibitor treatment, lined up in the ATM-chk2-p53 axis. Moreover, autophagic regulation was found as a major regulator in mTOR inhibitor-induced PTEN-mediated death axis from our study. The current work critically intersected the PTEN-mediated stress balancing mechanism where autophagy has been utilized as a part of the KSHV stress management system and is specifically fitted and switched toward autophagy-mediated apoptosis directing toward a therapeutic perspective.
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Affiliation(s)
| | | | | | | | | | | | - Tathagata Choudhuri
- Department of Biotechnology, Visva-Bharati, Santiniketan, West Bengal, India
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15
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Polz A, Morshed K, Bibik R, Drop B, Drop A, Polz-Dacewicz M. Serum and Saliva Level of miR-31-5p and miR-let 7a in EBV Associated Oropharyngeal Cancer. Int J Mol Sci 2023; 24:11965. [PMID: 37569339 PMCID: PMC10418762 DOI: 10.3390/ijms241511965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/23/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Epstein-Barr virus (EBV) has a well-documented association with head and neck neoplasms, including nasopharyngeal carcinoma (NPC). In the last few years, research aimed at elucidating the role of the miRs in the pathogenesis of head and neck cancer (HNC) has gained importance. The study of miRs expression has set new directions in the search for biomarkers with diagnostic and prognostic value, and even in the search for new therapeutic targets for various tumors, including HNC. The aim of current study was to approximate the importance of miR-31-5p and miR-let 7a in the pathogenesis of EBV associated oropharyngeal cancer. For this purpose, experiments were carried out to determine the level of mentioned miRs in serum among patients diagnosed with oropharyngeal cancer linked to EBV infection, depending on histological differentiation-grading (G1-G3) and TNM classification. All clinical specimens stratified by HPV status were HPV negative. The level of antibodies EBNA and EBVCA was also assessed. The obtained results showed a significantly increased serum level of miR-31-5p but decreased level of miR-let 7a in EBV positive oropharyngeal cancer patients. We demonstrated association between the level of tested miRs and clinical stage. Our findings showed that miR-31-5p and miR-let-7a may be involved in development and progression of EBV associated oropharyngeal cancer. Therefore, it seems important to further study these molecules, as well as to determine whether they could be important biomarkers in the diagnosis of oropharyngeal cancer associated with EBV infection.
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Affiliation(s)
- Anna Polz
- Synevo Poland, 80-180 Gdańsk, Poland;
| | - Kamal Morshed
- Department of Otolaryngology Head and Neck Cancer, University of Technology and Humanities in Radom, 26-600 Radom, Poland;
| | - Robert Bibik
- Department of Radiation Oncology, Oncology Center of Radom, 26-600 Radom, Poland;
| | - Bartłomiej Drop
- Department of Computer Science and Medical Statistics with the e-Health Laboratory, 20-090 Lublin, Poland;
| | - Andrzej Drop
- 1st Department of Medical Radiology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Małgorzata Polz-Dacewicz
- Department of Virology with Viral Diagnostics Laboratory, Medical University of Lublin, 20-093 Lublin, Poland
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16
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Dżaman K, Czerwaty K. Extracellular Vesicle-Based Drug Delivery Systems for Head and Neck Squamous Cell Carcinoma: A Systematic Review. Pharmaceutics 2023; 15:pharmaceutics15051327. [PMID: 37242569 DOI: 10.3390/pharmaceutics15051327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 04/07/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
It is estimated that there are over 890,000 new cases of head and neck squamous cell carcinoma (HNSCC) worldwide each year, accounting for approximately 5% of all cancer cases. Current treatment options for HNSCC often cause significant side effects and functional impairments, thus there is a challenge to discover more acceptable treatment technologies. Extracellular vesicles (EVs) can be utilized for HNSCC treatment in several ways, for example, for drug delivery, immune modulation, as biomarkers for diagnostics, gene therapy, or tumor microenvironment modulation. This systematic review summarizes new knowledge regarding these options. Articles published up to 11 December 2022, were identified by searching the electronic databases PubMed/MEDLINE, Scopus, Web of Science, and Cochrane. Only full-text original research papers written in English were considered eligible for analysis. The quality of studies was assessed using the Office of Health Assessment and Translation (OHAT) Risk of Bias Rating Tool for Human and Animal Studies, modified for the needs of this review. Of 436 identified records, 18 were eligible and included. It is important to note that the use of EVs as a treatment for HNSCC is still in the early stages of research, so we summarized information on challenges such as EV isolation, purification, and standardization of EV-based therapies in HNSCC.
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Affiliation(s)
- Karolina Dżaman
- Department of Otolaryngology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland
| | - Katarzyna Czerwaty
- Department of Otolaryngology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland
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17
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Zhang Y, Shi D, Zhang X, Wu S, Liu W, Luo B. Downregulation of MUS81 expression inhibits cell migration and maintains EBV latent infection through miR-BART9-5p in EBV-associated gastric cancer. J Med Virol 2023; 95:e28725. [PMID: 37185865 DOI: 10.1002/jmv.28725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/15/2023] [Accepted: 03/30/2023] [Indexed: 05/17/2023]
Abstract
Epstein-Barr virus (EBV) infection is associated with the occurrence and development of gastric cancer (GC). Methyl methanesulfonate and ultraviolet-sensitive gene 81 (MUS81) is the catalytic component of a structure-specific endonuclease and plays an important role in chromosomal stability. However, the link between EBV infection and MUS81 remains unclear. In the present study, we found that MUS81 expression was much lower in EBV-associated GC cells than in EBV-negative GC. MUS81 acts as an oncogene in GC by inducing the cell migration and proliferation. Western blot and luciferase reporter assays revealed that miR-BART9-5p directly targeted MUS81 and downregulated its expression. Additionally, overexpression of MUS81 in EBV-positive GC cells inhibited the expression of EBV nuclear antigen 1 (EBNA1). EBNA1 is critical for the pathogenesis of EBV-associated tumors and the maintenance of a stable copy number of the viral genomes. Altogether, these results indicated that the lowering MUS81 expression might be a mechanism by EBV to maintain its latent infection.
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Affiliation(s)
- Yan Zhang
- Department of Pathogeny Biology, Basic Medicine College, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, China
| | - Duo Shi
- Department of Pathogeny Biology, Basic Medicine College, Qingdao University, Qingdao, China
| | - Xing Zhang
- Department of Pathogeny Biology, Basic Medicine College, Qingdao University, Qingdao, China
| | - Shuo Wu
- Department of Pathogeny Biology, Basic Medicine College, Qingdao University, Qingdao, China
- Laboratory Medicine Center of Qingdao, Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Wen Liu
- Department of Pathogeny Biology, Basic Medicine College, Qingdao University, Qingdao, China
| | - Bing Luo
- Department of Pathogeny Biology, Basic Medicine College, Qingdao University, Qingdao, China
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18
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Kandeel M. Oncogenic Viruses-Encoded microRNAs and Their Role in the Progression of Cancer: Emerging Targets for Antiviral and Anticancer Therapies. Pharmaceuticals (Basel) 2023; 16:ph16040485. [PMID: 37111242 PMCID: PMC10146417 DOI: 10.3390/ph16040485] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/18/2023] [Accepted: 03/21/2023] [Indexed: 04/29/2023] Open
Abstract
Approximately 20% of all cases of human cancer are caused by viral infections. Although a great number of viruses are capable of causing a wide range of tumors in animals, only seven of these viruses have been linked to human malignancies and are presently classified as oncogenic viruses. These include the Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), human herpesvirus 8 (HHV8), and human T-cell lymphotropic virus type 1 (HTLV-1). Some other viruses, such as the human immunodeficiency virus (HIV), are associated with highly oncogenic activities. It is possible that virally encoded microRNAs (miRNAs), which are ideal non-immunogenic tools for viruses, play a significant role in carcinogenic processes. Both virus-derived microRNAs (v-miRNAs) and host-derived microRNAs (host miRNAs) can influence the expression of various host-derived and virus-derived genes. The current literature review begins with an explanation of how viral infections might exert their oncogenic properties in human neoplasms, and then goes on to discuss the impact of diverse viral infections on the advancement of several types of malignancies via the expression of v-miRNAs. Finally, the role of new anti-oncoviral therapies that could target these neoplasms is discussed.
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Affiliation(s)
- Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
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19
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Li Q, Tie Y, Alu A, Ma X, Shi H. Targeted therapy for head and neck cancer: signaling pathways and clinical studies. Signal Transduct Target Ther 2023; 8:31. [PMID: 36646686 PMCID: PMC9842704 DOI: 10.1038/s41392-022-01297-0] [Citation(s) in RCA: 93] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/27/2022] [Accepted: 12/13/2022] [Indexed: 01/17/2023] Open
Abstract
Head and neck cancer (HNC) is malignant, genetically complex and difficult to treat and is the sixth most frequent cancer, with tobacco, alcohol and human papillomavirus being major risk factors. Based on epigenetic data, HNC is remarkably heterogeneous, and treatment remains challenging. There is a lack of significant improvement in survival and quality of life in patients with HNC. Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy. In addition, resistance to chemotherapy, radiotherapy and some targeted therapies is common. Therefore, it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients. Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies. A well understanding of the pathogenesis of HNC contributes to learning more about its inner association, which provides novel insight into the development of small molecule inhibitors. In this review, we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC, as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy, which may contribute to a more favorable prognosis of HNC. Targeted therapy in combination with other therapies and its limitations were also discussed.
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Affiliation(s)
- Qingfang Li
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Tie
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Aqu Alu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Huashan Shi
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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20
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PRLR and CACNA2D1 Impact the Prognosis of Breast Cancer by Regulating Tumor Immunity. J Pers Med 2022; 12:jpm12122086. [PMID: 36556307 PMCID: PMC9781148 DOI: 10.3390/jpm12122086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Phosphatase and tensin homolog (PTEN) is one of the highly susceptible genes to breast cancer (BC); however, the role of PTEN-related RNAs in BC remains poorly understood. Understanding the effect of PTEN-related RNAs and their mechanisms may be helpful to clinicians. We screened the differentially expressed RNAs (deRNAs) related to PTEN and established the competitive endogenous RNA (ceRNA) network by integrating several databases. After that, the RNA model, prolactin receptor (PRLR)/calcium voltage-gated channel auxiliary subunit alpha2delta 1 (CACNA2D1), was obtained by KM survival analysis and logistic regression analysis. Finally, mutation, methylation, functional enrichment, and immune correlation were analyzed to explore the roles of these RNAs. Our results showed that PRLR might be harmful to BC, while CACNA2D1 might be beneficial to BC. Furthermore, the abnormal expression of PRLR in BC might result from mutation and hypomethylation, while the aberrant expression of CACNA2D1 might be ascribed to methylation. Mechanistically, PRLR might affect the prognosis of BC by inhibiting the expression of immune checkpoints, while CACNA2D1 might improve the prognosis of BC by increasing the immune cells infiltrating into BC and up-regulating the expression of immune checkpoints. The abnormal expression of PRLR and CACNA2D1 in BC is closely related to the prognosis of BC, and they may serve as targets for the treatment of BC.
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21
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Shen D, Hong Y, Feng Z, Chen X, Cai Y, Peng Q, Tu J. Development of dynamical network biomarkers for regulation in Epstein-Barr virus positive peripheral T cell lymphoma unspecified type. Front Genet 2022; 13:966247. [PMID: 36544484 PMCID: PMC9760704 DOI: 10.3389/fgene.2022.966247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
Background: This study was performed to identify key regulatory network biomarkers including transcription factors (TFs), miRNAs and lncRNAs that may affect the oncogenesis of EBV positive PTCL-U. Methods: GSE34143 dataset was downloaded and analyzed to identify differentially expressed genes (DEGs) between EBV positive PTCL-U and normal samples. Gene ontology and pathway enrichment analyses were performed to illustrate the potential function of the DEGs. Then, key regulators including TFs, miRNAs and lncRNAs involved in EBV positive PTCL-U were identified by constructing TF-mRNA, lncRNA-miRNA-mRNA, and EBV encoded miRNA-mRNA regulatory networks. Results: A total of 96 DEGs were identified between EBV positive PTCL-U and normal tissues, which were related to immune responses, B cell receptor signaling pathway, chemokine activity. Pathway analysis indicated that the DEGs were mainly enriched in cytokine-cytokine receptor interaction and chemokine signaling pathway. Based on the TF network, hub TFs were identified regulate the target DEGs. Afterwards, a ceRNA network was constructed, in which miR-181(a/b/c/d) and lncRNA LINC01744 were found. According to the EBV-related miRNA regulatory network, CXCL10 and CXCL11 were found to be regulated by EBV-miR-BART1-3p and EBV-miR-BHRF1-3, respectively. By integrating the three networks, some key regulators were found and may serve as potential network biomarkers in the regulation of EBV positive PTCL-U. Conclusion: The network-based approach of the present study identified potential biomarkers including transcription factors, miRNAs, lncRNAs and EBV-related miRNAs involved in EBV positive PTCL-U, assisting us in understanding the molecular mechanisms that underlie the carcinogenesis and progression of EBV positive PTCL-U.
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Affiliation(s)
- Dan Shen
- Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yin Hong
- Department of Cardiothoracic Surgery, Suzhou BenQ Hospital, Suzhou, China
| | - Zhengyang Feng
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiangying Chen
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuxing Cai
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Qiliang Peng
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China,*Correspondence: Jian Tu, ; Qiliang Peng,
| | - Jian Tu
- Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, China,*Correspondence: Jian Tu, ; Qiliang Peng,
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22
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Meng Q, Sun H, Wu S, Familiari G, Relucenti M, Aschner M, Li X, Chen R. Epstein-Barr Virus-Encoded MicroRNA-BART18-3p Promotes Colorectal Cancer Progression by Targeting De Novo Lipogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202116. [PMID: 36307872 PMCID: PMC9762317 DOI: 10.1002/advs.202202116] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 07/29/2022] [Indexed: 05/14/2023]
Abstract
The Epstein-Barr virus (EBV) genome encodes a cluster of 22 viral microRNAs, called miR-BamHI-A rightward transcripts (miR-BARTs), which are shown to promote the development of cancer. Here, this study reports that EBV-miR-BART18-3p is highly expressed in colorectal cancer (CRC) and is closely associated with the pathological and advanced clinical stages of CRC. Ectopic expression of EBV-miR-BART18-3p leads to increased migration and invasion capacities of CRC cells in vitro and causes tumor metastasis in vivo. Mechanistically, EBV-miR-BART18-3p activates the hypoxia inducible factor 1 subunit alpha/lactate dehydrogenase A axis by targeting Sirtuin, which promotes lactate accumulation and acetyl-CoA production in CRC cells under hypoxic condition. Increased acetyl-CoA utilization subsequently leads to histone acetylation of fatty acid synthase and fatty acid synthase-dependent fat synthesis, which in turn drives de novo lipogenesis. The oncogenic role of EBV-miR-BART18-3p is confirmed in the patient-derived tumor xenograft mouse model. Altogether, the findings define a novel mechanism of EBV-miR-BART18-3p in CRC development through the lipogenesis pathway and provide a potential clinical intervention target for CRC.
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Affiliation(s)
- Qingtao Meng
- Beijing Key Laboratory of Environmental Toxicology, School of Public HealthCapital Medical UniversityBeijing100069P. R. China
- Department of OncologyCapital Medical UniversityBeijing100069P. R. China
| | - Hao Sun
- Department of Occupational HealthSchool of Public HealthShanxi Medical UniversityTaiyuan030001China
- Key Laboratory of Environmental Medicine EngineeringMinistry of EducationSchool of Public HealthSoutheast UniversityNanjing210009P. R. China
| | - Shenshen Wu
- Beijing Key Laboratory of Environmental Toxicology, School of Public HealthCapital Medical UniversityBeijing100069P. R. China
| | - Giuseppe Familiari
- Laboratory of Electron Microscopy “Pietro Motta”SAIMLAL DepartmentFaculty of Pharmacy and MedicineSapienza University of Romevia Alfonso Borelli 50Rome00161Italy
| | - Michela Relucenti
- Laboratory of Electron Microscopy “Pietro Motta”SAIMLAL DepartmentFaculty of Pharmacy and MedicineSapienza University of Romevia Alfonso Borelli 50Rome00161Italy
| | - Michael Aschner
- Department of Molecular PharmacologyAlbert Einstein College of MedicineForchheimer 209, 1300 Morris Park AvenueBronxNY10461USA
| | - Xiaobo Li
- Beijing Key Laboratory of Environmental Toxicology, School of Public HealthCapital Medical UniversityBeijing100069P. R. China
- Key Laboratory of Environmental Medicine EngineeringMinistry of EducationSchool of Public HealthSoutheast UniversityNanjing210009P. R. China
| | - Rui Chen
- Beijing Key Laboratory of Environmental Toxicology, School of Public HealthCapital Medical UniversityBeijing100069P. R. China
- Department of OncologyCapital Medical UniversityBeijing100069P. R. China
- Advanced Innovation Center for Human Brain ProtectionCapital Medical UniversityBeijing100069P. R. China
- Institute for Chemical CarcinogenesisGuangzhou Medical UniversityGuangzhou511436P. R. China
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23
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Li DK, Chen XR, Wang LN, Wang JH, Li JK, Zhou ZY, Li X, Cai LB, Zhong SS, Zhang JJ, Zeng YM, Zhang QB, Fu XY, Lyu XM, Li MY, Huang ZX, Yao KT. Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis. Cancer Gene Ther 2022; 29:1439-1451. [PMID: 35388172 PMCID: PMC9576596 DOI: 10.1038/s41417-022-00453-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/09/2021] [Accepted: 03/01/2022] [Indexed: 12/27/2022]
Abstract
Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.
