Reactive nitrogen species‐dependent DNA damage in EBV‐associated nasopharyngeal carcinoma: The relation to STAT3 activation and EGFR expression

Abstract

Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. Recently, reactive nitrogen and oxygen species are considered to participate in inflammationrelated carcinogenesis through DNA damage. In our study, we obtained biopsy and surgical specimens of nasopharyngeal tissues from NPC patients in southern China, and performed double immunofluorescent staining to examine the formation of 8-nitroguanine, a nitrative DNA lesion and 8-oxo-7,8-dihydro-2 0 -deoxyguanosine, an oxidative DNA lesion, in these specimens. Strong DNA lesions were observed in cancer cells and inflammatory cells in stroma of NPC patients. Intensive immunoreactivity of iNOS was detected in the cytoplasm of 8-nitroguanine-positive cancer cells. DNA lesions and iNOS expression were also observed in epithelial cells of EBV-positive patients with chronic nasopharyngitis, although their intensities were significantly weaker than those in NPC patients. In EBV-negative subjects, no or little DNA lesions and iNOS expression were observed. EGFR and phosphorylated STAT3 were strongly expressed in cancer cells of NPC patients, but NF-jB was not expressed, suggesting that STAT3-dependent mechanism is important for NPC carcinogenesis. IL-6 was expressed mainly in inflammatory cells of nasopharyngeal tissues of EBV-infected patients. EBV-encoded RNAs (EBERs) and latent membrane protein 1 (LMP1) were detected in cancer cells from all EBV-infected patients. In vitro cell system, nuclear accumulation of EGFR was observed in LMP1-expressing cells, and IL-6 induced phosphorylated STAT3 and iNOS. These data suggest that nuclear accumulation of EGFR and STAT3 activation by IL-6 play the key role in iNOS expression and resultant DNA damage, leading to EBV-mediated NPC. '

Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation

“…Indeed, it is detected in more than 75% of NPC cases. Growing evidence indicates that STAT3 activation contributes to the progression and invasiveness of NPC [16][17][18] . Therefore, the activation of STAT3 provides a promising and valid target for NPC therapeutic modalities.…”

“…Accumulating evidence has demonstrated that STAT3 is a promising molecule target for anticancer treatment and cancer prevention [14,15] . More recently, STAT3 has also been found to be activated in www.chinaphar.com Liu DB et al Acta Pharmacologica Sinica npg more than 75% of NPC cases, and this molecule plays a significant role in driving NPC progression and metastasis [16][17][18] . A recent study identified celecoxib as a novel inhibitor of STAT3 [6] .…”

8-Nitroguanine, a Potential Biomarker to Evaluate the Risk of Inflammation-Related Carcinogenesis

“…Thus, 8-nitroguanine is a potentially mutagenic DNA lesion, which can participate in initiation and promotion in the infection-related carcinogenesis (Loeb & Preston, 1986;. Our studies have demonstrated that 8-nitroguanine is formed at the sites of carcinogenesis in humans and experimental animals (Ma et al, 2004;Pinlaor et al, 2004b;Ding et al, 2005;Horiike et al, 2005;Ma et al, 2006;Hoki et al, 2007a;Hoki et al, 2007b;Fujita et al, 2008;Ma et al, 2008;Tanaka et al, 2008;Ma et al, 2009;Ma et al, 2010). Moreover, our studies have demonstrated that 8-nitroguanine was formed in Oct3/4-positve stem cells in S. haematobium-associated cystitis and cancer tissues.…”

Role of Chronic Inflammation and Resulting DNA Damage in Cervical Carcinogenesis Induced by Human Papillomavirus

“…These results suggest that 8-nitroguanine is a promising biomarker providing an assessment of the risk of inflammation-mediated carcinogenesis at the precancerous stage. Moreover, in EBV-infected patients, the staining intensity of 8-nirtroguanine was significantly stronger in nasopharyngeal cancer cells than in epithelial cells of chronic nasopharyngitis patients, suggesting that 8-nitroguanine accumulates during the development of chronic inflammation to cancer (Ma et al, 2008). In addition, 8-nitroguanine formation was observed under inflammatory conditions independent of infection.…”

“…Administration of the antiparasitic drug praziquantel and the antioxidant curcumin significantly reduced oxidative and nitrative DNA damage Prakobwong et al, 2011). We have also demonstrated that 8-nitroguanine was formed in the gastric gland epithelial cells from gastritis patients with Helicobacter pylori infection (Ma et al, 2004), in the hepatocytes of patients with chronic hepatitis C (Horiike et al, 2005) and in the nasopharyngeal epithelial cells and tumor tissues of patients infected with Epstein-Barr virus (EBV) (Ma et al, 2008). These results suggest that 8-nitroguanine is a promising biomarker providing an assessment of the risk of inflammation-mediated carcinogenesis at the precancerous stage.…”