Increasing evidence suggests that microRNAs are associated with many important biologic processes in carcinogenesis. Despite ample research revealing the dysregualtion of miR-486-5p in various cancers, little is known about the roles of miR-486-5p in colorectal carcinoma (CRC). In this study, we investigated the biological functions and molecular mechanisms of miR-486-5p in CRC growth and invasion, discussing the potential of using miR-486-5p as a biomarker for colorectal cancers. Our data revealed that miR-486-5p was significantly downregulated in CRC tissues compared with the paracancer tissue by quantitative real-time polymerase chain reaction and that miR-486-5p was downregulated to a greater extent in advanced stage cancer (stage III and IV) as compared to early stage cancer (stage I and II). Luciferase reporter assay verified that neuropilin-2 was a direct functional target of miR-486-5p in the CRC cells, and upregulation of miR-486-5p in CRC cells negatively correlated with the expression of neuropilin-2. Furthermore, overexpression of miR-486-5p inhibited the tumor growth and lymphangiogenesis in nude mice, which was reversed by overexpression of neuropilin-2. Taken together, our study suggested miR-486-5p might be a suppressor of CRC.

Background: Alternative splicing (AS) is an important mechanism of regulating eukaryotic gene expression. Understanding the most common AS events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Methods: Publicly available RNA-seq data of 28 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify AS events using PSI and DEXSeq methods. Result: The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified AS events in 9 genes in CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6). Except for CHEK1, all other 8 splicing events were confirmed by TCGA data with 382 CRC tumors and 51 normal controls. The combination of three splicing events was used to build a logistic regression model that can predict sample type (CRC or normal) with near perfect performance (AUC = 1). Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The AS features of the 9 genes are highly consistent with previous reports and/or relevant to cancer biology. Conclusions: The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a "double-hit" neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.

A hydroponic study was conducted to determine the effects of selenium (Se: 0μmol• L −1 , 3μmol• L −1 , 6μmol• L −1 ) on senescence-related oxidative stress in garlic plants grown under two sulfur (S) levels. We evaluated the yields of plants harvested at 160 and 200 days after sowing. Plants grown under a low-Se dose (0.3 μmol•L −1 ) at low S level showed higher yields (12.0% increase in fresh weight yield, 13.7% increase in dry weight yield) than those of controls, despite a decrease in chlorophyll concentration. Compared with control plants, the Se-treated plants showed lower levels of lipid peroxidation. The Se-treated plants also showed higher activities of glutathione peroxidase and catalase, but lower superoxide dismutase activities. Changes in Fv/Fm values and proline contents were affected more strongly by S than by Se. On the basis of our results, we can conclude that Se plays a key role in the antioxidant systems in garlic seedlings. It delays senescence by alleviating the peroxide stress, but it can be toxic at high levels. A high S level may increase tolerance to high Se concentrations through reducing Se accumulation in plants.

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BackgroundThe RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor family and is closely involved in a variety of cellular processes including development, differentiation, participation in the regulation of p53-dependent DNA damage response and/or tumorigenesis. Emerging evidence indicates that RUNX3 is a candidate tumor suppressor in several types of human tumors including colorectal cancer (CRC). However, the correlation of RUNX3 inactivation with CRC remains unclear. In the study reported here, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of RUNX3 hypermethylation/expression on the incidence of CRC.MethodsA detailed search of the literature was made using Medline® and Web of Science for related research publications written in English. The methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of the pooled data were performed. Odds ratios (ORs) and hazard ratios were calculated and summarized, respectively.ResultsA final analysis of 1,427 CRC patients from eleven eligible studies was performed. We observed that RUNX3 hypermethylation was significantly higher in CRC than in normal colorectal mucosa. The pooled OR from six studies comprising 289 CRC and 188 normal colorectal mucosa was OR =0.07 (confidence interval [CI] =0.03–0.18, P<0.00001). Aberrant RUNX3 hypermethylation/expression was significantly higher in advanced CRC than in early staged CRC (OR =0.54, CI =0.41–0.71, P<0.0001). Aberrant RUNX3 hypermethylation/expression was also significantly higher in microsatellite instability (MSI)-positive CRC than in MSI-negative CRC (OR =0.44, CI =0.3–0.66, P<0.0001). In addition, CRC patients with RUNX3 hypermethylation or lacking RUNX3 protein expression had a lower survival rate than those without RUNX3 hypermethylation or those who did not express RUNX3 protein.ConclusionThe results of this meta-analysis suggest that RUNX3 hypermethylation is associated with an increased risk of CRC, increased risk of progression of CRC, and a poorer CRC survival rate. RUNX3 hypermethylation, which induces the inactivation of RUNX3 gene, plays an important role in colorectal carcinogenesis, high levels of MSI, as well as CRC progression and development.