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Affiliation(s)
- Deng-Ke Li
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xing-Rui Chen
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Li-Na Wang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Guangzhou First People's Hospital, School of Medicine, Southern China University of Technology, Guangzhou, 510180, China
| | - Jia-Hong Wang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Ji-Ke Li
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zi-Ying Zhou
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xin Li
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, 518110, China
| | - Lin-Bo Cai
- Guangdong Sanjiu Brain Hospital, Guangzhou, 510510, China
| | | | - Jing-Jing Zhang
- Department of Radiotherapy, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, 528403, China
| | - Yu-Mei Zeng
- Department of Pathology, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, 528403, China
| | - Qian-Bing Zhang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiao-Yan Fu
- Department of Otorhinolaryngology Head and Neck Surgery, General Hospital of Southern Theater Command, People's Liberation Army of China, Guangzhou, 510010, China
| | - Xiao-Ming Lyu
- Department of laboratory medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Min-Ying Li
- Department of Radiotherapy, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, 528403, China.
| | - Zhong-Xi Huang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Kai-Tai Yao
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
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24
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Skalsky RL. MicroRNA-mediated control of Epstein-Barr virus infection and potential diagnostic and therapeutic implications. Curr Opin Virol 2022; 56:101272. [PMID: 36242893 DOI: 10.1016/j.coviro.2022.101272] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 09/07/2022] [Accepted: 09/15/2022] [Indexed: 11/03/2022]
Abstract
Herpesviruses, such as Epstein-Barr virus (EBV), encode multiple viral microRNAs that are expressed throughout various infection stages. While much progress has been made in evaluating both the viral and host microRNAs (miRNAs) that are detected during infection as well as elucidating their molecular targets in vitro, our understanding of their contributions to pathogenesis in vivo, viral oncogenesis, and clinical implications for these small molecules remains limited. miRNAs are widely recognized as key regulators of global cellular processes, including apoptosis, cell differentiation, and development of immune responses. This review discusses the roles of miRNAs in EBV infection and current advances in miRNA-based diagnostic and therapeutic strategies potentially applicable toward EBV-associated diseases.
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Affiliation(s)
- Rebecca L Skalsky
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, USA.
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25
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Liu X, Deng Y, Huang Y, Ye J, Xie S, He Q, Chen Y, Lin Y, Liang R, Wei J, Li Y, Zhang J. Nasopharyngeal Carcinoma Progression: Accumulating Genomic Instability and Persistent Epstein–Barr Virus Infection. Curr Oncol 2022; 29:6035-6052. [PMID: 36135044 PMCID: PMC9498130 DOI: 10.3390/curroncol29090475] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/09/2022] [Accepted: 08/19/2022] [Indexed: 12/01/2022] Open
Abstract
Genomic instability facilitates the evolution of cells, tissues, organs, and species. The progression of human malignancies can be regarded as the accumulation of genomic instability, which confers a high evolutionary potential for tumor cells to adapt to continuous changes in the tumor microenvironment. Nasopharyngeal carcinoma (NPC) is a head-and-neck squamous-cell carcinoma closely associated with Epstein–Barr virus (EBV) infection. NPC progression is driven by a combination of accumulated genomic instability and persistent EBV infection. Here, we present a review of the key characteristics of genomic instability in NPC and the profound implications of EBV infection. We further discuss the significance of profiling genomic instability for the assessment of disease progression and treatment efficacy, as well as the opportunities and challenges of targeted therapies for NPC based on its unique genomic instability.
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Affiliation(s)
- Xue Liu
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
| | - Yayan Deng
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
| | - Yujuan Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
| | - Jiaxiang Ye
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
| | - Sifang Xie
- Department of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning 530021, China
| | - Qian He
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yong Chen
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
| | - Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
| | - Jiazhang Wei
- Department of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning 530021, China
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
- Correspondence: (Y.L.); (J.Z.)
| | - Jinyan Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, China
- Correspondence: (Y.L.); (J.Z.)
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26
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Li HL, Deng NH, He XS, Li YH. Small biomarkers with massive impacts: PI3K/AKT/mTOR signalling and microRNA crosstalk regulate nasopharyngeal carcinoma. Biomark Res 2022; 10:52. [PMID: 35883139 PMCID: PMC9327212 DOI: 10.1186/s40364-022-00397-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumours of the head and neck in Southeast Asia and southern China. The Phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in processes related to tumour initiation/progression, such as proliferation, apoptosis, metastasis, and drug resistance, and is closely related to the clinicopathological features of NPC. In addition, key genes involved in the PI3K/AKT/mTOR signalling pathway undergo many changes in NPC. More interestingly, a growing body of evidence suggests an interaction between this signalling pathway and microRNAs (miRNAs), a class of small noncoding RNAs. Therefore, in this review, we discuss the interactions between key components of the PI3K/AKT/mTOR signalling pathway and various miRNAs and their importance in NPC pathology and explore potential diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Hai-Long Li
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Medical College, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P.R. China
| | - Nian-Hua Deng
- Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P.R. China
| | - Xiu-Sheng He
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Medical College, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P.R. China.
| | - Yue-Hua Li
- Department of Medical Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001, Hengyang, P.R. China.
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27
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Erfanparast L, Taghizadieh M, Shekarchi AA. Non-Coding RNAs and Oral Cancer: Small Molecules With Big Functions. Front Oncol 2022; 12:914593. [PMID: 35898889 PMCID: PMC9309727 DOI: 10.3389/fonc.2022.914593] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/16/2022] [Indexed: 12/24/2022] Open
Abstract
Oral cancer remains a major public concern with considerable socioeconomic impact in the world. Despite substantial advancements have been made in treating oral cancer, the five-year survival rate for oral cancer remained undesirable, and the molecular mechanisms underlying OSCC carcinogenesis have not been fully understood. Noncoding RNAs (ncRNAs) include transfer RNAs (tRNAs), as well as small RNAs such as microRNAs, and the long ncRNAs such as HOTAIR are a large segment of the transcriptome that do not have apparent protein-coding roles, but they have been verified to play important roles in diverse biological processes, including cancer cell development. Cell death, such as apoptosis, necrosis, and autophagy, plays a vital role in the progression of cancer. A better understanding of the regulatory relationships between ncRNAs and these various types of cancer cell death is therefore urgently required. The occurrence and development of oral cancer can be controlled by increasing or decreasing the expression of ncRNAs, a method which confers broad prospects for oral cancer treatment. Therefore, it is urgent for us to understand the influence of ncRNAs on the development of different modes of oral tumor death, and to evaluate whether ncRNAs have the potential to be used as biological targets for inducing cell death and recurrence of chemotherapy. The purpose of this review is to describe the impact of ncRNAs on cell apoptosis and autophagy in oral cancer in order to explore potential targets for oral cancer therapy.
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Affiliation(s)
- Leila Erfanparast
- Department of Pediatric Dentistry, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Mohammad Taghizadieh,
| | - Ali Akbar Shekarchi
- Department of Pathology, Tabriz University of Medical Sciences, Tabriz, Iran
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28
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Wu G, Huang W, Xu J, Li W, Wu Y, Yang Q, Liu K, Zhu M, Balasubramanian PS, Li M. Dynamic contrast-enhanced MRI predicts PTEN protein expression which can function as a prognostic measure of progression-free survival in NPC patients. J Cancer Res Clin Oncol 2022; 148:1771-1780. [PMID: 34398299 DOI: 10.1007/s00432-021-03764-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/10/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVES The objective of our study was to investigate whether a phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression was associated with dynamic contrast-enhanced MRI (DCE-MRI) parameters and prognosis in nasopharyngeal carcinoma (NPC). METHODS Two-hundred-and-forty-five (245) patients with NPC who underwent pretreatment biopsy, expression of PTEN detected by immunohistochemistry of biopsy, and radical intensity-modulated radiation therapy (IMRT) with or without chemotherapy were included. Tumor segmentations were delineated on pretreatment MRI manually. The pharmacokinetic parameters (Ktrans, Kep, Ve, and Vp) derived from dynamic contrast-enhanced MRI (DCE-MRI) using the extended Toft's model within the tumor segmentations were estimated. The following demographics and clinical features were assessed and correlated against each other: gender, age, TNM stage, clinical-stage, Epstein-Barr virus (EBV), pathological type, progression-free survival (PFS), and prognosis status. DCE parameter evaluation and clinical feature comparison between the PTEN positive and negative groups were performed and correlation between PTEN expression with the PFS and prognosis status using Cox regression for survival analysis were assessed. RESULTS A significantly lower Ktrans and Kep were found in NPC tumors in PTEN negative patients than in PTEN positive patients. Ktrans performed better than Kep in detecting PTEN expression with the ROC AUC of 0.752. PTEN negative was associated with later TNM stage, later clinical-stage, shorter PFS, and worse prognosis. Moreover, N stage, pathological type, Kep, and prognostic status can be considered as independent variables in discrimination of PTEN negative expression in NPCs. CONCLUSIONS PTEN negative indicated a shorter PFS and worse prognosis than PTEN positive in NPC patients. Ktrans and Kep derived from DCE-MRI, which yielded reliable capability, may be considered as potential imaging markers that are correlated with PTEN expression and could be used to predict PTEN expression noninvasively. Combined radiological and clinical features can improve the performance of the classification of PTEN expression.
