Epstein-Barr Virus Infection to Epstein-Barr Virus-Negative Nasopharyngeal Carcinoma Cell Line TW03 Enhances Its Tumorigenicity

Teramoto, Norihiro; Maeda, Akihiko; Kobayashi, Keita; Hayashi, Kazuhiko; Oka, Takashi; Takahashi, Kiyoshi; Takada, Kenzo; Klein, Georg; Akagi, Tadaatsu

doi:10.1038/labinvest.3780035

Cited by 24 publications

(26 citation statements)

References 22 publications

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“…It has been shown that the loss of EBV from NPC cells leads to the loss or reduction of tumorigenicity, and the reintroduction of EBV enhances the tumorigenicity. 51 The observation indicates that the maintenance of EBV is important for the oncogenic activity of the infected cells. On the other hand, EBV might be driven away easily from the host cells.…”

Section: Discussionmentioning

confidence: 99%

“…17,50 Detailed detections show that the cells in the periphery of the main tumor and all cells in the daughter nodules are easy to be found EBV-positive. 51 The monoclonality of the viral DNA also indicates that the malignancy has arisen from clonal expansion of EBV-infected progenitor cell(s). 50,52 Thus, it seems that EBV-infected cells are also tufted in NPC tumor tissues, and the mechanism of cell-tocell contact might help us to understand the virus infection and clonal expansion in EBV's association with NPC.…”

Section: Discussionmentioning

confidence: 99%

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Epstein–Barr virus facilitates the malignant potential of immortalized epithelial cells: from latent genome to viral production and maintenance

Tang

et al. 2010

Laboratory Investigation

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Epstein-Barr virus (EBV) is closely associated with several malignancies, including nasopharyngeal carcinoma. To investigate the EBV activity in tumor development, we tried to establish a malignant model of EBV-infected cells in nude mice. On the basis of the Maxi-EBV system, a human embryonic kidney epithelial cell line (293) with a low malignant potential was used for a stable EBV genome infection. The derived cell line, termed 293-EBV, exhibited obvious morphological transformation and significantly increased growth ability, with the cell cycle redistributed. The clonability and tumorigenicity were also substantially accelerated. In 293-EBV cells, the expression level of the transcription factor NF-kB and JNK2 were upregulated. The result suggested that latent membrane protein 1 (LMP1) was an important viral protein responsible for the enhanced malignant potential. Matured and budding virus particles were observed in tumor tissues, confirming the spontaneous reactivation of EBV from latent genome to lytic cycle at the site of tumor development. Primary culture of tumor tissues showed two patterns about the EBV maintenance or not in newly grown cells, and this was dependent on the thickness of the planted tissues. Moreover, the tumor cells lost EBV genome easily when subcultured at low density. Our findings revealed the cell-to-cell contact mechanism, which was required for the EBV maintenance in the tumor cells during the expansion of EBV-infected cells. This mechanism might give an explanation to the phenomenon that EBV genome in epithelial tumor cells becomes easily lost during subculture in vitro. Our results provided further evidence of a function for EBV in the etiology of tumor development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus facilitates the malignant potential of immortalized epithelial cells: from latent genome to viral production and maintenance

Tang

et al. 2010

Laboratory Investigation

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“…RAT-2 fibroblasts and TWO3 nasopharyngeal carcinoma cells were propagated at 37°C in DMEM, supplemented with 10% FBS, 100 units͞ml Ϫ1 penicillin, and 100 g͞ml Ϫ1 streptomycin. TWO3 cells have lost the Epstein-Barr virus episome through serial passaging, and are no longer overtly transformed (16). To derive NTR2 cells, RAT-2 cells were transfected with ErbB2͞NeuNT, and cells were maintained in media (DMEM plus 5% FBS) until foci developed (2-3 weeks).…”

Section: Methodsmentioning

confidence: 99%

“…For this purpose, we used TWO3 human epithelial cells, which express the EGF receptor (EGFR) and respond to EGF (16). As shown in Fig.…”

