Positive regulation of HIF-1A expression by EBV oncoprotein LMP1 in nasopharyngeal carcinoma cells

Sung, Wei-Wen; Chu, Yi-Chih; Chen, Peir-Rong; Liao, Ming-Hui; Lee, Jeng-Woei

doi:10.1016/j.canlet.2016.08.021

Cited by 47 publications

(49 citation statements)

References 47 publications

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“…Otherwise, Tumor necrosis factor alpha (TNFα) from the inflammatory microenvironment also induces Warburg‐like metabolism in cancer cells (Vaughan, Garcia‐Smith, Dorsey, et al, ; Vaughan, Garcia‐Smith, Trujillo, et al, ). LMP1 also increase HIF‐1A transcription by activating ERK1/2/NF‐κB pathway (Sung, Chu, Chen, Liao, & Lee, ).Thus constitutive activation of NF‐κB signaling intergrate inflammation and energe metabolism reprogramming (Figure ). Targeting LMP‐1 mediated glycolysis successfully increase sensitivity of NPC cells to radio‐therapy in a experimental model (Xiao et al, ), making it's a attractive for clinical therapeutic application (Figure ).…”

Section: Nf‐κb Signaling Determine Ebv‐mediated Metabolic Reprogrammimentioning

confidence: 99%

Rediscovery of NF‐κB signaling in nasopharyngeal carcinoma: How genetic defects of NF‐κB pathway interplay with EBV in driving oncogenesis?

Man

Cai

et al. 2018

Journal Cellular Physiology

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Nasopharyngeal carcinoma (NPC) is a unique EBV-associated subtype of head and neck cancer, which has the highest incidence in Southern China and eastern South Asia. The interaction between genetic risk factors and environmental challenge, have been considered to contribute to the development of nasopharyngeal carcinogenesis. Constitutive activation of NF-κB signaling has been seen in NPC tissues and is associated with unfavorable prognosis. Recently, several whole exome sequencing study consistently revealed that high frequency mutations of NF-κB pathway negative regulators is common in nasopharyngeal carcinoma, which reinforce the importance of NF-κB driving oncogenesis. This review focuses on the current state of research in role of NF-κB in NPC carcinogenesis. We summarized the newly identified loss of function (LOF) mutations on NF-κB negative regulators leading to it's activation bypass LMP-1 stimulation. We discussed the critical role of NF-κB activation in immortalization and transformation of nasopharygeal epithelium. We also depicted how NF-κB signaling mediated chronic inflammation contribute to persistent EBV infection, immune evasion of EBV infected cells, metabolic reprogramming, and cancer stem cells (CSCs) formation in NPC. Lastly, we discussed the clinical resonance of targeting NF-κB for NPC precise therapy.

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Section: Nf‐κb Signaling Determine Ebv‐mediated Metabolic Reprogrammimentioning

confidence: 99%

Rediscovery of NF‐κB signaling in nasopharyngeal carcinoma: How genetic defects of NF‐κB pathway interplay with EBV in driving oncogenesis?

Man

Cai

et al. 2018

Journal Cellular Physiology

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“…Thus, in NPC cells, EBV might activate these pathways to promote CCL5 production. Considering that LMP1 is a major oncoprotein of EBV and can modulate multiple signaling pathways, including the NF‐κB, PI3K/AKT, and HIF‐1α pathways, most likely, LMP1 drives CCL5 production in EBV‐infected cells. Further studies on the mechanisms of CCL5 upregulation in EBV‐infected cells are essential to elucidate the role of EBV infection and could be significant in the development of CCL5‐targeted therapy in NPC.…”

Section: Discussionmentioning

confidence: 99%

Induction of chemokine (C‐C motif) ligand 5 by Epstein–Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma

