Inflammation-Related DNA Damage and Cancer Stem Cell Markers in Nasopharyngeal Carcinoma

Wang, Shumin; Ma, Ning; Zhao, Weilin; Midorikawa, Katsumi; Kawanishi, Shosuke; Hiraku, Yusuke; Oikawa, Shinji; Zhang, Zhe; Huang, Guangwu; Murata, Mariko

doi:10.1155/2016/9343460

Cited by 14 publications

(13 citation statements)

References 49 publications

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“…Western blot was done according to the standard protocol as described previously [ 31 ]. Cultured cells were harvested at 70-80% confluence and lysed using RIPA buffer (Cell Signaling Technology Inc., Dancers, MA, USA) supplemented PMSF (Phenylmethylsulfonyl fluoride, NACALAI TESQUE, INC., Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma

Zhao

Wang

et al. 2017

J Exp Clin Cancer Res

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BackgroundNasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types.MethodsRERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2’-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines.Results RERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818–0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts.ConclusionsOur results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0554-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma

Zhao

Wang

et al. 2017

J Exp Clin Cancer Res

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“…Nasopharyngeal carcinoma is a human epithelial tumor with a high prevalence in Southeast Asia and Southern China and has a strong association with EB virus infection [ 11 , 26 ]. We examined stemness markers (CD44v6, ALDH1A1, CD24) in human nasopharyngeal carcinoma tissues [ 27 ]. IHC staining of CD44v6 and ALDH1A1 was observed in cancer tissues, but that of CD24 was not.…”

Section: Oxidative and Nitrative Damage Of Biomacromolecules In Inflamentioning

confidence: 99%

Inflammation and cancer

Murata

2018

Environ Health Prev Med

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Infection and inflammation account for approximately 25% of cancer-causing factors. Inflammation-related cancers are characterized by mutagenic DNA lesions, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-nitroguanine. Our previous studies demonstrated the formation of 8-oxodG and 8-nitroguanine in the tissues of cancer and precancerous lesions due to infection (e.g., Opisthorchis viverrini-related cholangiocarcinoma, Schistosoma haematobium-associated bladder cancer, Helicobacter pylori-infected gastric cancer, human papillomavirus-related cervical cancer, Epstein-Barr virus-infected nasopharyngeal carcinoma) and pro-inflammatory factors (e.g., asbestos, nanomaterials, and inflammatory diseases such as Barrett’s esophagus and oral leukoplakia). Interestingly, several of our studies suggested that inflammation-associated DNA damage in cancer stem-like cells leads to cancer development with aggressive clinical features. Reactive oxygen/nitrogen species from inflammation damage not only DNA but also other biomacromolecules, such as proteins and lipids, resulting in their dysfunction. We identified oxidatively damaged proteins in cancer tissues by 2D Oxyblot followed by MALDI-TOF/TOF. As an example, oxidatively damaged transferrin released iron ion, which may mediate Fenton reactions and generate additional reactive oxygen species. Dysfunction of anti-oxidative proteins due to this damage might increase oxidative stress. Such damage in biomacromolecules may form a vicious cycle of oxidative stress, leading to cancer development. Epigenetic alterations such as DNA methylation and microRNA dysregulation play vital roles in carcinogenesis, especially in inflammation-related cancers. We examined epigenetic alterations, DNA methylation and microRNA dysregulation, in Epstein-Barr virus-related nasopharyngeal carcinoma in the endemic area of Southern China and found several differentially methylated tumor suppressor gene candidates by using a next-generation sequencer. Among these candidates, we revealed higher methylation rates of RAS-like estrogen-regulated growth inhibitor (RERG) in biopsy specimens of nasopharyngeal carcinoma more conveniently by using restriction enzyme-based real-time PCR. This result may help to improve cancer screening strategies. We profiled microRNAs of nasopharyngeal carcinoma tissues using microarrays. Quantitative RT-PCR analysis confirmed the concordant downregulation of miR-497 in cancer tissues and plasma, suggesting that plasma miR-497 could be used as a diagnostic biomarker for nasopharyngeal carcinoma. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses. These changes may be useful biomarkers in liquid biopsy for early detection and prevention of cancer.

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“…TAM‐secreted TNF‐α trigger chromosomal instability and enhance the self‐renewal of liver progenitor cells (Li, Chen, et al, ) (Figure ). Wang et al () measured 8‐Nitroguanine formation in NPC samples, which serve as a indicator of inflammation‐related DNA lesions. They observed that high level of 8‐Nitroguanine was detected in both CD44v6‐ and ALDH1A1‐positive stem cells in NPC tissues.…”

Section: Nf‐κb Stimulated Chronic Inflammation Promotes Cancer Stem Cmentioning

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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Inflammation-Related DNA Damage and Cancer Stem Cell Markers in Nasopharyngeal Carcinoma

Cited by 14 publications

References 49 publications

RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma

RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma

Inflammation and cancer

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

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