Resveratrol enhances MUC2 synthesis via the ANRIL-miR-34a axis to mitigate IBD.

BACKGROUND/AIMS: Resveratrol (RSV) is a natural polyphenol with strong biological activity that confers a measure of protection against the development of inflammatory bowel disease (IBD), and the long noncoding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) is closely related to inflammation. The present study determined whether resveratrol attenuated IBD by regulating ANRIL and its specific molecular mechanism. METHODS: In vivo model of IBD was induced by dextran sulfate sodium (DSS). In total, 60 BALB/c mice were randomly divided into 3 groups (normal control - NC, DSS, RSV), and their weight changes, fecal traits, colon length and tissue hematoxylin-eosin (H&E) were observed. Moreover, human colonic epithelial cells (HCoEpiC) treated with lipopolysaccharide (LPS) were used as cell models of IBD. The tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, IL-10, lncRNA ANRIL, and miR-34a levels were measured by RT-PCR. The expression of mucin 2 (MUC2) and an enzyme associated with MUC2 synthesis, polypeptide N-acetylgalactosaminyltransferase 7 (GALNT7), was measured by RT-PCR and western blot analysis. RESULTS: Resveratrol treatment mitigated colitis by significantly decreasing the expression of pro-inflammatory cytokines (i.e. TNF-α, IL-1ß, IL-6) and miR-34a, and increasing the levels of anti-inflammatory cytokine (i.e. IL-10), MUC2, GLNAT7, and lncRNA ANRIL in mice and HCoEpiC (all P<0.05). The elevated synthesis of MUC2 could be attributed to the ANRIL-miR-34a axis. CONCLUSIONS: Resveratrol attenuates IBD by promoting MUC2 synthesis via the ANRIL-miR-34a axis.

Tumor­suppressive miR­299­3p inhibits gastric cancer cell invasion by targeting heparanase.

Gastric cancer (GC) remains a leading cause of cancer­associated mortality globally. Emerging evidence suggests that microRNAs (miRs) function as oncogenes or tumor suppressors, contributing to various aspects of cancer progression, including invasion and metastasis. In the present study, the specific role of miR­299­3p in the invasion of GC cells was investigated. The expression level of miR­299­3p was measured using reverse transcription­quantitative PCR and in situ hybridization in human GC tissues. Effects of miR­299­3p on GC cell invasion were determined by Transwell assay. Bioinformatics and luciferase reporter assays were performed to identify and verify the downstream effectors of miR­299­3p. miR­299­3p expression analysis in clinical GC samples revealed a significant downregulation of miR­299­3p compared with non­tumor tissues. Inhibition of miR­299­3p promoted the invasive abilities of GC cells, whereas its overexpression significantly suppressed cell invasion. Bioinformatics and luciferase reporter assays identified heparanase (HPSE) as a direct target of miR­299­3p, the ectopic expression of which reversed the impairment in cell invasion induced by miR­299­3p upregulation. Furthermore, HPSE expression was negatively associated with miR­299­3p levels in human GC tissues. Overall, the present study indicated that miR­299­3p functions as a tumor suppressor by directly targeting HPSE, highlighting its potential as a target for the treatment of GC.

Biomarkers in Tumor Microenvironment? Upregulation of Fibroblast Activation Protein-α Correlates with Gastric Cancer Progression and Poor Prognosis.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Recent evidence points to importance of cross talk between cancer cells and the surrounding stroma on gastric cancer progression. Tumor microenvironment biomarkers thus represent a new opportunity for diagnostics innovation. Reactive stromal fibroblasts selectively express the fibroblast activation protein alpha (FAP-α), a homodimeric integral membrane gelatinase that belongs to the serine protease family. We report here that FAP-α expression is significantly elevated in gastric cancer samples by more than fivefold (p < 0.05), using transcriptome data from The Cancer Genome Atlas. Notably, the greatest FAP-α upregulation was observed in the poorly differentiated group (p < 0.001). Moreover, elevated FAP-α expression levels correlated with adverse clinical-pathological characteristics, such as diffuse histological subtype (p < 0.001), advanced pathological stage (p < 0.01) and poor survival. Functional annotation analysis demonstrated that FAP-α upregulation was associated with activation of biological processes implicated in tumor progression, including cell migration and angiogenesis pathways. These observations underscore the possible prognostic significance of FAP-α in gastric cancer and its potential as a novel biomarker for personalized medicine. We caution, however, that further multiomics, biochemical, and animal studies are necessary to ascertain the role of FAP-α as a causative and mechanistic biomarker. Based on pathway analyses, we hypothesize that gastric cancer patients exhibiting FAP-α upregulation might presumably benefit from antiangiogenic drugs in addition to standard therapeutic regimens. We call for future research focusing on the tumor microenvironment biomarkers in clinical oncology.