Section: Receptor Tyrosine Kinase Activation Stimulates Apoptosis In mentioning

confidence: 99%

Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins

Howard

Chia

Rizzo

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Signal transduction pathways are typically controlled by proteinprotein interactions, which are mediated by specific modular domains. One hypothetical use of such interaction domains is to generate new signaling pathways and networks during eukaryotic evolution, through the joining of distinct binding modules in novel combinations. In this manner, new polypeptides may be formed that make innovative connections among preexisting proteins. Receptor tyrosine kinases (RTKs) typically transmit signals that promote cell growth and survival and can be constitutively activated by mutations that induce malignant cell transformation (1). Specific autophosphorylated tyrosine motifs on activated RTKs serve as docking sites for the Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains of cytoplasmic adaptors, such as Grb2 and ShcA, and these modules can therefore target specific complexes to activated RTKs (2, 3). In signaling from normal or oncogenic tyrosine kinases, the nature of the signal activated by these phosphotyrosine (pTyr) recognition domains depends on the sequences to which they are linked. The SH2 domain of the Grb2 adaptor, for example, is flanked by two Src homology 3 (SH3) domains that bind proteins, such as the Sos guanine nucleotide exchange factor and the Gab1 docking protein, which are involved in activation of the Ras and phosphatidylinositol 3Ј kinase pathways, respectively (4, 5). Grb2 therefore couples pTyr-X-Asn motifs, recognized selectively by the SH2 domain, to signaling pathways that are recruited by the SH3 domains, and promote cell proliferation, growth, and survival. A variation on this theme is provided by mammalian docking proteins, such as Shc, FRS2, and IRS-1 family members. These proteins all possess a PTB domain that binds phosphorylated NPXY motifs on activated RTKs, and are phosphorylated on tyrosine on recruitment to the receptor. Their phosphorylation creates binding sites for the SH2 domains of cytoplasmic signaling proteins, including Grb2, and thereby potentiates the activation of specific biochemical pathways that stimulate growth and survival (6).The activation of signaling pathways through adaptor proteins comprised of modular interaction domains is not limited to RTK signaling, but is a common mechanism used by diverse cellsurface receptors. For example, members of the tumor necrosis factor-receptor superfamily contain cytoplasmic domains and motifs that interact with corresponding domains on adaptor proteins. This occurrence is typified by the Fas receptor, which contains a death domain (DD) in its C-terminal tail (7,8). Trimerization of the receptor leads to binding of the Fas DD to the DD of an adaptor, Fadd, which also possesses a death effector domain (DED) (9). The DED of Fadd associates with the DEDs of procaspase 8͞10 (10). Fadd therefore bridges the Fas receptor to procaspases. The assembly of this multiprotein complex leads to caspase dimerization and activation, followed by caspase autocleavage and the stimulation of pathways that elicit apoptosis (11-13...

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“…On the other hand, the increase of lysophosphatidic acid resulting from up-regulation of autotaxin is the main reason that EBV infection can promote the growth of Hodgkin lymphoma cells (3). Among the epithelial-derived malignancies, reinfection with EBV enhances the tumorigenicity of NPC cells (62). In gastric carcinoma cells, EBV promotes cell proliferation through the induction of insulin-like growth factor-mediated signaling in an autocrine fashion (24).…”

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confidence: 99%

Dysregulation of HER2/HER3 Signaling Axis in Epstein-Barr Virus-Infected Breast Carcinoma Cells

Lin

Tsai

Chu

et al. 2007

J Virol

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The role of Epstein-Barr virus (EBV) in the pathogenesis of breast cancer has been of long-standing interest to the field. Breast epithelial cells can be infected by EBV through direct contact with EBV-bearing lymphoblastoid cells, and EBV infection has recently been shown to confer breast cancer cells an increased resistance to chemotherapeutic drugs. In this study, we established EBV-infected breast cancer MCF7 and BT474 cells and demonstrated that EBV infection promotes tumorigenic activity of breast cancer cells. Firstly, we showed that the EBV-infected MCF7-A and BT474-A cells exhibited increased anchorage-independent growth in soft agar. The increased colony formation capacity in soft agar was associated with increased expression and activation of HER2/HER3 signaling cascades, as evidenced by the findings that the treatment of HER2 antibody trastuzumab (Herceptin), phosphatidylinositol 3-kinase inhibitor, or MEK inhibitor completely abolished the tumorigenic capacity. In the EBV-infected breast cancer cells, the expression of EBV latency genes including EBNA1, EBER1, and BARF0 was detected. We next showed that BARF0 alone was sufficient to efficiently up-regulate HER2/HER3 expression and promoted tumorigenic activity in MCF7 and BT474 cells by the use of both overexpression and small interfering RNA knock-down. Collectively, we demonstrated that EBV-encoded BARF0 promotes the tumorigenic activity of breast cancer cells through activation of HER2/ HER3 signaling cascades.

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Epstein-Barr Virus Infection to Epstein-Barr Virus-Negative Nasopharyngeal Carcinoma Cell Line TW03 Enhances Its Tumorigenicity

Cited by 24 publications

References 22 publications

Epstein–Barr virus facilitates the malignant potential of immortalized epithelial cells: from latent genome to viral production and maintenance

Epstein–Barr virus facilitates the malignant potential of immortalized epithelial cells: from latent genome to viral production and maintenance

Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins

Dysregulation of HER2/HER3 Signaling Axis in Epstein-Barr Virus-Infected Breast Carcinoma Cells

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