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Abstract. Decorin (DCN) has been suggested to display an anti-metastatic role by antagonizing bioactive TGF-β in advanced human cancers. However, the epigenetic mechanisms by which defective expression of DCN causes cancer metastasis remain unclear. We focused on non-small cell lung cancer (NSCLC) cell lines with low metastatic potential (95C) and high metastatic potential (95D), which share a similar genetic background. Quantitative PCR and clonal bisulfite sequencing indicated that the methylation levels of the +58CpG site in the DCN 5'-UTR region was significantly higher in 95D cells with low expression of DCN mRNA compared to 95C cells with high expression of DCN mRNA. In silico prediction and ChIP assay showed a correlation between +58CpG site and AhR, which was reported as a transcriptional activator. Importantly, EMSA and luciferase reporter gene assays suggested that +58CpG methylation specifically diminished the recruitment of AhR to DCN 5'-UTR sequence and caused a reduction of approximately 50% in transcriptional activity. At baseline, 95D cells exhibited higher p-Smad3 levels and lower E-cadherin expression when compared with 95C cells. The demethylating agent 5-Aza significantly led to restoration of DCN expression, reduced level of p-Smad3, increased expression of E-cadherin in 95D cells. Taken together, we identified the methylated +58CpG in DCN 5'-UTR associated with reduced expression of DCN mRNA, and revealed that +58CpG methylation may be one of the mechanisms accounting for reduced recruitment of the transcriptional activator AhR to DCN 5'-UTR, and suggest that this mechanism promotes TGF-β/Smad signaling by enhancing the phosphorylation of Smad3, thereby downregulating E-cadherin in NSCLC cells with high metastatic potential.

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Background:The normal range of red cell distribution width (RDW) level is <15%. Several studies have indicated that a high RDW level was associated with mortality in critically ill patients, and the patients with a high RDW level need increased focus in clinical practice. In view of the difficulty in defining the specific value of high RDW level, the key is to focus on the patient with the level beyond the normal upper limit. This study aimed to determine whether dynamic change of RDW levels, rather than the level itself, is predictive of death in elderly patients with septic shock when RDW level is beyond 15%.Methods:Between September 2013 and September 2015, the elderly septic shock patients with RDW level beyond 15% were enrolled in this study. The RDW levels were measured at enrollment (day 1), and days 4 and 7 after enrollment. Sequential Organ Failure Assessment (SOFA) scores were recorded simultaneously.Results:A total of 45 patients, including 32 males and 13 females, were included in the final analysis. Based on their hospital outcomes, these patients were divided into the survivor group (n = 26) and the nonsurvivor group (n = 19). There were no significant differences in age, gender, body mass index, initial level of RDW, Acute Physiology and Chronic Health Evaluation II scores, and SOFA scores between survivors and nonsurvivors. At days 4 and 7 measurement, both RDW level (median [interquartile range]: day 4: 15.8 [2.0]% vs. 16.7 [2.0]%, P = 0.011; and day 7: 15.6 [1.8]% vs. 17.7 [2.5]%, P = 0.001) and SOFA scores (day 4: 7.0 [4.0] vs. 16.0 [5.0], P < 0.001, day 7: 5.5 [4.0] vs. 17.0 [5.0], P < 0.001) were significantly lower in survivors than those in nonsurvivors. Dynamic changes of RDW and SOFA scores in survivor group were significantly different from those in nonsurvivor group (all P < 0.05). Continuous increase in RDW level was observed in 10 of the 13 nonsurvivors, but only in 3 of the 26 survivors. The level of RDW7 and dynamic changes significantly correlated with their counterparts of SOFA scores (all P < 0.05), whereas the levels of RDW1 and RDW4 had no significant correlation with their counterparts of SOFA scores (all P > 0.05).Conclusions:Continuous increase in RDW level, rather than the level of RDW itself, was more useful in predicting hospital death in elderly patients with septic shock when the level of RDW was >15%. The dynamic changes of RDW were highly correlated with the SOFA score in the patients.

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