Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma

Kondo, Satoru; Okabe, Atsushi; Nakagawa, Takuya; Matsusaka, Keisuke; Fukuyo, Masaki; Rahmutulla, Bahityar; Dochi, Hirotomo; Mizokami, Harue; Kitagawa, Yuuki; Kurokawa, Tomoya; Mima, Masato; Endo, Kazuhira; Sugimoto, Hisashi; Wakisaka, Naohiro; Misawa, Kiyoshi; Yoshizaki, Tomokazu; Kaneda, Atsushi

doi:10.1016/j.bbadis.2022.166598

Cited by 7 publications

(8 citation statements)

References 63 publications

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“…We have shown that LMP1-expressing NPC cells upregulate multiple metastatic pathways. 1,2,39 Moreover, our results suggest that NPC tumor cells induce SPARC expression in NAT cells, indicating that NAT cells become the defeated cells; hence, SPARC-expressing NAT cells are eliminated from cancer cells, facilitating the easy invasion and metastasis of NPC cells. It is noteworthy that SPARC has also been identified as an early marker expressed in loser cells.…”

Section: Discussionmentioning

confidence: 66%

“…One of its unique features is its high potential for metastasis, mainly attributable to latent membrane protein-1 (LMP-1), an EBV primary oncogene. 1,2 A recent study revealed that tumors surrounding normal adjacent tissue (NAT), as well as the cancer cells themselves, play a pivotal role in determining the malignant potential, including invasive and metastatic properties, of the whole malignant tumor tissue. The interaction of tumor components is quite complicated, and EBV is now considered to affect the behavior of uninfected cells surrounding the tumor.…”

Section: Introductionmentioning

confidence: 99%

“…Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV) associated malignant tumor. One of its unique features is its high potential for metastasis, mainly attributable to latent membrane protein‐1 (LMP‐1), an EBV primary oncogene 1,2 . A recent study revealed that tumors surrounding normal adjacent tissue (NAT), as well as the cancer cells themselves, play a pivotal role in determining the malignant potential, including invasive and metastatic properties, of the whole malignant tumor tissue.…”

Section: Introductionmentioning

confidence: 99%

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Peritumoral SPARC expression induced by exosomes from nasopharyngeal carcinoma infected Epstein‐Barr virus: A poor prognostic marker

Dochi,

Kondo,

Komura

et al. 2023

Intl Journal of Cancer

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Epstein‐Barr virus (EBV)‐associated nasopharyngeal carcinoma (NPC) cells have high metastatic potential. Recent research has revealed that the interaction of between tumor cells and the surrounding stroma plays an important role in tumor invasion and metastasis. In this study, we showed the prognostic value of expression of SPARC, an extracellular matrix protein with multiple cellular functions, in normal adjacent tissues (NAT) surrounding NPC. In the immunohistochemical analysis of 51 NPC biopsy specimens, SPARC expression levels were significantly elevated in the NAT of EBER (EBV‐encoded small RNA)‐positive NPC compared to that in the NAT of EBER‐negative NPC. Moreover, increased SPARC expression in NAT was associated with a worsening of overall survival. The enrichment analysis of RNA‐seq of publicly available NPC and NAT surrounding NPC data showed that high SPARC expression in NPC was associated with epithelial mesenchymal transition promotion, and there was a dynamic change in the gene expression profile associated with interference of cellular proliferation in NAT, including SPARC expression. Furthermore, EBV‐positive NPC cells induce SPARC expression in normal nasopharyngeal cells via exosomes. Induction of SPARC in cancer‐surrounding NAT cells reduced intercellular adhesion in normal nasopharyngeal structures and promoted cell competition between cancer cells and normal epithelial cells. These results suggest that epithelial cells loosen their own binding with the extracellular matrix as well as stromal cells, facilitating the invasion of tumor cells into the adjacent stroma by activating cell competition. Our findings reveal a new mechanism by which EBV creates a pro‐metastatic microenvironment by upregulating SPARC expression in NPC.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peritumoral SPARC expression induced by exosomes from nasopharyngeal carcinoma infected Epstein‐Barr virus: A poor prognostic marker

Dochi,

Kondo,

Komura

et al. 2023

Intl Journal of Cancer

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“…Here, LMP1 and LMP2A/B are also expressed together with the transcripts for EBERs, EBNA1, and BamHI-A. Only around 20% of biopsies had LMP1 protein levels that were unequivocally positive in NPC, while this latency II pattern of EBV latent gene expression is a recurrent feature of virus-associated HL [ 88 , 89 , 90 ].…”

