Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR
Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR
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DOI：
10.1093/carcin/bgt295
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发表时间：
2013-12-01
期刊：
影响因子：
4.7
通讯作者：
Mertens-Talcott, Susanne
中科院分区：
文献类型：
--
作者：
Banerjee, Nivedita;Kim, Hyemee;Mertens-Talcott, Susanne
研究了石榴多酚类物质鞣花单宁和花色苷的抗肿瘤活性。先前已经研究过，其中细胞毒性、抗炎和抗氧化作用在各种癌症模型中是明显的。本研究的目的是研究miR-126/血管细胞粘附分子1（VCAM-1）和miR-126/磷脂酰肌醇-3-激酶（PI 3 K）/AKT/哺乳动物雷帕霉素靶蛋白（mTOR）在体内和体外研究中的作用。Sprague-Dawley大鼠（n = 10/组）接受石榴汁（2504.74 mg没食子酸当量/l）或无多酚对照饮料10周，并在第2周和第3周皮下注射氧化偶氮甲烷（AOM）（15 mg/kg）。石榴汁的消耗抑制异常隐窝病灶（ACF）和发育不良ACF的数量分别为29和53.5%（P = 0.05和0.04），并显着降低粘膜细胞的增殖。枸杞汁显著下调促炎酶一氧化氮合酶和环氧合酶-2信使RNA（mRNA）和蛋白质的表达。此外，它抑制核因子-κ B和VCAM-1的mRNA和蛋白质的表达在AOM处理的大鼠。PdR还抑制PI 3 K/AKT和mTOR表达的磷酸化，并增加miR-126的表达。在HT-29结肠癌细胞系中研究miR-126的特异性靶点和功能。在体外，使用针对miR-126的ApomiR证实了miR-126的参与，其中石榴逆转了ApomiR对miR-126、VCAM-1和PI 3 K p85 β表达的影响。总之，石榴在结肠肿瘤发生中的治疗潜力部分归因于靶向miR-126调节的途径，这有助于潜在的抗炎机制。
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 (15 mg/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-kappa B 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 p85 beta. 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.