Grape seed extract efficacy against azoxymethane-induced colon tumorigenesis in A/J mice: interlinking miRNA with cytokine signaling and inflammation.
Grape seed extract efficacy against azoxymethane-induced colon tumorigenesis in A/J mice: interlinking miRNA with cytokine signaling and inflammation.
复制标题
葡萄籽提取物对 A/J 小鼠中氧化偶氮甲烷诱导的结肠肿瘤发生的功效：将 miRNA 与细胞因子信号传导和炎症联系起来。
DOI：
10.1158/1940-6207.capr-13-0053
复制
发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Agarwal C
中科院分区：
文献类型：
--
作者：
Derry MM;Raina K;Balaiya V;Jain AK;Shrotriya S;Huber KM;Serkova NJ;Agarwal R;Agarwal C
结直肠癌（CRC）是癌症相关死亡的第二大原因，这表明需要额外的策略来预防/控制这种恶性肿瘤。由于CRC的生长和进展涉及一个很大的窗口期（10-15年），因此化学预防干预可能是一种实用/转化策略。氧化偶氮甲烷（AOM）诱导的小鼠结肠肿瘤发生在ACF发展为息肉、腺瘤和癌以及相关分子机制方面类似于人类CRC。因此，在此，我们研究了葡萄籽提取物（GSE）对A/J小鼠中AOM诱导的结肠肿瘤发生的功效。在最后一次AOM注射后两周开始以0.25%或0.5%（w/w）剂量在饲料中饲喂GSE，持续18或28周。我们的研究结果表明，GSE喂养显着降低结肠肿瘤的多样性和整体肿瘤大小。在生物标志物分析中，GSE显示出显著的抗增殖和促凋亡活性。详细的机制研究强调，GSE强烈调节细胞因子/白细胞介素和miRNA表达谱以及与NF-κB、β-catenin和MAPK信号转导改变相关的miRNA加工机制。使用免疫组织化学分析的其他研究发现，GSE确实抑制NF-κB活化并降低与炎症信号传导相关的下游靶点（考克斯-2、iNOS、VEGF）的表达，下调β-连环蛋白信号传导并降低其靶基因C-myc，并降低磷酸化ERK 1/2水平。总之，这些发现表明GSE靶向炎症、增殖和凋亡以预防CRC。总之，本研究首次显示了GSE在A/J小鼠散发性CRC模型中对AOM诱导的结肠肿瘤发生的效力中的miRNA和细胞因子表达的改变，支持其在CRC化学预防中的翻译潜力。
Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths, suggesting that additional strategies are needed to prevent/control this malignancy. Since CRC growth and progression involve a large window (10-15 years), chemopreventive intervention could be a practical/translational strategy. Azoxymethane (AOM)-induced colon tumorigenesis in mice resembles human CRC in terms of progression of ACF to polyps, adenoma and carcinomas, and associated molecular mechanisms. Accordingly, herein we investigated grape seed extract (GSE) efficacy against AOM-induced colon tumorigenesis in A/J mice. GSE was fed in diet at 0.25% or 0.5% (w/w) dose starting two-weeks after last AOM injection for 18 or 28 weeks. Our results showed that GSE feeding significantly decreases colon tumor multiplicity and overall tumor size. In biomarker analysis, GSE showed significant anti-proliferative and pro-apoptotic activities. Detailed mechanistic studies highlighted that GSE strongly modulates cytokines/interleukins and miRNA expression profiles as well as miRNA processing machinery associated with alterations in NF-κB, β-catenin and MAPK signaling. Additional studies using immunohistochemical analyses found that indeed GSE inhibits NF-κB activation and decreases the expression of its downstream targets (COX-2, iNOS, VEGF) related to inflammatory signaling, down-regulates β-catenin signaling and decreases its target gene C-myc, and reduces phosphorylated ERK1/2 levels. Together, these finding suggested that inflammation, proliferation and apoptosis are targeted by GSE to prevent CRC. In summary, this study for the first time shows alterations in the expression of miRNAs and cytokines by GSE in its efficacy against AOM-induced colon tumorigenesis in A/J mouse sporadic CRC model, supporting its translational potential in CRC chemoprevention.