Modulation of the tumor microenvironment by Epstein‐Barr virus latent membrane protein 1 in nasopharyngeal carcinoma

Yoshizaki, Tomokazu; Kondo, Satoru; Endo, Kazuhira; Nakanishi, Yosuke; Aga, Mitsuharu; Kobayashi, Eiji; Hirai, Nobuyuki; Sugimoto, Hisashi; Hatano, Miyako; Ueno, Takayoshi; Ishikawa, Kazuya; Wakisaka, Naohiro

doi:10.1111/cas.13473

Cited by 45 publications

(40 citation statements)

References 72 publications

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“…Distant metastasis of tumor cells is the main cause of poor prognosis of NPC, and it is directly related to down-regulation or deletion of tumor-suppressor genes or over-activation of oncogenes [4]. In past studies, a large number of oncogenes have been identified to be closely related to the prognosis, radiotherapy resistance and metastasis of NPC, but the regulation of the immunological characteristics of NPC cells by these oncogenes has rarely been reported [20,21]. Studies show that tumor tissues are infiltrated with a large number of natural and acquired immune cells, such as CD4 þ T cells, CD8 þ T cells, NK cells, macrophages, mast cells, and dendritic cells [22,23].…”

Section: Resultsmentioning

confidence: 99%

MACC1 facilitates the escape of nasopharyngeal carcinoma cells from killing by natural killer cells

Zhao

Liu

Zeng

et al. 2019

Biotechnology & Biotechnological Equipment

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This study examined the regulation of phenotype and function of natural killer (NK) cells by nasopharyngeal carcinoma (NPC) cells with metastasis-associated in colon cancer-1 (MACC1) overexpression. Thirty patients with NPC and 20 healthy subjects were included. Peripheral blood (5 mL) was collected, and NK cells were purified using Ficoll and negative separation. NPC HONE1 cells were transfected with pcDNA3.1-MACC1 or negative control plasmids, and culture supernatant was collected for co-culture with NK cells. Flow cytometry was used to determine the expression of activated and inhibitory receptors on the cells. Western blotting was used to determine the expression of proteins. The results showed that the ratio of NK cells in the peripheral blood of NPC patients was elevated, but the activity and tumor-killing effect of NK cells were reduced. MACC1 promoted the escape of HONE1 cells from killing by NK cells. HONE1 with overexpression of MACC1 down-regulated the expression of NKG2D in NK cells, inhibited the proliferation of NK cells and escaped the immune surveillance by NK cells. MACC1 downregulated the expression of NKG2D in NK cells by up-regulating the expression of TGF-b1 in HONE1 cells, thereby inhibiting the activity of NK cells. MACC1 inhibited the cell cycle of NK cells via TGF-b1 pathway. The study demonstrated that MACC1 elevated the expression of TGF-b1 by NPC HONE1 cells, thereby inhibiting NKG2D expression and G1/S transition in NK cells. MACC1 helped NPC HONE1 cells avoid killing by NK cells.

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Section: Resultsmentioning

confidence: 99%

MACC1 facilitates the escape of nasopharyngeal carcinoma cells from killing by natural killer cells

Zhao

Liu

Zeng

et al. 2019

Biotechnology & Biotechnological Equipment

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“…при изучении пролиферативной активности ВЭБ-ассоциированной назофарингеальной карциномы. Авторы указывают на усиление пролиферативной активности и снижение апоптоза за счет активации белка-онкогена LMP-1 на начальных стадиях онкогенеза [21].…”

Section: Discussionunclassified

“…Кроме того, T. Yoshizaki и соавт. уделяют большое внимание микроокружению опухоли, поскольку именно взаимодействие стромального компонента с находящимися в нем вирусными онкогенами и опухолью приводит к появлению инвазивных свойств и прогрессии опухоли [21].…”

Section: Discussionunclassified

“…14 Диагностика и лечение опухолей мочеполовой системы. Рак мочевого пузыря в опухолевой ткани, хронической герпес-и ВПЧ-вирусной инфекции имеют место повышение пролиферативной активности и снижение апоптоза на этапе «премалигнизации» [21]. По мере прогрессии опухоли происходит активизация факторов ангиогенеза, адгезии и факторов роста.…”

Section: Discussionunclassified

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Immunohistochemical characteristics of bladder cancer in patients with virus-positive tumors