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Affiliation(s)
- Gang Wu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, No. 3, Xueyuan Road, Longhua District, HaiKou, 571199, Hainan, People's Republic of China
- Department of Radiotherapy, Affiliated Hainan Hospital of Hainan Medical University (Hainan General Hospital), HaiKou, People's Republic of China
| | - Weiyuan Huang
- Department of Radiology, Affiliated Hainan Hospital of Hainan Medical University (Hainan General Hospital), HaiKou, People's Republic of China
| | - Junnv Xu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, No. 3, Xueyuan Road, Longhua District, HaiKou, 571199, Hainan, People's Republic of China
- Department of Medical Oncology, the Second Affiliated Hospital of Hainan Medical University, HaiKou, People's Republic of China
| | - Wenzhu Li
- Department of Radiology, Affiliated Hainan Hospital of Hainan Medical University (Hainan General Hospital), HaiKou, People's Republic of China
| | - Yu Wu
- Department of Pathology, Affiliated Hainan Hospital of Hainan Medical University (Hainan General Hospital), HaiKou, People's Republic of China
| | - Qianyu Yang
- Department of Radiology, Affiliated Hainan Hospital of Hainan Medical University (Hainan General Hospital), HaiKou, People's Republic of China
| | - Kun Liu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, No. 3, Xueyuan Road, Longhua District, HaiKou, 571199, Hainan, People's Republic of China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, No. 3, Xueyuan Road, Longhua District, HaiKou, 571199, Hainan, People's Republic of China
| | | | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, No. 3, Xueyuan Road, Longhua District, HaiKou, 571199, Hainan, People's Republic of China.
- Institution of Tumor, Hainan Medical University, No. 3, Xueyuan Road, Longhua District, HaiKou, 571199, Hainan, People's Republic of China.
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29
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Yang T, You C, Meng S, Lai Z, Ai W, Zhang J. EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis. Front Cell Infect Microbiol 2022; 12:935205. [PMID: 35846746 PMCID: PMC9283984 DOI: 10.3389/fcimb.2022.935205] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 05/31/2022] [Indexed: 01/05/2023] Open
Abstract
Viral oncogenes may drive cellular metabolic reprogramming to modulate the normal epithelia cell malignant transformation. Understanding the viral oncogene-mediated signaling transduction dysregulation that involves in metabolic reprogramming may provide new therapeutic targets for virus-associated cancer treatment. Latent EBV infection and expression of viral oncogenes, including latent membrane proteins 1 and 2 (LMP1/2), and EBV-encoded BamH I-A rightward transcripts (BART) microRNAs (miR-BARTs), have been demonstrated to play fundamental roles in altering host cell metabolism to support nasopharyngeal carcinoma (NPC) pathogenesis. Yet, how do EBV infection and its encoded oncogenes facilitated the metabolic shifting and their roles in NPC carcinogenesis remains unclear. In this review, we will focus on delineating how EBV infection and its encoded oncoproteins altered the metabolic reprograming of infected cells to support their malignances. Furthermore, based on the understanding of the host's metabolic signaling alterations induced by EBV, we will provide a new perspective on the interplay between EBV infection and these metabolic pathways and offering a potential therapeutic intervention strategy in the treatment of EBV-associated malignant diseases.
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Affiliation(s)
- Tingting Yang
- Department of Pharmacy, Shenzhen University General Hospital, Shenzhen, China
| | - Chanping You
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Shuhui Meng
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, Shenzhen People’s Hospital, Shenzhen, China
| | - Zhengquan Lai
- Department of Pharmacy, Shenzhen University General Hospital, Shenzhen, China
| | - Weipeng Ai
- Department of Pharmacy, Shenzhen University General Hospital, Shenzhen, China
| | - Jun Zhang
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, China
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30
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Jasinski-Bergner S, Blümke J, Bauer M, Skiebe SL, Mandelboim O, Wickenhauser C, Seliger B. Novel approach to identify putative Epstein-Barr-virus microRNAs regulating host cell genes with relevance in tumor biology and immunology. Oncoimmunology 2022; 11:2070338. [PMID: 35529676 PMCID: PMC9067544 DOI: 10.1080/2162402x.2022.2070338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 11/07/2022] Open
Abstract
The human Epstein-Barr virus is associated with several human solid and hematopoietic malignancies. However, the underlying molecular mechanisms including virus-encoded microRNAs (miRs), which lead to the malignant transformation of infected cells and immune evasion of EBV-associated tumors, have not yet been characterized. The expression levels of numerous known EBV-specific miRs and their suitability as diagnostic and/or prognostic markers were determined in different human EBV-positive tissues followed by in silico analyses to identify putative EBV-miR-regulated target genes, thereby offering a suitable screening strategy to overcome the limited available data sets of EBV-miRs and their targeted gene networks. Analysis of microarray data sets from healthy human B cells and malignant-transformed EBV-positive B cells of patients with Burkitt's lymphoma revealed statistically significant (p < 0.05) deregulated genes with known functions in oncogenic properties, immune escape and anti-tumoral immune responses. Alignments of in vivo and in silico data resulted in the prediction of putative candidate EBV-miRs and their target genes. Thus, a combinatorial approach of bioinformatics, transcriptomics and in situ expression analyses is a promising tool for the identification of EBV-miRs and their potential targets as well as their eligibility as markers for EBV detection in different EBV-associated human tissue.
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Affiliation(s)
- Simon Jasinski-Bergner
- Institute for Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Juliane Blümke
- Institute for Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Marcus Bauer
- Institute for Pathology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Saskia Luise Skiebe
- Institute for Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Ofer Mandelboim
- Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, En Kerem, P.O. Box 12271, Jerusalem91120, Israel
| | - Claudia Wickenhauser
- Institute for Pathology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Barbara Seliger
- Institute for Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
- Department of Good Manufacturing Practice (GMP) Development & Advanced Therapy Medicinal Products (ATMP) Design, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany
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31
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Yang H, Qin G, Luo Z, Kong X, Gan C, Zhang R, Jiang W. MFSD4A inhibits the malignant progression of nasopharyngeal carcinoma by targeting EPHA2. Cell Death Dis 2022; 13:332. [PMID: 35410462 PMCID: PMC9001682 DOI: 10.1038/s41419-022-04793-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/03/2022] [Accepted: 03/22/2022] [Indexed: 11/23/2022]
Abstract
DNA Methylation can lead to abnormal gene expression. In the present study, we investigated whether the expression of methylated MFSD4A (major facilitator superfamily domain containing 4 A) was downregulated in nasopharyngeal carcinoma (NPC) and whether it is associated with malignant progression and poor prognosis of NPC. Bioinformatic analysis, bisulfite pyrosequencing, quantitative real-time reverse transcription PCR, and western blotting assays were performed to explore the relationship between hypermethylation of MFSD4A and its expression in NPC. The role of MFSD4A in NPC was verified by Cell Cycle Kit 8, transwell assays and flow cytometry in vitro and by animal experiments in vivo. Mass spectrometry, co-immunoprecipitation, and immunofluorescence assays were applied to explore the mechanism by which MFSD4A inhibits NPC. The prognostic significance of MFSD4A or EPHA2 was investigated by immunohistochemical analysis of clinical specimens. Hypermethylation of the promoter region of MFSD4A led to decreased expression of MFSD4A. When MFSD4A expression was upregulated or downregulated, the proliferation, apoptosis, migration, and invasion abilities of NPC cells were altered accordingly. Mechanistically, MFSD4A could specifically bind to and degrade EPH receptor A2 (EPHA2) by recruiting ring finger protein 149 (RNF149), which led to alterations in the EPHA2-mediated PI3K-AKT-ERK1/2 pathway and epithelial-mesenchymal transition (EMT), thereby affecting NPC progression. Clinically, high MFSD4A expression or low-EPHA2 expression was associated with better prognosis for patients with NPC. In all, reduced MFSD4A expression in NPC is caused by promoter hypermethylation. MFSD4A or EPHA2 expression is associated with the malignant biological behavior and prognosis of NPC. MFSD4A is a promising potential therapeutic target for NPC.
