MicroRNA-21 regulates prostaglandin E2 signaling pathway by targeting 15-hydroxyprostaglandin dehydrogenase in tongue squamous cell carcinoma.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) is one of the most aggressive forms of head and neck/oral cancer (HNOC), and is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. Identifying the deregulation of microRNA-mRNA regulatory modules (MRMs) is crucial for understanding the role of microRNA in OTSCC. METHODS: A comprehensive bioinformatics analysis was performed to identify MRMs in HNOC by examining the correlation among differentially expressed microRNA and mRNA profiling datasets and integrating with 12 different sequence-based microRNA target prediction algorithms. Confirmation experiments were performed to further assess the correlation among MRMs using OTSCC patient samples and HNOC cell lines. Functional analyses were performed to validate one of the identified MRMs: miR-21-15-Hydroxyprostaglandin Dehydrogenase (HPGD) regulatory module. RESULTS: Our bioinformatics analysis revealed 53 MRMs that are deregulated in HNOC. Four high confidence MRMs were further defined by confirmation experiments using OTSCC patient samples and HNOC cell lines, including miR-21-HPGD regulatory module. HPGD is a known anti-tumorigenic effecter, and it regulates the tumorigenic actions of Prostaglandin E2 (PGE2) by converts PGE2 to its biologically inactive metabolite. Ectopic transfection of miR-21 reduced the expression of HPGD in OTSCC cell lines, and the direct targeting of the miR-21 to the HPGD mRNA was confirmed using a luciferase reporter gene assay. The PGE2-mediated upregulation of miR-21 was also confirmed which suggested the existence of a positive feed-forward loop that involves miR-21, HPGD and PGE2 in OTSCC cells that contribute to tumorigenesis. CONCLUSIONS: We identified a number of high-confidence MRMs in OTSCC, including miR-21-HPGD regulatory module, which may play an important role in the miR-21-HPGD-PGE2 feed-forward loop that contributes to tumorigenesis.

Effects of chronic intermittent hypoxia on allergen-induced airway inflammation in rats.

Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more TH-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma.