RESUMO
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy, which is notorious among head-and-neck cancers with its metastatic feature. Epstein-Barr virus (EBV) infection plays a fundamental role in NPC development with the mechanism is not well understood. Here we demonstrate that EBV oncoprotein LMP1 drives EMT and metastasis of NPC by reactivating the adhesion molecule, cadherin 6 (CDH6), which normally occurs in embryogenesis with unknown role in NPC. CDH6 was found to be upregulated in LMP1-positive NPC tissues, and was identified as a target of the epithelium-specific miR-203. LMP1-activated NF-κB transcriptionally repressed the miR-203 expression by binding to the promoter region of miR-203 gene. CDH6 activation in turn induced EMT and promoted metastasis in NPC. CDH6 depletion, NF-κB inhibitor and miR-203 overexpression were able to impair the EMT effects. The miR-203 downregulation in NPC tissues was strongly associated with metastasis clinically. The CDH6 activator, Runt-related transcription factor 2 (RUNX2), was also activated by EBV in the event. For both CDH6 and RUNX2 are components at TGF-ß downstream, CDH6 became a node protein for the interplay of multiple signalings including NF-κB and TGF-ß. Therefore, the switch-on of miR-203 was important for nasopharyngeal epithelial cells to maintain normal phenotype. This study demonstrates that EBV has evolved sophisticated strategies by driving epithelial cells to obtain malignant features, particularly in NPC metastasis, providing novel biomarkers for the therapy and prognosis of EBV-associated NPC.
RESUMO
Objective: To explore the expression of serum interleukin-13 (IL-13) and significance of its gene polymorphism on the patients with acute exacerbation of bronchiectasis in acute exacerbation period. Methods: Forty-three patients with bronchiectasis in acute exacerbation period admitted into the respiratory ward of Fujian Provincial Hospital from December, 2014 to March, 2016 were included as bronchiectasis group. Thirty-three healthy controls from normal people of health examination were included as control group during the corresponding period. A total of 5 ml fasting peripheral blood sample was extracted from each individual. The IL-13 levels were determined by enzyme-linked immunosorbent assay (ELISA). IL-13 gene polymorphisms in+ 1923 C/T site and+ 2044 site were genotyped in these two groups by using polymerase chain reaction (PCR) combined with gene sequencing methods. About 7 days after admission, thirty patients with improved condition among the 43 patients were included as bronchiectasis improvement group, all had the extraction of 3 ml peripheral blood for IL-13 detection determined by ELISA. The expression of serum IL-13 and gene polymorphisms between bronchiectasis group and control group were analyzed statistically. The changes of serum IL-13 between bronchiectasis group and bronchiectasis improvement group were also analyzed statistically. Results: The serum IL-13 level was lower in the bronchiectasis group in acute exacerbation period than that of the healthy controls [(31.1±26.3) vs (70.6±53.6) µg/L, P<0.05]. There was no significant difference of the genotype distribution in + 1923C/T site of IL-13 gene between the two groups (χ(2)=0.915, P>0.05). In the bronchiectasis group, the C and T allele frequencies at+ 1923 site of IL-13 gene were 79.1% and 20.9%, respectively, and its single nucleotide polymorphism (SNP) was in strong linkage disequilibrium with the SNP IL-13+ 2044G/A site (R(2)=0.835, P<0.001). There was no significant difference of the serum IL-13 between allele T_ groups and allele CC group, and also no significant difference between allele A_ groups and allele GG group (P>0.05). Conclusion: The IL-13 levels decreased specifically in the bronchiectasis group in acute exacerbation period, but IL-13+ 1923C/T and+ 2044G/A polymorphisms are not significantly related to the susceptibility of bronchiectasis.