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The World of Oral Cancer and Its Risk Factors Viewed from the Aspect of MicroRNA Expression Patterns. Genes (Basel) 2022; 13:genes13040594. [PMID: 35456400 PMCID: PMC9027895 DOI: 10.3390/genes13040594] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 01/27/2023] Open
Abstract
Oral cancer is one of the leading causes of death worldwide, with a reported 5-year survival rate of around 50% after treatment. Epigenetic modifications are considered to have a key role in oral carcinogenesis due to histone modifications, aberrant DNA methylation, and altered expression of miRNAs. MicroRNAs (miRNAs) are small non-coding RNAs that have a key role in cancer development by regulating signaling pathways involved in carcinogenesis. MiRNA deregulation identified in oral cancer has led to the idea of using them as potential biomarkers for early diagnosis, prognosis, and the development of novel therapeutic strategies. In recent years, a key role has been observed for risk factors in preventing and treating this malignancy. The purpose of this review is to summarize the recent knowledge about the altered mechanisms of oral cancer due to risk factors and the role of miRNAs in these mechanisms.
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Han S, Tay JK, Loh CJL, Chu AJM, Yeong JPS, Lim CM, Toh HC. Epstein–Barr Virus Epithelial Cancers—A Comprehensive Understanding to Drive Novel Therapies. Front Immunol 2021; 12:734293. [PMID: 34956172 PMCID: PMC8702733 DOI: 10.3389/fimmu.2021.734293] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
Epstein–Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour–microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.
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Affiliation(s)
- Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joshua K. Tay
- Department of Otolaryngology—Head & Neck Surgery, National University of Singapore, Singapore, Singapore
| | | | | | - Joe Poh Sheng Yeong
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Chwee Ming Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- *Correspondence: Han Chong Toh,
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34
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Valverde A, Seal A, Nares S, Shukla D, Naqvi AR. Human herpesvirus-encoded MicroRNA in host-pathogen interaction. Adv Biol Regul 2021; 82:100829. [PMID: 34560402 PMCID: PMC11646283 DOI: 10.1016/j.jbior.2021.100829] [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: 06/21/2021] [Revised: 08/28/2021] [Accepted: 09/13/2021] [Indexed: 11/17/2022]
Abstract
Human herpesviruses (HHV) are ubiquitous, linear dsDNA viruses that establish lifelong latency, disrupted by sporadic reactivation. HHV have evolved diverse ingenious mechanisms to evade robust host defenses. Incorporation of unique stem loop sequences that generate viral microRNAs (v-miRs) exemplifies one such evolutionary adaptation in HHV. These noncoding RNAs can control cellular and viral transcriptomes highlighting their ability in shaping host-HHV interactions. We summarize recent developments in functional characterization of HHV-encoded miRNAs in shaping the outcome of host-pathogen interaction. Non-immunogenic dissemination of v-miRs through exosomes confer added advantage to HHV in incessant modulation of host microenvironment. This review delineates the mechanistic role of v-miRs in facilitating viral persistence and tropism by targeting genes associated with cellular (apoptosis, angiogenesis, cell migration, etc.) and viral life cycle (latency, lytic and reactivation). Burgeoning evidences indicate plausible association of v-miRs in various immune-mediated diseases (nasopharyngeal carcinoma, neurological disorders, periodontal diseases, etc.) and herpesvirus-related malignancies indicating their broad-spectrum impact on host cellular pathways. We propose to exploit tisssue and systemic levels of v-miRs as diagnostic and prognostic markers for cancers and immune-mediated diseases. Therapeutic targeting of v-miRs will advance the promising outcomes of preclinical discoveries to bedside application.
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Affiliation(s)
- Araceli Valverde
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Alexandra Seal
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Salvador Nares
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Deepak Shukla
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, United States; Department of Ophthalmology and Visual Sciences, University of Illinois Medical Center, Chicago, IL, United States
| | - Afsar Raza Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States.
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35
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Chen W, Xie Y, Wang T, Wang L. New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review). Oncol Rep 2021; 47:13. [PMID: 34779497 PMCID: PMC8600424 DOI: 10.3892/or.2021.8224] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/19/2021] [Indexed: 02/05/2023] Open
Abstract
Epstein-Barr virus (EBV) is endemic worldwide and is associated with a number of human tumors. EBV-associated tumors have unique mechanisms of tumorigenesis. EBV encodes multiple oncogenic molecules that can be loaded into exosomes released by EBV+ tumor cells to mediate intercellular communication. Moreover, different EBV+ tumor cells secrete exosomes that act on various target cells with various biological functions. In addition to oncogenicity, EBV+ exosomes have potential immunosuppressive effects. Investigating EBV+ exosomes could identify the role of EBV in tumorigenesis and progression. The present review summarized advances in studies focusing on exosomes and the functions of EBV+ exosomes derived from different EBV-associated tumors. EBV+ exosomes are expected to become a new biomarker for disease diagnosis and prognosis. Therefore, exosome-targeted therapy displays potential.
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Affiliation(s)
- Wei Chen
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yao Xie
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Tingting Wang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lin Wang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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36
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Wang Y, Zheng M, Jiang Q, Xu Y, Zhou X, Zhang N, Sun D, Li H, Chen L. Chemical Components of the Fruits of Morus nigra Linn.: Methyl Caffeate as a Potential Anticancer Agent by Targeting 3-Phosphoglycerate Dehydrogenase. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:12433-12444. [PMID: 34664962 DOI: 10.1021/acs.jafc.1c03215] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Two previously undescribed compounds, moranigrine A (1) and morusamine (2), along with 18 known compounds were isolated from the fruits of Morus nigra Linn. and structurally characterized using spectroscopic data and electronic circular dichroism analyses. All isolates were evaluated for their inhibitory effects on the 3-phosphoglycerate dehydrogenase (PHGDH) enzyme, which catalyzes the first committed step for the synthesis of glucose-derived serine and is associated with many kinds of cancers. Among these compounds, methyl caffeate (3) exhibited effective inhibition against PHGDH and was directly bound to PHGDH based on the microscale thermophoresis method and the cellular thermal shift assay. Further biochemical assays revealed that 3 was a noncompetitive inhibitor with respect to the substrate of 3-phosphoglycerate and exhibited a concentration-dependent inhibition. Molecular docking demonstrated that 3 coordinated in an allosteric site of PHGDH with low binding energy. Meanwhile, 3 was selectively toxic to high PHGDH-expressing cancer cell lines and could cause apoptosis of cervical cancer cells in micromolar concentrations and could obviously inhibit tumor growth in the HeLa xenograft mouse model with low toxicities. Therefore, 3 could be developed as a potential inhibitor of PHGDH for the treatment of cancers. Our present study provides information about M. nigra as a functional food or pharmaceutical supplement in the application of cancer prevention and treatment.
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Affiliation(s)
- Yali Wang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Mengzhu Zheng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qinghua Jiang
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yang Xu
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xuechen Zhou
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Na Zhang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
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Li DK, Chen XR, Wang LN, Wang JH, Wen YT, Zhou ZY, Li JK, Liu JX, Cai LB, Zhong SS, Lyu XM, Damola FO, Li MY, Zhang JJ, Zeng YM, Wang QL, Zhang QB, Lyu H, Fu XY, Wang W, Li X, Huang ZX, Yao KT. Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma. Mol Cancer Res 2021; 20:161-175. [PMID: 34654722 DOI: 10.1158/1541-7786.mcr-21-0164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/21/2021] [Accepted: 09/30/2021] [Indexed: 11/16/2022]
Abstract
Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.
