Meeker Stacey, Seamons Audrey, Paik Jisun, Treuting Piper M, Brabb Thea, Grady William M, Maggio-Price Lillian
Department of Comparative Medicine, University of Washington, Seattle, Washington.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Gastroenterology, University of Washington Medical School, Seattle, Washington.
Cancer Res. 2014 Aug 15;74(16):4398-408. doi: 10.1158/0008-5472.CAN-13-2820. Epub 2014 Jun 17.
Epidemiologic studies associate low serum vitamin D levels with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD). 129-Smad3(tm1Par)/J (Smad3(-/-)) mice are a model of bacteria-driven colitis and colon cancer when infected with Helicobacter bilis (H. bilis). Thus, we used this mouse model to determine whether increased dietary vitamin D would reduce inflammation and colon cancer. Smad3(-/-) mice were fed purified diet with either maintenance (1 IU vitamin D/g diet; maintenance) or increased concentrations of vitamin D (5 IU vitamin D/g diet; high vitamin D). One week after diet initiation, mice were inoculated with broth or H. bilis and were necropsied at several time points postinoculation to assess inflammation, dysplasia, and neoplasia incidence. At 16 weeks postinfection, 11% of mice fed high vitamin D diet had cancer compared with 41% of mice fed maintenance diet (P = 0.0121). Evaluation at an early time point (1 week postinfection) showed that animals fed high vitamin D had decreased MAPK (p-P38 and p-JNK) activation in lamina propria leukocytes as well as decreased NFκB activation in colonic epithelial cells. Reduction in MAPK and NFκB activation correlated with decreased IBD scores (2.7 vs. 15.5; P < 0.0001) as well as decreased inflammatory cell infiltrates and reduced expression of proinflammatory cytokines in cecal tissue. These findings suggest that increased dietary vitamin D is beneficial in preventing inflammation-associated colon cancer through suppression of inflammatory responses during initiation of neoplasia or early-stage carcinogenesis.
流行病学研究表明，血清维生素D水平低与结肠癌及炎症性疾病（如炎症性肠病，IBD）风险增加相关。129-Smad3(tm1Par)/J（Smad3基因敲除）小鼠在感染胆汁螺杆菌（H. bilis）后是细菌驱动性结肠炎和结肠癌的模型。因此，我们使用该小鼠模型来确定增加饮食中的维生素D是否会减轻炎症和降低结肠癌风险。给Smad3基因敲除小鼠喂食纯化饮食，其中一种是维持剂量（每克饮食含1 IU维生素D；维持组），另一种是增加维生素D浓度（每克饮食含5 IU维生素D；高维生素D组）。开始饮食一周后，给小鼠接种肉汤或胆汁螺杆菌，并在接种后的几个时间点进行尸检，以评估炎症、发育异常和肿瘤发生率。感染后16周，喂食高维生素D饮食的小鼠中有11%患癌，而喂食维持饮食的小鼠中这一比例为41%（P = 0.0121）。在早期时间点（感染后1周）评估发现，喂食高维生素D的动物固有层白细胞中的MAPK（磷酸化P38和磷酸化JNK）激活减少，结肠上皮细胞中的NFκB激活也减少。MAPK和NFκB激活的减少与IBD评分降低（2.7对15.5；P < 0.0001）以及盲肠组织中炎症细胞浸润减少和促炎细胞因子表达降低相关。这些发现表明，增加饮食中的维生素D通过在肿瘤形成起始或早期致癌过程中抑制炎症反应，对预防炎症相关的结肠癌有益。
