EBV‐LMP1 induces APOBEC3s and mitochondrial DNA hypermutation in nasopharyngeal cancer

Wakae, Kousho; Kondo, Satoru; Pham, Hai Thanh; Wakisaka, Naohiro; Que, Lusheng; Li, Yingfang; Zheng, Xin; Fukano, Kento; Kitamura, Koichi; Watashi, Koichi; Aizaki, Hideki; Ueno, Takayoshi; Moriyama‐Kita, Makiko; Ishikawa, Kazuya; Nakanishi, Yosuke; Endo, Kazuhira; Muramatsu, Masamichi; Yoshizaki, Tomokazu

doi:10.1002/cam4.3357

Cited by 13 publications

(11 citation statements)

References 32 publications

(79 reference statements)

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“…Another cell compartment containing nucleic acids is mitochondria; however, the data on whether cytidine deaminases are capable of introducing mutations into mitochondrial DNA are contradictory. In nasopharyngeal cancer induced by the Epstein-Barr virus, induction of APOBEC3B and APOBEC3F, which correlated with the frequency of G→A transitions in mitochondrial DNA, was found [29]. However, the analysis of mitochondrial DNA from B-cell lymphoma lines with high levels of AID expression reveals almost no mutations caused by cytidine deaminases [30].…”

Section: Mechanisms Of Regulationmentioning

confidence: 99%

Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis

2022

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Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against viruses, the introduction of point mutations into DNA during somatic hypermutation, and antibody isotype switching. Since these deaminases, especially AID, are potent mutagens, their expression, activity, and specificity are regulated by several intracellular mechanisms. In this review, we discuss the mechanisms of impaired expression and activation of AID/APOBEC proteins in human tumors and their role in carcinogenesis and tumor progression. Also, the diagnostic and potential therapeutic value of increased expression of AID/APOBEC in different types of tumors is analyzed. We assume that in the case of solid tumors, increased expression of endogenous deaminases can serve as a marker of response to immunotherapy since multiple point mutations in host DNA could lead to amino acid substitutions in tumor proteins and thereby increase the frequency of neoepitopes.

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Section: Mechanisms Of Regulationmentioning

confidence: 99%

Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis

2022

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“…The LMP1 has been known as the primary EBV oncogene that drive carcinogenesis for decades [ 11 , 27 ]. LMP1 drives proliferation, causes immortalization, affects immune modulation, promotes angiogenesis, increases genomic instability and modulates cell migration [ 27 , 28 ]. Our finding further confirmed the established role of LMP1 in promoting carcinogenesis in clinical nasopharyngeal carcinoma sample.…”

Section: Discussionmentioning

confidence: 99%

Immune cells markers within local tumor microenvironment are associated with EBV oncoprotein in nasopharyngeal cancer

et al. 2022

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Introduction EBV infection in nasopharyngeal cancer ensued in latent infection mode. In this latent infection various EBV oncoproteins such as EBNA1 and LMP1 was expressed. EBV oncoproteins could theoretically recruit immune cells, which might help to control cancer. Therefore, this study was aimed to elucidate the association with EBV oncoproteins (EBNA1 and LMP1), immune markers (CD4, CD8, and FOXP3) from nasopharyngeal cancer microenvironment with tumor progression. Method Nasopharyngeal biopsy was obtained from patients suspected to have nasopharyngeal cancer. Those samples with microscopically confirmed nasopharyngeal cancer were tested for EBNA1, LMP1, CD4, CD8, and FOXP3 concentration with ELISA, then verified with IHC. Each patient tumor volume was assessed for primary nasopharyngeal tumor volume (GTVp) and neck nodal metastases tumor volume (GTVn). Correlation test with Spearman correlation and scatterplot were carried out. Result Total 23 samples with nasopharyngeal cancer were analyzed. There was moderate correlation (ρ = 0.45; p value = 0.032) between LMP1 and GTVp. There was strong correlation (ρ = 0.81; p value < 0.001) between CD8 and GTVp. There was also moderate correlation (ρ = 0.6; p value = 0.002) between FOXP3 and GTVp. The CD8 concentration has moderate correlation with both EBNA1 (ρ = 0.46; p value = 0.026) and LMP1 (ρ = 0.47; p value = 0.023). While FOXP3 has moderate correlation with only LMP1 (ρ = 0.58; p value = 0.004). No correlation was found between all the markers tested here with GTVn. Discussion We found larger primary nasopharyngeal tumor was associated with higher CD8 marker. This was thought due to the presence of abundance CD8 T cells in the nasopharynx, but those abundance CD8 T cells were suspected to be dysfunctional. The nasopharyngeal cancer was also known to upregulate chemokines that could recruit T regulatory FOXP3 cells. Furthermore, T regulatory FOXP3 cells differentiation was induced through several pathways which was triggered by EBNA1. The correlation found in this study could guide further study to understand nasopharyngeal carcinogenesis and the relationship with our immune system.

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“…EBV can establish latent or lytic infection in host cells, both of which are involved in the carcinogenesis of NPC. Among them, EBV infection of NPC is dominantly based on latent infection [ 32 ]. EBV-encoded latent membrane protein 1 is the primary oncogenic protein of NPC, and many of its downstream events are mediated through activation of NF-κB [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Cullin 4A/protein arginine methyltransferase 5 (CUL4A/PRMT5) promotes cell malignant phenotypes and tumor growth in nasopharyngeal carcinoma

2022

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Targeted therapy is an important therapeutic strategy currently, however, the development of targeted therapy for nasopharyngeal carcinoma (NPC) is relatively lagging. Cullin 4A (CUL4A) was reported to be overexpressed in NPC; nevertheless, the specific role of CUL4A remains unrevealed. NPC cells and tumor-bearing mice were cultivated to explore the role and mechanism of CUL4A in NPC. After evaluating CUL4A levels in NPC cells, functional experiments were carried out to investigate the effects of CUL4A knockdown and overexpression on cell proliferative, invasive and migratory aptitude as well as NF-κB signaling. Following the GeneMANIA database predicted that protein arginine methyltransferase 5 (PRMT5) was downstream of CUL4A, the mediated role of PRMT5 in the regulation of CUL4A on cells was then determined. Moreover, the tumor volumes and weights of tumor-bearing mice were recorded, and the levels of proliferation-, migration-, and NF-κB signaling-related proteins in the tumor were determined. Herein, CUL4A was enhanced in NPC cells, and its knockdown and overexpression separately suppressed and promoted cell proliferative, invasive, and migratory aptitude as well as NF-κB signal activation. Novelty, PRMT5 knockdown reversed the influences of CUL4A overexpression on these aspects. In addition, its knockdown likewise reversed the facilitating impact of CUL4A expression on tumor growth and declined the expression levels of proliferation-, migration-, and NF-κB signaling-related protein in the tumor. Together, this paper indicated that CUL4A promoted the proliferative, invasive, and migratory aptitude of NPC cells as well as tumor growth by promoting PRMT5 to activate NF-κB signaling.

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EBV‐LMP1 induces APOBEC3s and mitochondrial DNA hypermutation in nasopharyngeal cancer

Cited by 13 publications

References 32 publications

Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis

Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis

Immune cells markers within local tumor microenvironment are associated with EBV oncoprotein in nasopharyngeal cancer

Cullin 4A/protein arginine methyltransferase 5 (CUL4A/PRMT5) promotes cell malignant phenotypes and tumor growth in nasopharyngeal carcinoma

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