基于胆汁酸稳态调控的维生素D对结直肠癌的抑制作用及机制研究  

Inhibitory effect of vitamin D on colorectal cancer based on bile acid homeostasis regulation and its mechanism

作　　者：钟雅男 陈春霞 赵峰 郝志翔 徐吟雪 印晓星 周雪妍 ZHONG Ya-nan;CHEN Chun-xia;ZHAO Feng;HAO Zhi-xiang;XU Yin-xue;YIN Xiao-xing;ZHOU Xue-yan(Jiangsu Key Lab of New Drugs Research and Clinical Pharmacy,Xuzhou Medical University,Xuzhou Jiangsu 221004,China)

机构地区：[1]徐州医科大学药学院,江苏省新药研究与临床药学重点实验室,江苏徐州221004

出　　处：《中国药理学通报》2020年第3期379-385,共7页Chinese Pharmacological Bulletin

基　　金：江苏省高等学校自然科学研究重大项目(18KJA350002);江苏省自然科学基金面上项目(SBK2018021825);江苏省研究生科研创新计划项目(KYCX18_2199)。

摘　　要：目的考察维生素D(vitamin D,VD)是否可以通过调控胆汁酸内稳态,进而抑制AOM+DSS诱导的小鼠结直肠癌(colorectal cancer,CRC)的发生发展,并探讨其可能机制。方法将小鼠随机分为Control组、CRC组、CRC+VD组,采用AOM+DSS诱导建立CRC小鼠模型。HE染色检测组织病理情况;LC-MS/MS检测血清和结肠中各类型的胆汁酸含量;qPCR检测FXR、CYP7A1 mRNA的表达。结果CRC组小鼠结肠组织呈浸润性生长、病理性核分裂像可见;与CRC组相比,CRC+VD组小鼠结直肠长度增加,HE染色显示结肠各层结构相对清晰。CRC组小鼠血清中11种胆汁酸含量降低,而结肠组织中疏水性胆汁酸含量明显升高;而CRC+VD组T-LCA,LCA,T-CA,T-DCA,T-HDCA水平升高,结肠部位疏水性胆汁酸水平趋于正常。CRC组FXR、CYP7A1mRNA表达明显升高,而CRC+VD组CYP7A1 mR-NA表达较CRC组降低。结论CRC小鼠体内胆汁酸内稳态失衡,维生素D可调控CRC状态下循环及结肠部位胆汁酸稳态水平,调节疏水性胆汁酸比例,进而影响CRC的发生发展。Aim To investigate whether vitamin D(VD)levels could regulate homeostasis of bile acids and inhibit colorectal canceration and to explore the possible mechanism in colorectal cancer(CRC)mice.Methods The mice were stochastically divided into control group,CRC group,and CRC+VD group.CRC mouse model was induced by AOM+DSS.HE staining was used to determine colon histopathology of mice.LC-MS/MSwasemployed to detect different kinds of bile acids in serum and colon tissues of mice.qPCR was used to detect the mRNA expression levels of FXR,CYP7A1.Results Thecolon tissues of CRC mice showed invasive growth and pathological mitotic images.When compared to CRC group,the length of colon in CRC+VD group increased,and HE staining showed that the structures of each layer of colon were relatively clear.In CRC group,nearly 11 bile acids were significantly down-regulated,but hydrophobic bile acids were significantly up-regulated in colon,while the addition of vitamin D wassufficient to increase the levels of T-LCA,LCA,T-CA,T-DCA,T-HDCA and reverse the accumulation of hydrophobic bile acids compared to CRC group in colon tissues.The mRNA expressions of FXR and CYP7A1 of CRC group were significantly higher than those incontrol group,and the level of CYP7A1 in CRC+VD group decreased.Con-clusions The homeostasis of bile acids has been im-paired in CRC mice.Vitamin D could regulate the cir-culating and colonic bile acid homeostasis and change the proportion of hydrophobic bile acids,which in turn affects the development of colorectal cancer.

关 键 词：维生素D 结肠直肠癌 胆汁酸稳态 氧化偶氮甲烷 硫酸葡聚糖钠盐 液相层析串联质谱 

分 类 号：R-332[医药卫生] R322.45