College of Food Science, Northeast Agricultural University, Harbin, Heilongjiang 150030, P.R. China.
Int J Mol Med. 2018 Apr;41(4):1887-1898. doi: 10.3892/ijmm.2018.3423. Epub 2018 Jan 25.
Resistant starch is as common soluble fiber that escapes digestion in the small intestine and can regulate intestinal function, metabolism of blood glucose and lipids, and may prevent tumorigenesis of gastrointestinal cancer. Epidemiology and other evidence have suggested that resistant starch may prevent colon cancer development. The aim of the current study was to explore the ameliorative effects and potential mechanisms of resistant starch in the tumorigenesis of colon tumors induced by dimethylhydrazine in C57BL/6 mice. Western blot analysis, ELISA, microscopy, immunofluorescence and immunohistochemistry were used to analyze the efficacy of resistant starch on the metabolic balance in the colon and tumorigenesis of colon tumors. The results demonstrated that a diet containing resistant starch decreased the animal body weight and reduced free ammonia, pH and short chain fatty acids in feces compared with mice that received a standard diet. Resistant starch reduced the incidence of colon tumors and suppressed the expression of carcinogenesis‑associated proteins, including heat shock protein 25, protein kinase C‑d and gastrointestinal glutathione peroxidase in colon epithelial cells compared with standard starch and control groups. Colon tumor cells proliferation and dedifferentiation were significantly decreased by a resistant starch diet. The results also demonstrated that resistant starch increased the apoptosis of colon tumor cells through regulation of apoptosis‑associated gene expression levels in colon tumor cells. Oxidative stress and endoplasmic reticulum stress were upregulated, and elevation eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor‑4 and secretase‑β expression levels were increased in the resistant starch diet group. Additionally, the activity of eIF2α and PERK were increased in colon tumor cells from mice that had received resistant starch. Increasing DNA damage‑inducible transcript 3 protein (CHOP), binding immunoglobulin protein (BIP) and caspase‑12 expression levels upregulated by resistant starch diet may contribute to the resistant starch‑induced apoptosis of colon tumor cells induced by 1,2‑dimethylhydrazine. In vitro assays demonstrated that knockdown of eIF2α inhibited apoptosis of colon tumor cells isolated from mice fed with resistant starch, which also downregulated CHOP, BIP and caspase‑3 expression levels compared with controls. Furthermore, long‑term survival of experimental mice was prolonged by the resistant starch diet compared with the standard diet group. In conclusion, the results indicate that resistant starch in the diet may prevent carcinogenesis of colon epithelial cells, mediated by enhancing apoptosis through an endoplasmic reticulum stress‑mediated mitochondrial apoptosis pathway.
抗性淀粉是一种常见的可溶性纤维，它可以在小肠中逃避消化，并调节肠道功能、血糖和血脂代谢，并且可能预防胃肠道癌症的发生。流行病学和其他证据表明，抗性淀粉可能预防结肠癌的发展。本研究旨在探讨抗性淀粉在二甲基肼诱导的 C57BL/6 小鼠结肠癌发生中的改善作用及其潜在机制。采用 Western blot 分析、ELISA、显微镜、免疫荧光和免疫组化分析抗性淀粉对结肠代谢平衡和结肠癌发生的疗效。结果表明，与接受标准饮食的小鼠相比，含抗性淀粉的饮食降低了动物体重，并降低了粪便中的游离氨、pH 值和短链脂肪酸。抗性淀粉降低了结肠癌的发生率，并抑制了结肠癌上皮细胞中与癌变相关的蛋白表达，包括热休克蛋白 25、蛋白激酶 C-d 和胃肠道谷胱甘肽过氧化物酶，与标准淀粉和对照组相比。抗性淀粉饮食显著降低了结肠肿瘤细胞的增殖和去分化。结果还表明，抗性淀粉通过调节结肠肿瘤细胞中凋亡相关基因的表达水平，增加了结肠肿瘤细胞的凋亡。氧化应激和内质网应激增加，eIF2α（真核翻译起始因子 2α）、激活转录因子-4 和β-分泌酶的表达水平上调，在抗性淀粉饮食组中。此外，接受抗性淀粉的小鼠的结肠肿瘤细胞中，eIF2α 和 PERK 的活性增加。抗性淀粉饮食上调的 DNA 损伤诱导转录物 3 蛋白（CHOP）、结合免疫球蛋白蛋白（BIP）和半胱天冬酶-12 表达水平可能有助于抗性淀粉诱导 1,2-二甲基肼诱导的结肠肿瘤细胞凋亡。体外实验表明，敲低 eIF2α 抑制了从喂食抗性淀粉的小鼠分离的结肠肿瘤细胞的凋亡，与对照组相比，CHOP、BIP 和 caspase-3 的表达水平也下调。此外，与标准饮食组相比，抗性淀粉饮食延长了实验小鼠的长期生存时间。综上所述，结果表明，饮食中的抗性淀粉可能通过增强内质网应激介导的线粒体凋亡途径的凋亡来预防结肠上皮细胞的癌变。
