title: Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR.
abstract: The antitumorigenic activities of polyphenols such as ellagitannins and anthocyanins in pomegranate (Punica granatum L.) have been previously studied where cytotoxic, anti-inflammatory and antioxidant effects were evident in various cancer models. The objective of this study was to investigate the role of miR-126/vascular cell adhesion molecule 1 (VCAM-1) and miR-126/phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) in pomegranate-mediated anti-inflammatory and anticarcinogenic effects in vivo and in vitro. Sprague-Dawley rats (n = 10 per group) received pomegranate juice (2504.74 mg gallic acid equivalents/l) or a polyphenol-free control beverage ad libitum for 10 weeks and were injected with azoxymethane (AOM) subcutaneously (15mg/kg) at weeks 2 and 3. Consumption of pomegranate juice suppressed the number of aberrant crypt foci (ACF) and dysplastic ACF by 29 and 53.5% (P = 0.05 and 0.04), respectively, and significantly lowered proliferation of mucosa cells. Pomegranate juice significantly downregulated proinflammatory enzymes nitric oxide synthase and cyclooxygenase-2 messenger RNA (mRNA) and protein expression. In addition, it suppressed nuclear factor-κB and VCAM-1 mRNA and protein expression in AOM-treated rats. Pomegranate also inhibited phosphorylation of PI3K/AKT and mTOR expression and increased the expression of miR-126. The specific target and functions of miR-126 were investigated in HT-29 colon cancer cell lines. In vitro, the involvement of miR-126 was confirmed using the antagomiR for miR-126, where pomegranate reversed the effects of the antagomiR on the expression of miR-126, VCAM-1 and PI3K p85β. In summary, therapeutic potentials of pomegranate in colon tumorigenesis were due in part to targeting miR-126-regulated pathways, which contributes in the underlying anti-inflammatory mechanisms.
authors.affiliation: Interdisciplinary Program of Toxicology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Banerjee
authors.forename: Hyemee
authors.initials: H
authors.lastname: Kim
authors.forename: Stephen
authors.initials: S
authors.lastname: Talcott
authors.forename: Susanne
authors.initials: S
authors.lastname: Mertens-Talcott
mesh_terms: D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001397:Azoxymethane / Q000009:adverse effects; D001628:Beverages; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D029561:Lythraceae; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D059808:Polyphenols / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D035683:MicroRNAs; D059808:Polyphenols; D019010:Vascular Cell Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D001397:Azoxymethane