Preventive effects of fermented brown rice and rice bran against N-nitrosobis (2-oxopropyl) amine-induced pancreatic tumorigenesis in male hamsters.
Preventive effects of fermented brown rice and rice bran against N-nitrosobis (2-oxopropyl) amine-induced pancreatic tumorigenesis in male hamsters.
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DOI：
10.3892/ol.2015.3809
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发表时间：
2015-12
期刊：
影响因子：
2.9
通讯作者：
Mori H
中科院分区：
文献类型：
--
作者：
Kuno T;Takahashi S;Tomita H;Hisamatsu K;Hara A;Hirata A;Kobayashi H;Mori H
已知米曲霉（FBRA）发酵糙米具有预防啮齿类动物结肠、肝脏、食道、膀胱、胃和肺部化学致癌的潜力。本研究探讨了 FBRA 对 N-亚硝基双（2-氧代丙基）胺 (BOP) 诱导的仓鼠胰腺肿瘤发生可能具有的化学预防作用。五周大的雄性叙利亚金仓鼠被分为七组。第1-5组在第6周皮下注射BOP（10毫克/千克体重）四次以诱导胰腺肿瘤，而第6组和第7组注射生理盐水。在起始阶段，第 2 组和第 3 组分别饲喂含有 5% 和 10% FBRA 的饮食。相比之下，第 4 组和第 5 组在启动后阶段分别饲喂含有 5% 和 10% FBRA 的饮食。第 6 组在整个实验过程中接受含有 10% FBRA 的饮食，第 7 组仅保持基础饮食并作为未处理的对照。在研究结束时（第 22 周），在启动后阶段口服 10% FBRA（第 5 组）被确定可显着降低导管腺癌 [胰腺上皮内瘤变 3 (PanIN3)；原位癌和浸润性癌]与第1组对照仓鼠相比（0.24±0.44 vs. 0.71±0.72；P<0.05）。在起始后阶段用 10% FBRA 治疗可抑制正常/癌前病变（PanIN1，轻度增生性病变；和 PanIN2，乳头状增生）向导管腺癌的进展。此外，在起始阶段（第3组）和起始后阶段（第5组）饮食中暴露于10% FBRA显着降低了PanIN2的多重性（第3组，0.55±0.69；第5组，0.45±0.69；与第1组，1.26±1.24；分别为P<0.05和P<0.01）。还证实第5组中PanIN2的Ki-67阳性率显着降低（第5组，0.05±0.03；第1组，0.22±0.12；P<0.01）。使用末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记，在非病变导管上皮和增殖性病变中，FBRA 暴露对细胞凋亡的增强并不明显。这些发现表明，由于肿瘤细胞增殖率降低，FBRA 对 BOP 诱导的仓鼠胰腺肿瘤发生具有抑制作用。因此，FBRA 可能是人类胰腺癌的一种有前途的化学预防剂。
Fermented brown rice by Aspergillus oryzae (FBRA) is known to have the potential to prevent chemical carcinogenesis of the colon, liver, esophagus, urinary bladder, stomach and lungs in rodents. The present study examined the possible chemopreventive effects of FBRA on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic tumorigenesis in hamsters. Five-week-old male Syrian golden hamsters were divided into seven groups. Groups 1–5 were subcutaneously injected with BOP (10 mg/kg body weight) four times during week 6 to induce pancreatic tumors, while groups 6 and 7 were injected with saline. Groups 2 and 3 were fed diets containing 5 and 10% FBRA, respectively, during the initiation phase. By contrast, groups 4 and 5 were fed diets containing 5 and 10% FBRA, respectively, during the post-initiation phase. Group 6 received a diet containing 10% FBRA throughout the experiment, and group 7 was kept on the basal diet alone and served as the untreated control. At the termination of the study (week 22), oral intake of 10% FBRA (group 5) during the post-initiation phase was identified to have significantly reduced the multiplicity (number of lesions/animal) of ductal adenocarcinoma [pancreatic intraepithelial neoplasia 3 (PanIN3); carcinoma in situ and invasive carcinoma] in comparison with group 1 control hamsters (0.24±0.44 vs. 0.71±0.72; P<0.05). Treatment with 10% FBRA in the post-initiation phase inhibited the progression of normal/precancerous lesions (PanIN1, mild hyperplastic lesions; and PanIN2, papillary hyperplasia) to ductal adenocarcinomas. Furthermore, dietary exposure to 10% FBRA during the initiation (group 3) and post-initiation phases (group 5) significantly reduced the multiplicity of PanIN2 (group 3, 0.55±0.69; group 5, 0.45±0.69; versus group 1, 1.26±1.24; P<0.05 and P<0.01, respectively). A significant reduction of Ki-67 positivity of PanIN2 in group 5 was also confirmed (group 5, 0.05±0.03; group 1, 0.22±0.12; P<0.01). Using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, augmentation of apoptosis by FBRA exposure in the non-lesional ductal epithelium and proliferative lesions was not evident. These findings indicate that FBRA exhibits inhibitory effects on BOP-induced pancreatic tumorigenesis in hamsters due to the reduced proliferation rate of tumor cells. Thus, FBRA may be a promising chemopreventive agent in human pancreatic cancer.