ZNF488 is an independent prognostic indicator in nasopharyngeal carcinoma and promotes cell adhesion and proliferation via collagen IV/FAK/AKT/Cyclin D1 pathway.

Background: ZNF488 acts as an oncogene which promotes cell invasion and endows tumor cells stem cell capacity in nasopharyngeal carcinoma (NPC), but its correlation with clinicopathologic characteristics and patients' survival in NPC remain undefined. Methods: In this study, 158 cases of confirmed NPC were subjected to immunohistochemistry staining for evaluating endogenous expression. Kaplan-Meier method and log-rank test were used to estimate the survival rates. The relationship between ZNF488 and clinicopathological characteristics was statistically calculated by chi-squared test, univariate and multivariate analysis. In addition, adhesion assay, MTT and colony formation assays were performed for measuring adhesion and proliferation capacity. Cell cycle analysis via flow cytometry was conducted to explore cell cycle distribution. Western blot was used to detect pathway protein levels, and the pFAK (Y397) kit was used for focal adhesion kinase (FAK) activation. Results: We demonstrated that high expression of ZNF488 was significantly correlated with locoregional failure (P=0.018) and distant metastasis (P=0.001). Patients with high ZNF488 expression had poorer overall survival (P<0.001), loco-regional recurrence-free survival (P<0.001), distance metastasis-free survival (P<0.001) and progression-free survival (P<0.001) than those with low ZNF488 group. Multivariate analysis showed that ZNF488 expression was an independent prognostic indicator for predicting NPC patients' survival (HR, 3.314; 95% CI, 1.489-7.386; P=0.003). Additionally, ZNF488-induced collagen IV/FAK/AKT to enhance adhesion ability meanwhile led to the upregulation of Cyclin D1 to facilitate cell proliferation through promoting cell cycle progression and inhibition of apoptosis through caspase-independent way. Conclusion: These results reveal that ZNF488, as an independent prognostic indicator, promotes cell adhesion and proliferation through collagen IV/FAK/AKT/Cyclin D1 pathway in NPC.

Protective properties of Huperzine A through activation Nrf2/ARE-mediated transcriptional response in X-rays radiation-induced NIH3T3 cells.

Huperzine A (HupA), derived from Huperzia Serrata, has exhibited a variety of biological actions, in particular neuroprotective effect. However, the protective activities of HupA on murine embryonic fibroblast NIH3T3 cells after X-rays radiation have not been fully elucidated. Herein, HupA treatment dramatically promoted cell viability, abated a G0/G1 peak accumulation, and ameliorated increase of cell apoptosis in NIH3T3 cells after X-rays radiation. Simultaneously, HupA notably enhanced activities of anti-oxidant enzymes, inhibited activity of lipid peroxide, and efficiently eliminated production of reactive oxygen species in NIH3T3 cells after X-rays radiation. Dose-dependent increase of antioxidant genes by HupA were associated with up-regulated Nrf2 and down-regulated Keap-1 expression, which was confirmed by increasing nuclear accumulation, and inhibiting of degradation of Nrf2. Notably, augmented luciferase activity of ARE may explained Nrf2/ARE-mediated signaling pathways behind HupA protective properties. Moreover, expression of Nrf2 HupA-mediated was significant attenuated by AKT inhibitor (LY294002), p38 MAPK inhibitor (SB202190) and ERK inhibitor (PD98059). Besides, HupA-mediated cell viability, and ROS production were dramatically bated by LY294002, SB202190, and PD98059. Taken together, HupA effectively ameliorated X-rays radiation-induced damage Nrf2-ARE-mediated transcriptional response via activation AKT, p38, and ERK signaling in NIH3T3 cells.

Effectiveness of Cetuximab in Combination with Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A 1:2 Propensity Score-matched Analysis.

Background: This study aimed to compare concurrent chemoradiotherapy (CCRT) plus cetuximab (C) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma(NPC). Methods: A total of 682 locoregionally advanced NPC patients who had undergone chemoradiotherapy with or without cetuximab were included. Propensity score-matching method was used to match patients. Progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared between the two treatment arms. Results: After matching, 225 patients were identified for the analysis. Compared to CCRT, CCRT plus C was associated with significantly improved 3-year PFS (83.7% vs 71.9%, P = 0.036), LRFS (98.6% vs 90.2%, P = 0.034) but not OS (91.4% vs 85.4%, P = 0.117). Among patients with T4 and/or N3 category, CCRT plus C significantly prolonged 3-year PFS (81.0% vs 61.4%, P = 0.022) and increased 3-year OS (88.0% vs 77.9%, P = 0.086). No significant differences were observed between CCRT plus C and CCRT alone groups with regard to 3-year PFS, OS, LRFS and DMFS rates in stage III patients. Acute oral and oropharyngeal mucositis during radiotherapy were more common in the CCRT plus C than that in CCRT, but late toxicities were comparable. Conclusions: This study reveals that patients with locoregionally advanced NPC could benefit from the addition of cetuximab to CCRT, and this therapeutic gain mainly originated from T4 and/or N3 subgroup although suffering more acute moderate to severe toxicities.

