Dietary-induced ERβ upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice
Dietary-induced ERβ upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice
复制标题
DOI：
10.1093/carcin/bgp275
复制
发表时间：
2010-02-01
期刊：
影响因子：
4.7
通讯作者：
Di Leo, Alfredo
中科院分区：
文献类型：
--
作者：
Barone, Michele;Tanzi, Sabina;Di Leo, Alfredo
大多数散发性结直肠癌 (CRC) 通过腺瘤-癌序列途径发展，并由腺瘤性结肠息肉病 (APC) 基因突变引发。雌激素受体β（ERβ）被认为会逐渐减少其在人类腺瘤和癌组织中的表达。此外，ERβ缺乏会增强啮齿类动物小肠肿瘤的发生。在 Apc(Min/+) 小鼠模型中，我们在高脂肪/低纤维饮食中添加 ER β 选择性激动剂水飞蓟素 (SIL) 和/或木质素 (LIG) 组合后，评估了肠息肉的发育和 ER β 表达以及影响肿瘤生长的其他生物学参数（上皮细胞增殖、凋亡和迁移）。将 45 只 Apc(Min/+) 小鼠分为四组：以致瘤高脂肪/低纤维饮食喂养的动物、添加 SIL (0.02%) 或纯化 LIG (6.24%) 或 SIL (0.005%) + LIG (6.24%) 的致瘤饮食动物。在这些动物中，我们评估了息肉的数量和体积及其不典型增生的程度，以及 ER β 信使 RNA (mRNA) 和蛋白质水平以及上皮细胞增殖、迁移和凋亡。在正常和腺瘤粘膜中评估后一组参数，并将结果与以对照饮食喂养的野生型（WT）小鼠中发现的结果进行比较。在饮食中添加 SIL 或 LIG，以及两者的特定组合，可以显着抑制肠道肿瘤的发生，并增加 ER β mRNA 和蛋白质水平。细胞增殖和凋亡重新平衡，细胞迁移加速，恢复了与 WT 动物中观察到的相似值。我们的结果进一步支持 ER beta 对 CRC 的保护作用，表明使用 SIL-LIG 组合作为对抗 CRC 发展的潜在方法。
Most sporadic colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence pathway and are initiated by adenomatous polyposis coli (APC) gene mutations. Estrogen receptor beta (ER beta) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ER beta deficiency enhances small intestinal tumorigenesis in rodents. In the Apc(Min/+) mouse model, we evaluated intestinal polyp development and ER beta expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ER beta-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five Apc(Min/+) mice were divided in four groups: animals fed on the tumorigenic high-fat/low-fiber diet, the tumorigenic diet supplemented with SIL (0.02%) or purified LIG (6.24%) or SIL (0.005%) + LIG (6.24%). In these animals, we assessed polyp number and volume and their degree of dysplasia together with ER beta messenger RNA (mRNA) and protein levels and epithelial cell proliferation, migration and apoptosis. The latter group of parameters was evaluated in normal and adenomatous mucosa and the results compared with those found in wild-type (WT) mice fed on the control diet. The addition of SIL or LIG to the diet and even more the specific combination of the two significantly counteracted intestinal tumorigenesis and increased ER beta mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in WT animals. Our results further support a protective effect of ER beta in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.