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Affiliation(s)
- Deng-Ke Li
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Xing-Rui Chen
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Li-Na Wang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China.,Guangzhou First People's Hospital, School of Medicine, Southern China University of Technology, Guangzhou, P.R. China
| | - Jia-Hong Wang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Yue-Ting Wen
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Zi-Ying Zhou
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Ji-Ke Li
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Jing-Xian Liu
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Lin-Bo Cai
- Guangdong Sanjiu Brain Hospital, Guangzhou, P.R. China
| | | | - Xiao-Ming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Faleti Oluwasijibomi Damola
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Min-Ying Li
- Department of Radiotherapy, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, P.R. China
| | - Jing-Jing Zhang
- Department of Radiotherapy, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, P.R. China
| | - Yu-Mei Zeng
- Department of Pathology, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, P.R. China
| | - Qian-Li Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, P.R. China
| | - Qian-Bing Zhang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Hao Lyu
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Xiao-Yan Fu
- Department of Otorhinolaryngology Head and Neck Surgery, General Hospital of Southern Theater Command, People's Liberation Army of China, Guangzhou, P.R. China
| | - Wei Wang
- Department of Pathology, General Hospital of Southern Theater Command, People's Liberation Army of China, Guangzhou, P.R. China
| | - Xin Li
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, P.R. China.
| | - Zhong-Xi Huang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China.
| | - Kai-Tai Yao
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China.
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Epstein-Barr Virus miR-BART1-3p Regulates the miR-17-92 Cluster by Targeting E2F3. Int J Mol Sci 2021; 22:ijms222010936. [PMID: 34681596 PMCID: PMC8539899 DOI: 10.3390/ijms222010936] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 12/21/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with several tumors and generates BamHI A rightward transcript (BART) microRNAs (miRNAs) from BART transcript introns. These BART miRNAs are expressed at higher levels in EBV-associated epithelial malignancies than in EBV-infected B lymphomas. To test the effects of EBV miRNA on the cell cycle and cell growth, we transfected miR-BART1-3p, a highly expressed EBV-associated miRNA, into gastric carcinoma cells. We found that miR-BART1-3p induced G0/G1 arrest and suppressed cell growth in gastric carcinoma cells. As our microarray analyses showed that E2F3, a cell cycle regulator, was inhibited by EBV infection, we hypothesized that miR-BART1-3p regulates E2F3. Luciferase assays revealed that miR-BART1-3p directly targeted the 3′-UTR of E2F3 mRNA. Both E2F3 mRNA and encoded protein levels were reduced following miR-BART1-3p transfection. In contrast, E2F3 expression in AGS-EBV cells transfected with a miR-BART1-3p inhibitor was enhanced. As E2F3 has been shown to regulate the expression of highly conserved miR-17-92 clusters in vertebrates, we examined whether this expression is affected by miR-BART1-3p, which can downregulate E2F3. The expression of E2F3, miR-17-92a-1 cluster host gene (MIR17HG), and miR-17-92 cluster miRNAs was significantly reduced in EBV-associated gastric carcinoma (EBVaGC) patients compared with EBV-negative gastric carcinoma (EBVnGC) patients. Further, miR-BART1-3p as well as the siRNA specific to E2F3 inhibited the expression of the miR-17-92 cluster, while inhibition of miR-BART1-3p enhanced the expression of the miR-17-92 cluster in cultured GC cells. Our results suggest a possible role of miR-BART1-3p in cell cycle regulation and in regulation of the miR-17-92 cluster through E2F3 suppression.
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Ge J, Wang J, Xiong F, Jiang X, Zhu K, Wang Y, Mo Y, Gong Z, Zhang S, He Y, Li X, Shi L, Guo C, Wang F, Zhou M, Xiang B, Li Y, Li G, Xiong W, Zeng Z. Epstein-Barr Virus-Encoded Circular RNA CircBART2.2 Promotes Immune Escape of Nasopharyngeal Carcinoma by Regulating PD-L1. Cancer Res 2021; 81:5074-5088. [PMID: 34321242 PMCID: PMC8974435 DOI: 10.1158/0008-5472.can-20-4321] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 05/02/2021] [Accepted: 07/27/2021] [Indexed: 01/07/2023]
Abstract
Epstein-Barr virus (EBV) infection is an established cause of nasopharyngeal carcinoma (NPC) and is involved in a variety of malignant phenotypes, including tumor immune escape. EBV can encode a variety of circular RNAs (circRNA), however, little is known regarding the biological functions of these circRNAs in NPC. In this study, EBV-encoded circBART2.2 was found to be highly expressed in NPC where it upregulated PD-L1 expression and inhibited T-cell function in vitro and in vivo. circBART2.2 promoted transcription of PD-L1 by binding the helicase domain of RIG-I and activating transcription factors IRF3 and NF-κB, resulting in tumor immune escape. These results elucidate the biological function of circBART2.2, explain a novel mechanism of immune escape caused by EBV infection, and provide a new immunotherapy target for treating NPC. SIGNIFICANCE: This work demonstrates that circBART2.2 binding to RIG-I is essential for the regulation of PD-L1 and subsequent immune escape in nasopharyngeal carcinoma.
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Affiliation(s)
- Junshang Ge
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Jie Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Fang Xiong
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xianjie Jiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Kunjie Zhu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yian Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Yongzhen Mo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Zhaojian Gong
- Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shanshan Zhang
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yi He
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lei Shi
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Can Guo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Fuyan Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Yong Li
- Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
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40
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Jasinski-Bergner S, Mandelboim O, Seliger B. Molecular mechanisms of human herpes viruses inferring with host immune surveillance. J Immunother Cancer 2021; 8:jitc-2020-000841. [PMID: 32616556 PMCID: PMC7333871 DOI: 10.1136/jitc-2020-000841] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2020] [Indexed: 02/06/2023] Open
Abstract
Several human herpes viruses (HHVs) exert oncogenic potential leading to malignant transformation of infected cells and/or tissues. The molecular processes induced by viral-encoded molecules including microRNAs, peptides, and proteins contributing to immune evasion of the infected host cells are equal to the molecular processes of immune evasion mediated by tumor cells independently of viral infections. Such major immune evasion strategies include (1) the downregulation of proinflammatory cytokines/chemokines as well as the induction of anti-inflammatory cytokines/chemokines, (2) the downregulation of major histocompatibility complex (MHC) class Ia directly as well as indirectly by downregulation of the components involved in the antigen processing, and (3) the downregulation of stress-induced ligands for activating receptors on immune effector cells with NKG2D leading the way. Furthermore, (4) immune modulatory molecules like MHC class Ib molecules and programmed cell death1 ligand 1 can be upregulated on infections with certain herpes viruses. This review article focuses on the known molecular mechanisms of HHVs modulating the above-mentioned possibilities for immune surveillance and even postulates a temporal order linking regular tumor immunology with basic virology and offering putatively novel insights for targeting HHVs.
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Affiliation(s)
- Simon Jasinski-Bergner
- Institute for Medical Immunology, Martin-Luther-Universitat Halle-Wittenberg, Halle (Saale), Germany
| | - Ofer Mandelboim
- Immunology & Cancer Research Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Barbara Seliger
- Institute for Medical Immunology, Martin-Luther-Universitat Halle-Wittenberg, Halle (Saale), Germany
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Zhou X, Lin Y, Chen Y, Wang L, Peng X, Liao J, Zeng H, Luo W, Wu D, Cai L. Epstein-Barr virus (EBV) encoded microRNA BART8-3p drives radioresistance-associated metastasis in nasopharyngeal carcinoma. J Cell Physiol 2021; 236:6457-6471. [PMID: 33694159 DOI: 10.1002/jcp.30320] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 12/16/2022]
Abstract
Radiotherapy plays an important role in the treatment of nasopharyngeal carcinoma (NPC), however, 20% of patients with NPC exhibit unusual radioresistance. Patients with radioresistance are at risk of recurrence, so it is imperative to explore the mechanism of resistance to radiotherapy. In the past, studies on the mechanism of radioresistance have been restricted to DNA damage and related cell cycle remodeling or apoptosis. So far, no studies have explored the relationship between radioresistance and metastasis. Through the analysis of clinical samples, we observed that the metastasis rate of recurrent NPC was much higher than that of primary patients. In vitro and in vivo experiments showed that NPC cells with acquired radioresistance exhibited a stronger ability for invasion and metastasis. Mechanistically, we found that the Epstein-Barr virus (EBV)-encoded miRNA BART8-3p was increased in patients with NPC, and its expression was positively correlated with adverse prognostic factors, such as radioresistance. Besides this, miR-BART8-3p promoted the epithelial-mesenchymal transition, invasion, and metastasis of radioresistant NPC cells by targeting and inhibiting their PAG1 host gene. These findings suggested a novel role for EBV-miR-BART8-3p in promoting NPC radioresistance-associated metastasis and highlighted its potential value as a prognostic indicator or therapeutic target.
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Affiliation(s)
- Xiaohan Zhou
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanling Lin
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuting Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lingzhi Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- First Clinical Medical College, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaohong Peng
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinrong Liao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Second Clinical Medical College, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hanyi Zeng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenxiao Luo
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dehua Wu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Longmei Cai
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers. Cancers (Basel) 2021; 13:cancers13153909. [PMID: 34359809 PMCID: PMC8345394 DOI: 10.3390/cancers13153909] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/27/2021] [Accepted: 08/01/2021] [Indexed: 12/12/2022] Open
Abstract
EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.