Long-Term Results of Concurrent Chemoradiotherapy for Advanced N2-3 Stage Nasopharyngeal Carcinoma.

BACKGROUND: N-stage is related to distant metastasis in nasopharyngeal carcinoma (NPC) patients. The purpose of this study was to evaluate the efficacy and toxicity of different nedaplatin-based chemotherapy regimens in advanced N2-3 stage NPC patients treated with intensity modulated radiation therapy (IMRT). PATIENTS AND METHODS: Between April 2005 and December 2009, a total of 128 patients with N2-3 advanced NPC were retrospectively analyzed. Patients were treated with IMRT concurrent with 2 cycles of chemotherapy consisting of either nedaplatin plus paclitaxel (NP group, n = 67) or nedaplatin plus fluorouracil and paclitaxel (NFP group, n = 61). Two to four cycles of adjuvant chemotherapy were then administered every 21 days following concurrent chemoradiotherapy. RESULTS: With a median follow-up of 60 months, the 5-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) for all patients were 81.4%, 71.5%, 87.8% and 82.0%, respectively. No significant difference in PFS (66.6% vs. 76.7%, P = 0.212) and LRRFS rates (89.0% vs. 86.3%, P = 0.664) was observed between the NP and NFP groups. The 5-year OS (75.4% vs. 88.5%, P = 0.046) and DMFS (75.1% vs. 89.0%, P = 0.042) rate were superior in the NFP group compared with the NP group. The NFP group had a higher incidence of grade 3-4 acute toxicities including bone marrow suppression (leukopenia: χ2 = 3.935, P = 0.047; anemia: χ2 = 9.760, P = 0.002; thrombocytopenia: χ2 = 8.821, P = 0.003), and both liver and renal dysfunction (χ2 = 5.206, P = 0.023) compared with the NP group. Late toxicities were moderate and no difference was observed between the two groups. CONCLUSION: IMRT concurrent with nedaplatin-based chemotherapy is an advocated regimen for patients with advanced N2-3 stage NPC. Patients with advanced N2-3 stage may be better candidates for the NFP regimen although this regimen was associated with a high acute toxicity rate.

Impact of plasma Epstein-Barr virus-DNA and tumor volume on prognosis of locally advanced nasopharyngeal carcinoma.

This retrospective study aims to examine the association of plasma Epstein-Barr virus- (EBV-) DNA levels with the tumor volume and prognosis in patients with locally advanced nasopharyngeal carcinoma (NPC). A total of 165 patients with newly diagnosed locally advanced NPC were identified from September 2011 to July 2012. EBV-DNA was detected using fluorescence quantitative polymerase chain reaction (PCR) amplification. The tumor volume was calculated by the systematic summation method of computer software. The median copy number of plasma EBV-DNA before treatment was 3790 copies/mL. The median gross tumor volume of the primary nasopharyngeal tumor (GTVnx), the lymph node lesions (GTVnd), and the total GTV before treatment were 72.46, 23.26, and 106.25 cm(3), respectively; the EBV-DNA levels were significantly correlated with the GTVnd and the total GTV (P < 0.01). The 2-year overall survival (OS) rates in patients with positive and negative pretreatment plasma EBV-DNA were 100% and 98.4% (P = 1.000), and the disease-free survival (DFS) rates were 94.4% and 80.8% (P = 0.044), respectively. These results indicate that high pretreatment plasma EBV-DNA levels in patients with locally advanced NPC are associated with the degree of lymph node metastasis, tumor burden, and poor prognosis.

The myeloperoxidase-463 G>A polymorphism influences risk of colorectal cancer in southern China: a case-control study.

OBJECTIVE: Oxidative stress may be involved in colorectal carcinogenesis. Myeloperoxidase (MPO) is an endogenous oxidant enzyme that generates reactive oxygen species (ROS). We hypothesized that the MPO -463 locus polymorphism might therefore contribute to genetic susceptibility to colorectal adenomas. METHODS: RFLP-PCR analysis identified the MPO genotypes in 325 Chinese colorectal adenomas cases and 345 controls matched by age, sex, smoking status, and alcohol use. An epidemiological interview elicited detailed information on demographic data and lifestyle characteristics. RESULTS: Individuals with a GA/AA genotype had a significantly lower risk of colorectal cancer (adjusted OR = 0.57, 95% CI, 0.41-0.79) than those with the GG genotype. On stratification analysis, the decreased risk was more pronounced among older subjects (adjusted OR = 0.56, 95% CI, 0.39-0.81), males (0.47, 0.33-0.68), smokers (0.54, 0.35-0.85), and ever-drinkers (0.44, 0.27-0.71). CONCLUSION: For a similar level of exposure to established carcinogens, individuals with MPO A-allele genotypes appear to have a reduced risk of colorectal adenomas in southern Chinese population, especially among older subjects, men, smokers, and ever-drinkers.