Feng

Zhang

et al. 2018

Cancer Science

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Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein–Barr virus (EBV) infection and is known to be highly vascularized. Previous studies have suggested that EBV oncoproteins contribute to NPC angiogenesis. However, the regulatory network of EBV in angiogenesis still remains elusive. Herein, we reveal a novel mechanism of EBV‐induced angiogenesis in NPC. First, we showed that EBV‐infected NPC cell lines generated larger tumors with more microvessels in mouse xenograft models. Subsequent proteomic analysis revealed that EBV infection increased the expression of a series of angiogenic factors, including chemokine (C‐C motif) ligand 5 (CCL5). We then proved that CCL5 was a target of EBV in inducing tumor angiogenesis and growth. Further investigation through transcriptome analysis indicated that the pro‐angiogenic function of CCL5 might be mediated by the PI3K/AKT pathway. Furthermore, we confirmed that activation of the PI3K/AKT and hypoxia‐inducible factor‐1α pathways was essential for CCL5‐promoted angiogenesis. Finally, the immunohistochemical analysis of human NPC specimens also showed that CCL5 was correlated with angiogenesis. Taken together, our study identifies CCL5 as a key EBV‐regulated molecular driver that promotes NPC angiogenesis, suggesting it as a potential therapeutic target.

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“…HIF-1α can exert anti-apoptotic and pro-apoptotic effects simultaneously, HIF-1α can increase the anaerobic metabolism and glucose extraction, and downregulate the expression of apoptotic genes to play an anti-apoptotic role (8); at the same time, HIF-1α can increase the level of p53 protein by inhibiting its degradation to play a pro-apoptotic role (9). Therefore, how to regulate HIF-1α to increase tumor cell apoptosis is an important task for studies on treatment of tumors.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor-9 in hypoxic nasopharyngeal carcinoma cells and its correlation with cell proliferation and apoptosis

2017

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Abstract. The purpose of this study was to investigate the correlation between the expression of Toll-like receptor-9 (TLR-9) and cell proliferation and apoptosis in hypoxic nasopharyngeal carcinoma cells. Human nasopharyngeal carcinoma cell line HNE-1 (EBV positive) and CNE-1 (EBV negative) were used. Cells were divided into normal control group, hypoxia group and hyperoxia group. Hypoxic conditions were 5% CO 2 and 0.01% partial pressure of oxygen, hyperoxia conditions were 5% CO 2 and 10% partial pressure of oxygen. Reverse transcription-PCR (RT-PCR) and western blot analysis were used to detect the expression of TLR-9 mRNA and protein at 6, 12 and 24 h after the beginning of cell culture. MTT assay was used to detect the cell proliferation rate and flow cytometry was used to detect cell apoptosis rate. Expression levels of TLR-9 mRNA and protein in hypoxia group reached the peak at 12 h after the beginning of cell culture, and were significantly higher than those of hyperoxia group at all time-points, expression levels of TLR-9 mRNA and protein of control group were the lowest, difference between groups were all statistically significant (P<0.05). No significant changes in expression levels of TLR-9 mRNA and protein were found in control group and hyperoxia group between different timepoints (P>0.05). Compared with the other two groups, cell proliferation rate was gradually decreased and apoptotic rate was gradually decreased in hypoxia group, significant differences were found between hypoxia group, and control group and hyperoxia group (P<0.05), no significant differences were found between control group and hyperoxia group (P>0.05).In conclusion, TLR-9 was highly expressed in hypoxic nasopharyngeal carcinoma cells regulating cell proliferation and apoptosis, which may be an important mechanism of tumorigenesis and a potential target for intervention therapy.

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Positive regulation of HIF-1A expression by EBV oncoprotein LMP1 in nasopharyngeal carcinoma cells

Cited by 47 publications

References 47 publications

Rediscovery of NF‐κB signaling in nasopharyngeal carcinoma: How genetic defects of NF‐κB pathway interplay with EBV in driving oncogenesis?

Rediscovery of NF‐κB signaling in nasopharyngeal carcinoma: How genetic defects of NF‐κB pathway interplay with EBV in driving oncogenesis?

Induction of chemokine (C‐C motif) ligand 5 by Epstein–Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma

Toll-like receptor-9 in hypoxic nasopharyngeal carcinoma cells and its correlation with cell proliferation and apoptosis

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