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Wang W, Guo J, Wang Y. MicroRNA-30b-5p promotes the proliferation and migration of human airway smooth muscle cells induced by platelet-derived growth factor by targeting phosphatase and tensin homolog deleted on chromosome ten. Bioengineered 2021; 12:3662-3673. [PMID: 34251961 PMCID: PMC8806833 DOI: 10.1080/21655979.2021.1950401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Dysfunction of airway smooth muscle (ASM) cells is crucial in asthma pathogenesis. Here, microRNA-30b-5p (miR-30b-5p)’s function and mechanism in ASM cells’ multiplication and migration were investigated. Microarray was utilized for identifying the differentially expressed miRNAs in the bronchial epithelial cells of the asthma patients and healthy controls. Platelet-derived growth factor (PDGF) was employed to treat ASM cells to establish an in-vitro asthma model. Quantitative real-time PCR (qRT-PCR) was conducted for detecting the expressions of miR-30b-5p and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2ʹ-deoxyuridine (BrdU) assays were used for examining cell multiplication; Transwell assay was performed for detecting cell migration; cell cycle was analyzed through flow cytometry. The targeted relationship between PTEN and miR-30b-5p was verified using a dual-luciferase reporter gene assay. Western blot was used for detecting the expressions of phosphorylated (p)-phosphatidylinositol 3-kinase (PI3K), PTEN, PI3K, protein kinase B (AKT) and p-AKT in ASM cells. We demonstrated that, miR-30b-5p expression in the bronchial epithelial cells of asthmatic patients was up-regulated. It was also increased in PDGF-stimulated ASM cells. Transfection of miR-30b-5p mimics facilitated ASM cells’ multiplication, migration and cycle progression, while inhibiting miR-30b-5p had the opposite effect. Furthermore, miR-30b-5p could target PTEN to repress PTEN expression. PTEN overexpression attenuated the effect of miR-30b-5p on ASM cells. Moreover, miR-30b-5p overexpression facilitated the expression of p-PI3K and p-AKT in PDGF-stimulated ASM cells. Collectively, miR-30b-5p activates the PI3K/AKT pathway by targeting PTEN to facilitate PDGF-induced dysfunction of ASM cells.
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Affiliation(s)
- Wentao Wang
- Department of Pediatrics, Affiliated Hospital of Chengde Medical University, Chengde City, Hebei Province, China
| | - Jian Guo
- Department of Neonatology, Affiliated Hospital of Chengde Medical University, Chengde City, Hebei Province, China
| | - Yan Wang
- Department of Pediatrics, Affiliated Hospital of Chengde Medical University, Chengde City, Hebei Province, China
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Wang H, Liu J, Zhang Y, Sun L, Zhao M, Luo B. Eukaryotic initiating factor eIF4E is targeted by EBV-encoded miR-BART11-3p and regulates cell cycle and apoptosis in EBV-associated gastric carcinoma. Virus Genes 2021; 57:358-368. [PMID: 34146250 DOI: 10.1007/s11262-021-01854-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 06/08/2021] [Indexed: 12/26/2022]
Abstract
The eukaryotic translation initiation factor 4E (eIF4E) is a component of the eukaryotic translation initiation factor 4F, a significant complex in the protein translation process. It has been found to be closely related to many human tumors, such as gastric carcinoma. It is known that the Epstein-Barr virus (EBV) upregulates eIF4E in various ways in nasopharyngeal carcinoma. However, there are very few studies on eIF4E in EBV-associated gastric carcinoma. We found that the expression level of eIF4E in EBV-associated gastric carcinoma was lower than other types of gastric carcinoma, and the downregulation of eIF4E could lead to increased apoptosis of gastric carcinoma cells, retardation at S phase, and decreased cell migration. The dual luciferase reporter experiment showed that EBV-miR-BART11-3p could directly target the 3'-UTR region of eIF4E, and BART11-3p is the key factor leading to the downregulation of eIF4E. It could provide a new evidence for EBV-regulating host gene to affect the development of gastric carcinoma.
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Affiliation(s)
- Hanqing Wang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Sandong, PR China
| | - Juanjuan Liu
- School of Basic Medicine, Qingdao University, Qingdao, Sandong, PR China
| | - Yan Zhang
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, Sandong, PR China
| | - Lingling Sun
- Department of Pathology, Affiliated Hospital of Qingdao University Medical College, 308 NingXia Road, Qingdao, 266021, PR China
| | - Menghe Zhao
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Sandong, PR China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Sandong, PR China.
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Liao C, Liu H, Luo X. The emerging roles of exosomal miRNAs in nasopharyngeal carcinoma. Am J Cancer Res 2021; 11:2508-2520. [PMID: 34249413 PMCID: PMC8263644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 04/13/2021] [Indexed: 06/13/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a unique subtype of head and neck cancer that is endemic to Southern China and Southeast Asia. Due to the concealed location and intrinsic invasiveness of this disease, majority of NPC patients are diagnosed with advanced stages (III and IV) and poor prognosis. Chemoradiotherapy resistance is a major problem for NPC patients, leading to incomplete local elimination, recurrence and metastasis. Therefore, it is of great significance to seek novel biomarkers and effective therapeutic regimen for clinical management of this deadly cancer. Exosomes are tiny membrane vesicles with a lipid bilayer secreted by most cells in the body, which are widely distributed in various body fluids. They are functionally active in different physiopathological process by carrying and transmitting important signal molecules such as miRNA, mRNA, protein, lipid, etc. Exosomal miRNAs play an important role in tumorigenesis and development of NPC. They are extensively involved in NPC cell proliferation, migration, invasion, neovascularization, radiotherapy resistance and the regulation of tumor immune microenvironment through intercellular communication and control of gene expression. Moreover, exosomal miRNAs can be used as valuable biomarkers for early diagnosis and therapeutic targets of NPC.
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Affiliation(s)
- Chaoliang Liao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South UniversityChangsha 410078, Hunan, PR China
- Cancer Research Institute, School of Basic Medicine, Central South UniversityChangsha 410078, Hunan, PR China
- Key Laboratory of Carcinogenesis, Chinese Ministry of HealthChangsha 410078, Hunan, PR China
| | - Huiwen Liu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South UniversityChangsha 410078, Hunan, PR China
- Cancer Research Institute, School of Basic Medicine, Central South UniversityChangsha 410078, Hunan, PR China
- Key Laboratory of Carcinogenesis, Chinese Ministry of HealthChangsha 410078, Hunan, PR China
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South UniversityChangsha 410078, Hunan, PR China
- Cancer Research Institute, School of Basic Medicine, Central South UniversityChangsha 410078, Hunan, PR China
- Key Laboratory of Carcinogenesis, Chinese Ministry of HealthChangsha 410078, Hunan, PR China
- Molecular Imaging Research Center of Central South UniversityChangsha 410078, Hunan, PR China
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityChangsha 410078, Hunan, China
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Zhang S, Wang B, Zheng L, Fu Z, Fu Y, Huang W, Cheng A. Advances in research on microRNAs related to the invasion and metastasis of nasopharyngeal carcinoma. Curr Mol Pharmacol 2021; 15:463-474. [PMID: 34126919 DOI: 10.2174/1874467214666210614150720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 01/22/2021] [Accepted: 02/22/2021] [Indexed: 12/24/2022]
Abstract
Nasopharyngeal carcinoma (NPC), which is associated with latent Epstein-Barr virus infection in most cases, is a unique epithelial malignancy arising from the nasopharyngeal mucosal lining. Accumulating evidence provides insights into the genetic and molecular aberrations that likely drive nasopharyngeal tumor development and progression. We review recent analyses of microRNAs (miRNAs), including Epstein-Barr virus-encoded miRNAs (EBV-encoded miRNAs) and dysregulated cellular miRNAs, that may be related to the metastasis of nasopharyngeal carcinoma. The studies summarized herein have greatly expanded our knowledge of the molecular biology of NPC involving miRNAs, and they may provide new biological targets for clinical diagnosis and reveal the potential of microRNA therapeutics. However, much information remains to be uncovered.