Косова¹,

Лоран²,

Синякова³

et al. 2018

Cancer Urology

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Background. Viral infection is a major factor in virus-associated carcinogenesis.Objective: to evaluate the expression of growth factors and markers of apoptosis, proliferative activity, and angiogenesis in patients with viral DNA-positive bladder cancer.Materials and methods. The study included 100 bladder cancer patients (72 males and 28 females) aged between 38 and 90 years (mean age 65 ± 10). Tumor tissue samples were tested by polymerase chain reaction to detect DNA of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2 respectively), high-risk human papillomavirus (HPV), cytomegalovirus (CMV), and Epstein—Barr virus (EBV). Immunohistochemical analysis was performed in 32 patients and included the following markers: proliferation marker Ki-67, p63, apoptosis regulator Bcl-2, p53, angiogenesis marker CD31, adhesion protein CD44, and epidermal growth factor receptor (EGFR).Results. Viral DNA in tumor tissue was detected in 34 patients; of them, 50 % had poorly-differentiated tumors. Twenty-seven patients were found to have EBV DNA in their tumor tissue; 6 patients had CMV DNA; 5 patients had high-risk HPV DNA (types 16, 39, 45, 52, and 59); 1 patient had HSV1 and HSV2 DNA. Four out of 34 participants had mixed infections (1 case of HPV 59 + EBV; 2 cases of EBV + CMV; 1 case of CMV + EBV + HPV 31 and 52). We observed a strong correlation between the presence of EBV DNA and levels of CD31 and Ki-67 expression as well as between high-risk HPV DNA and Bcl-2 expression. High levels of antibodies against EBV capsid antigen were associated with EGFR and Ki-67 expression, whereas the level of antibodies against EBV nuclear antigen correlated with CD44 expression. We evaluated specific characteristics of expression of the markers analyzed depending on the tumor stage, grade of anaplasia, and recurrence. We also assessed morphological characteristics of changes in lymphocytic and plasma cell infiltrates.Conclusion. We found a correlation between the presence of viral DNA in bladder cancer tissue and markers of proliferative activity, angiogenesis, and apoptosis. Viral infection is likely to increase proliferative activity and suppression of apoptosis, which may cause tumor progression. Further studies are needed to assess this correlation.

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“…Recurrence and metastasis are the main causes of death in patients with NPC 1 . The occurrence of NPC is associated with Epstein-Barr virus (EBV) infection, and EBV-encoded Latent membrane protein 1 (LMP1) promotes Ivyspring International Publisher proliferation, migration and invasion of NPC cells [2][3][4][5] . LMP1 is known to be a vital oncogenic protein encoded by the EBV genome, as it plays a critical role in the transformation of rodent fibroblasts and some immortalized epithelial cells in vitro [6][7] .…”

Section: Introductionmentioning

confidence: 99%

LMP1 Up-regulates Calreticulin to Induce Epithelial-mesenchymal Transition via TGF-β/Smad3/NRP1 Pathway in Nasopharyngeal Carcinoma Cells

Zhu

Zhao

et al. 2020

J. Cancer

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Background: Latent membrane protein 1 (LMP1) is known as an oncogenic protein encoded by the EBV genome. The purpose of this study was to investigate the mechanism of LMP1-induced cell epithelial-mesenchymal transition (EMT). Methods: The NP69 cell line of nasopharyngeal epithelial cells with high expression of LMP1 was established to observe the effect of high expression of LMP1 on cell growth, proliferation, cycle, apoptosis, migration and invasion. We used proteomics to screen and identify differentially expressed proteins related to LMP1-mediated epithelial cell transformation. Then, we analyzed the expression and significance of differentially expressed calreticulin (CRT) in nasopharyngeal carcinoma (NPC), and observed the effect of CRT expression on EMT in CNE2 cells of NPC. Finally, the expression of neuropilin-1 (NRP1), which is a protein downstream of the EMT-related signaling pathway TGF-β (transforming growth factor β), was detected. Results: LMP1 promoted NP69 cells proliferation, inhibited apoptosis and induced EMT. We identified 22 differentially expressed proteins associated with LMP1-induced EMT. Among them, CRT expression level was significantly increased in NPC compared with adjacent tissues, and was interrelated with TNM staging and lymph node metastasis of NPC. After knockdown of CRT expression, the phenomenon of cell EMT was reduced and the ability of cell migration and invasion was weakened. CRT regulated NRP1 expression by affecting SMAD3 phosphorylation. Conclusion: LMP1 induced cell EMT via TGF-β/Smad3/NRP1 pathway, which promoted migration and invasion of NPC cells.

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Modulation of the tumor microenvironment by Epstein‐Barr virus latent membrane protein 1 in nasopharyngeal carcinoma

Cited by 45 publications

References 72 publications

MACC1 facilitates the escape of nasopharyngeal carcinoma cells from killing by natural killer cells

MACC1 facilitates the escape of nasopharyngeal carcinoma cells from killing by natural killer cells

Immunohistochemical characteristics of bladder cancer in patients with virus-positive tumors

LMP1 Up-regulates Calreticulin to Induce Epithelial-mesenchymal Transition via TGF-β/Smad3/NRP1 Pathway in Nasopharyngeal Carcinoma Cells

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