Grape pomace (GP), a by-product of the wine and juice industry, is rich in bioflavonoids and dietary fibers. We hypothesized that GP has protective effects against colitis-associated colorectal cancer (CRC). Nine-week-old female mice were fed a control diet (CON) or CON with 5% grape pomace (GP) for 2 weeks, when mice were subjected to azoxymethane (AOM)/dextran sulfate sodium (DSS) induced-CRC induction. GP supplementation ameliorated the disease activity index (DAI) score, reduced tumor number, tumor size and pathological scores in AOM/DSS treated mice. Furthermore, dietary GP suppressed colonic expression of inflammatory cytokines, IL-1β and TNF-α, and inhibited NF-κB inflammatory signaling, while increased anti-inflammatory cytokine TGF-β mRNA expression. Colorectal inflammation is known to enhance Wnt signaling and cell proliferation. In agreement, the content of β-catenin, a key downstream mediator of Wnt signaling, was reduced as was the expression of Cyclin D1, phosphorylation and content of p53 and PCNA level in GP-fed mice. In addition, GP reduced the expression of ALDH1, a marker of cell stemness, and increased the expression of Cdx2, a key transcription factor initiating epithelial cell differentiation, DNA methylation of the promoter region of Cdx2 gene and hypermethylation of CpG island methylator phenotype (CIMP), which commonly occurs during CRC carcinogenesis, was alleviated in the GP group. In conclusion, GP supplementation suppressed colitis-associated CRC carcinogenesis, which was associated with the suppression of inflammation and cell proliferation and the enhancement of DNA demethylation in Cdx2 and CIMP genes in the colon. These data suggest that dietary GP supplementation has preventive effects against colorectal carcinogenesis.

葡萄渣（GP）是葡萄酒和果汁行业的副产品，富含生物类黄酮和膳食纤维。我们假设GP对结肠炎相关的大肠癌（CRC）具有保护作用。当对九周龄的雌性小鼠进行乙氧基甲烷（AOM）/右旋糖酐硫酸钠（DSS）诱导的CRC诱导时，喂饲对照饮食（CON）或含5％葡萄渣（GP）的CON 2周。GP补充改善了AOM / DSS处理的小鼠的疾病活动指数（DAI）评分，减少的肿瘤数量，肿瘤大小和病理学评分。此外，饮食GP抑制结肠炎性细胞因子IL-1β和TNF-α的表达，并抑制NF-κB炎症信号，同时增加抗炎细胞因子TGF-βmRNA表达。已知结直肠炎症会增强Wnt信号传导和细胞增殖。一致的是，在GP喂养的小鼠中，Wnt信号的关键下游介质β-catenin的含量降低，Cyclin D1的表达，磷酸化以及p53和PCNA的含量降低。此外，GP降低了细胞干性标志物ALDH1的表达，并增加了Cdx2的表达，Cdx2是启动上皮细胞分化的关键转录因子，Cdx2基因启动子区域的DNA甲基化以及CpG岛甲基化表型（CIMP）的超甲基化GP组缓解了通常在CRC致癌过程中发生的）。总之，补充GP可抑制结肠炎相关的CRC癌变，这与炎症和细胞增殖的抑制以及结肠Cdx2和CIMP基因中DNA脱甲基的增强有关。这些数据表明，饮食中补充GP对结直肠癌的发生具有预防作用。