Section: Latent Gene Products Of Ebvmentioning

confidence: 99%

“…Analysts should initially comprehend the capacity of EBV latent qualities communicated in NPC to assess the role of viral disease in the malignant growth process [ 90 ]. Likewise, complete information on the capacity of these EBV inactive qualities could prompt the formation of creative symptomatic and helpful strategies [ 72 ].…”

Section: Latent Gene Products Of Ebvmentioning

confidence: 99%

Updates on Epstein–Barr Virus (EBV)-Associated Nasopharyngeal Carcinoma: Emphasis on the Latent Gene Products of EBV

et al. 2022

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Nasopharyngeal carcinoma (NPC) is an uncommon type of malignancy/cancer worldwide. However, NPC is an endemic disease in southeast Asia and southern China and the reasons behind the underlying for such changes are unclear. Even though the Epstein–Barr infection (EBV) has been suggested as an important reason for undistinguishable NPC, the EBV itself is not adequate to source this type of cancer. The risk factors, for example, genetic susceptibility, and environmental factors might be associated with EBV to undertake a part in the NPC carcinogenesis. Normal healthy people have a memory B cell pool where the EBV persists, and any disturbance of this connection leads to virus-associated B cell malignancies. Less is known about the relationship between EBV and epithelial cell tumors, especially the EBV-associated nasopharyngeal carcinoma (EBVaNPC) and EBV-associated gastric carcinoma (EBVaGC). Currently, it is believed that premalignant genetic changes in epithelial cells contribute to the aberrant establishment of viral latency in these tumors. The early and late phases of NPC patients’ survival rates vary significantly. The presence of EBV in all tumor cells presents prospects for the development of innovative therapeutic and diagnostic techniques, despite the fact that the virus’s exact involvement in the carcinogenic process is presently not very well known. EBV research continues to shed light on the carcinogenic process, which is important for a more comprehensive knowledge of tumor etiology and the development of targeted cancer therapeutics. In order to screen for NPC, EBV-related biomarkers have been widely used in a few high-incidence locations because of their close associations with the risks of NPC. The current review highlights the scientific importance of EBV and its possible association with NPC.

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Phosphoribosyl pyrophosphate amidotransferase: Novel biomarker and therapeutic target for nasopharyngeal carcinoma

Kitagawa,

Kondo,

Fukuyo

et al. 2024

Cancer Science

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Cancer cells show a dynamic metabolic landscape, requiring a sufficient supply of nucleotides to proliferate. They are highly dependent on de novo purine biosynthetic pathways for their nucleotide requirements. Phosphoribosyl pyrophosphate amidotransferase (PPAT), catalyzing the first step of de novo purine biosynthesis, is highly expressed in various cancers. We observed an increased expression of PPAT in nasopharyngeal carcinoma (NPC). Moreover, our ribonucleic acid sequencing analysis showed high PPAT expression in Epstein–Barr virus‐positive NPC, which was supported by in vitro analysis. Through a gene knockdown study, we showed that the suppression of PPAT expression reduced the proliferation and invasion of NPC cells. We also demonstrated the regulation of PPAT by glutamine, a cosubstrate for PPAT. A glutamine antagonist, 6‐diazo‐5‐oxo‐L‐norleucine, blocked glutamine‐mediated induction of PPAT and reduced NPC cell proliferation. Immunohistochemical analysis of PPAT in NPC tissues revealed increased expression of PPAT with disease progression, which was significantly associated with poor prognosis. In summary, this study highlighted the biological function of PPAT in NPC, establishing its potential as a novel prognostic biomarker for aggressive NPC and a promising therapeutic target.

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Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma

Cited by 7 publications

References 63 publications

Peritumoral SPARC expression induced by exosomes from nasopharyngeal carcinoma infected Epstein‐Barr virus: A poor prognostic marker

Peritumoral SPARC expression induced by exosomes from nasopharyngeal carcinoma infected Epstein‐Barr virus: A poor prognostic marker

Updates on Epstein–Barr Virus (EBV)-Associated Nasopharyngeal Carcinoma: Emphasis on the Latent Gene Products of EBV

Phosphoribosyl pyrophosphate amidotransferase: Novel biomarker and therapeutic target for nasopharyngeal carcinoma

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