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Affiliation(s)
- ShanShan Zhang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, China
| | - BaiQi Wang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, China
| | - LuLu Zheng
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, China
| | - ZhuQiong Fu
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, China
| | - YiTing Fu
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, China
| | - WeiGuo Huang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, China
| | - AiLan Cheng
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, China
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Wu A, Zhang L, Luo N, Zhang L, Li L, Liu Q. Limb-bud and heart (LBH) inhibits cellular migration, invasion and epithelial-mesenchymal transition in nasopharyngeal carcinoma via downregulating αB-crystallin expression. Cell Signal 2021; 85:110045. [PMID: 34000384 DOI: 10.1016/j.cellsig.2021.110045] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 04/06/2021] [Accepted: 05/12/2021] [Indexed: 02/07/2023]
Abstract
Limb-bud and heart (LBH) gene has received increasing attention in recent cancer studies. Here we investigated the role of the LBH gene in regulating the metastasis capacity and epithelial-mesenchymal transition (EMT) of nasopharyngeal carcinoma (NPC) cells, and its potential mechanism. The expressions of LBH and αB-crystallin (CRYAB) were modulated by lentiviral infection, or plasmid/siRNA transfection, and the phosphorylation of p38 was suppressed by an inhibitor, to explore their functions in modulating NPC cell phenotypes, as well as the relationships of these factors with each other. Cellular proliferation, migration and invasion were examined by RTCA system, Transwell assays and Matrigel Transwell assays respectively. The EMT progression was indicated by RT-qPCR and Western blotting measuring the expressions of EMT biomarkers. NPC xenografts were constrcucted, and formed tumors were sectioned for morphology and immunohistofluorescence. The interaction between LBH and CRYAB was examined by colocalization and Fluorescence resonance energy transfer (FRET) analysis. We reached the conclusion that LBH inhibits the proliferation, migration, invasion and EMT of NPC cells, and its effects were partially achieved by suppressing p38 phosphorylation, which subsequently downregulates the mRNA expression and phosphorylation of CRYAB, while CRYAB directly interacts with LBH in NPC cells. This LBH-related pathway we revealed provides a novel therapeutic target for nasopharyngeal carcinoma research.
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Affiliation(s)
- Anbiao Wu
- Department of Cardiology, Laboratory of Heart Center, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Zhujiang Hospital, Southern Medical University, 253# Middle Industrial Avenue, Guangzhou 510280, PR China
| | - Ling Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 651# Dongfeng Road East, Guangzhou 510060, PR China
| | - Ning Luo
- Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2nd Avenue, Guangzhou 510080, PR China
| | - Lihong Zhang
- Department of Cardiology, Laboratory of Heart Center, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Zhujiang Hospital, Southern Medical University, 253# Middle Industrial Avenue, Guangzhou 510280, PR China
| | - Li Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 651# Dongfeng Road East, Guangzhou 510060, PR China.
| | - Qicai Liu
- Department of Cardiology, Laboratory of Heart Center, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Zhujiang Hospital, Southern Medical University, 253# Middle Industrial Avenue, Guangzhou 510280, PR China; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, PR China.
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48
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Zhao JZ, Ye Q, Wang L, Lee SC. Centrosome amplification in cancer and cancer-associated human diseases. Biochim Biophys Acta Rev Cancer 2021; 1876:188566. [PMID: 33992724 DOI: 10.1016/j.bbcan.2021.188566] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 12/07/2022]
Abstract
Accumulated evidence from genetically modified cell and animal models indicates that centrosome amplification (CA) can initiate tumorigenesis with metastatic potential and enhance cell invasion. Multiple human diseases are associated with CA and carcinogenesis as well as metastasis, including infection with oncogenic viruses, type 2 diabetes, toxicosis by environmental pollution and inflammatory disease. In this review, we summarize (1) the evidence for the roles of CA in tumorigenesis and tumor cell invasion; (2) the association between diseases and carcinogenesis as well as metastasis; (3) the current knowledge of CA in the diseases; and (4) the signaling pathways of CA. We then give our own thinking and discuss perspectives relevant to CA in carcinogenesis and cancer metastasis in human diseases. In conclusion, investigations in this area might not only identify CA as a biological link between these diseases and the development of cancer but also prove the causal role of CA in cancer and progression under pathophysiological conditions, potentially taking cancer research into a new era.
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Affiliation(s)
- Ji Zhong Zhao
- Institute of Biomedical Sciences and School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, PR China
| | - Qin Ye
- Institute of Biomedical Sciences and School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, PR China
| | - Lan Wang
- School of Life Sciences, Shanxi University, Taiyuan, Shanxi, PR China
| | - Shao Chin Lee
- Institute of Biomedical Sciences and School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, PR China.
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Xie Q, Guo H, He P, Deng H, Gao Y, Dong N, Niu W, Liu T, Li M, Wang S, Wu Y, Li J. Tspan5 promotes epithelial-mesenchymal transition and tumour metastasis of hepatocellular carcinoma by activating Notch signalling. Mol Oncol 2021; 15:3184-3202. [PMID: 33955149 PMCID: PMC8564648 DOI: 10.1002/1878-0261.12980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 01/08/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to a high rate of tumour metastasis and disease recurrence. In physiological conditions, tetraspanins interact with specific partner proteins in tetraspanin-enriched microdomains and regulate their subcellular localization and function. However, the function of Tspan5 in pathological processes, particularly in cancer biology and its clinical significance, are still unclear. Here, we describe that a high expression of Tspan5 is significantly associated with some clinicopathological features including invasive length, vascular invasion, clinical stage and poor overall survival of HCC patients. Alterations of Tspan5 expression by lentivirus transductions in HCC cells demonstrated that Tspan5 promotes wound healing and cell migration in vitro and tumour metastasis of HCC cells in vivo. Mechanistic studies revealed that Tspan5 promoted cell migration and tumour metastasis by increasing the enzymatic maturation of ADAM10 and activating Notch signalling via the increase of the cleavage of the Notch1 receptor catalysed by the γ-secretase complex. Activation of Notch signalling by Tspan5 was shown further to enhance the epithelial-mesenchymal transition (EMT) and actin skeleton rearrangement of tumour cells. In clinical HCC samples, Tspan5 expression is strongly correlated with many key molecules acting in Notch signalling and EMT, highlighting the role of Tspan5 in the regulation of Notch signalling, EMT and tumour metastasis of HCC. Our findings provide new insights into the mechanism of tumour metastasis and disease progression of HCC and may facilitate the development of novel clinical intervention strategies against HCC.
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Affiliation(s)
- Qian Xie
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Huiling Guo
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Peirong He
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Huan Deng
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Yanjun Gao
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Ningning Dong
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Wenbo Niu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Tiancai Liu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Ming Li
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Suihai Wang
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Yingsong Wu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Ji‐Liang Li
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
- Wenzhou Medical University Eye Hospital and School of Biomedical EngineeringChina
- Cancer Research CentreUniversity of Chinese Academy of Sciences Wenzhou InstituteChina
- Institute of Translational and Stratified MedicineUniversity of Plymouth Faculty of Medicine and DentistryUK
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Fattahi S, Nikbakhsh N, Ranaei M, Sabour D, Akhavan-Niaki H. Association of sonic hedgehog signaling pathway genes IHH, BOC, RAB23a and MIR195-5p, MIR509-3-5p, MIR6738-3p with gastric cancer stage. Sci Rep 2021; 11:7471. [PMID: 33811245 PMCID: PMC8018955 DOI: 10.1038/s41598-021-86946-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/22/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the leading cause of cancer-related mortality worldwide. Given the importance of gastric cancer in public health, identifying biomarkers associated with disease onset is an important part of precision medicine. The hedgehog signaling pathway is considered as one of the most significant widespread pathways of intracellular signaling in the early events of embryonic development. This pathway contributes also to the maintenance of pluripotency of cancer stem cells pluripotency. In this study, we analyzed the expression levels of sonic hedgehog (Shh) signaling pathway genes IHH, BOC, RAB23a and their regulatory miRNAs including MIR-195-5p, MIR-509-3-5p, MIR-6738-3p in gastric cancer patients. In addition, the impact of infection status on the expression level of those genes and their regulatory miRNAs was investigated. One hundred samples taken from 50 gastric cancer patients (50 tumoral tissues and their adjacent non-tumoral counterparts) were included in this study. There was a significant difference in all studied genes and miRNAs in tumoral tissues in comparison with their adjacent non-tumoral counterparts. The lower expression of IHH, BOC, RAB23, miR-195-5p, and miR-6738-3p was significantly associated with more advanced cancer stage. Additionally, IHH upregulation was significantly associated with CMV infection (P < 0.001). Also, receiver operating characteristic (ROC) curve analysis indicated that mir-195 was significantly related to several clinicopathological features including tumor stage, grade, age, gender, and infection status of gastric cancer and can be considered as a potential diagnostic biomarker for gastric cancer. This study confirms the important role of Shh signaling pathway genes in gastric cancer tumorigenesis and their potential as novel molecular biomarkers and therapeutic targets.
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Affiliation(s)
- Sadegh Fattahi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Novin Nikbakhsh
- Department of Surgery, Rouhani Hospital Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Ranaei
- Department of Pathology, Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Davood Sabour
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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