图1 各组小鼠体质量折线图
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To investigate the efficiency and underlying mechanism of baicalin in the treatment of colorectal cancer liver metastasis(CRLM) so as to provide a scientific foundation for the prevention and treatment of CRLM with traditional Chinese medicine.
Twenty-four C57BL/6J male mice aged 6 weeks were randomly divided into 4 groups: the normal diet group, the high-fat diet group, the low-dose baicalin group (50 mg/kg, fed with a high-fat diet) and the high-dose baicalin group (200 mg/kg, fed with a high-fat diet) with 6 mice in each group. The liver metastasis of colorectal cancer model was established after the mice were fed with the normal or high-fat diet for 4 weeks. Subsequent to the surgery, the mice were orally gavaged with baicalin or PBS daily for 4 weeks. The body weights of the mice in each group were recorded during the experiment. At the end of the experiment, blood samples were collected for detecting the levels of total cholesterol (TC), total triglyceride(TG), low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol (HDL-C). The mass of inguinal white adipose tissue (iWAT), epididymal white adipose tissue (eWAT) and dorsal brown adipose tissue (BAT) was weighed. Primary tumor weight, liver weight and the number of liver metastasis foci were recorded, and the liver index (the ratio of liver weight to body weight) and liver metastasis rate were calculated. HE staining was used to observe the morphological changes of the livers. The 16S rRNA gene sequence was used to analyze the structure and composition of the gut microbiota. The mRNA expression levels of epithelial mesenchymal transition (EMT) related genes including Vimentin、N-cadherin、E-cadherin, and Occludin were detected by RT-qPCR. The relationship between EMT related gene expression levels and Firmicutes microbiota abundance was determined using Pearson correlation analysis.
The body weight, serum levels of TC and LDL-C, fat weight, primary tumor weight, liver weight, liver index, the number of liver metastases and liver metastases rate in the high-fat diet group were significantly higher than those of mice in the normal diet group. The data of the low-dose and high-dose baicalin groups were lower than those of the high-fat diet group. All of the above differences were statistically significant (P<0.05). Firmicutes abundance and the ratio of Firmicutes/Bacteroidetes (F/B) were increased (P<0.05) in the high-fat diet group, and the F/B ratio decreased (P<0.05) after baicalin treatment. Compared with the normal diet group, the mRNA expression levels of Vimentin and N⁃cadherin in liver metastases in the high-fat diet group were significantly increased (P<0.05), while the mRNA expression levels of E⁃cadherin and Occludin were significantly decreased (P<0.05); compared with the high-fat diet group, after intervention with baicalin, the mRNA expression levels of Vimentin and N⁃cadherin were significantly decreased (P<0.05), while the mRNA expression levels of E‑cadherin and Occludin were significantly increased (P<0.05). The relative abundances of several Firmicutes bacteria were positively correlated with the expression levels of Vimentin and N⁃cadherin mRNA, but negatively correlated with the expression levels of E⁃cadherin and Occludin mRNA levels.
Baicalin effectively inhibits high-fat diet-induced colorectal cancer liver metastasis, which is associated with the restoration of gut microbiota structure and the reversal of EMT.
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结直肠癌(colorectal cancer,CRC)在恶性肿瘤中发病率高居第3位,并呈上升趋势,是癌症相关死亡的主要原因之一[
黄芩苷是黄芩中具有生物活性的黄酮类化合物。现代研究[
1.1.1 动物
6周龄C57BL/6J小鼠25只,SPF级,雄性,体质量18~22 g,购自上海吉辉实验动物饲养有限公司。动物生产许可证号:SCXK(沪)2017-0012。动物使用许可证号:XYXK(沪)2020-0009。实验小鼠饲养于上海中医药大学实验动物中心,饲养室温度为20~24 ℃,湿度为50%~70%,维持 12 h光照/12 h黑暗的昼夜节律,自由获取食物和水。本实验经上海中医药大学实验动物伦理委员会批准(伦理批准号:PZSHUTCM 201030020)。
1.1.2 细胞
小鼠结肠癌细胞株MC38,购于宁波明舟生物科技有限公司。
1.1.3 主要药物与试剂
黄芩苷,上海阿拉丁生化科技股份有限公司(批号:B110211);杜氏改良Eagle(DMEM)培养基,源培生物科技股份有限公司(批号:L110KJ);胎牛血清,美国Gibico公司(批号:10099-141);苏木精-伊红(HE)染色试剂盒,索莱宝科技有限公司(批号:G1120);总胆固醇(TC)测试盒、三酰甘油(TG)测试盒、低密度脂蛋白胆固醇(LDL-C)测试盒、高密度脂蛋白胆固醇(HDL-C)测试盒,南京建成生物工程研究所有限公司(批号:A111-1-1、A110-1-1、A113-1-1、A112-1-1);粪便DNA基因组提取试剂盒(QIAamp DNA Stool Mini Kit),德国Qiagen公司(批号:51504);TRIzol,碧云天生物技术有限公司(批号:R0016);预混液形式的两步法实时荧光定量逆转录聚合酶链式反应(RT-qPCR)试剂(去基因组)[HiScriptⅡQRT SuperMix for qPCR(+gDNA wiper)],诺唯赞生物科技有限公司(批号:R223-01);高灵敏性染料法定量PCR检测试剂盒[ChamQTM SYBR qPCR Master Mix(High ROX Premixed)],诺唯赞生物科技有限公司(批号:Q341-02);甘油醛-3-磷酸脱氢酶(GAPDH)、波形蛋白(Vimentin)、N-钙黏蛋白(N-cadherin)、E-钙黏蛋白(E-cadherin)和闭合蛋白(Occludin)基因的扩增引物由上海生工生物工程技术服务公司合成(批号:1528649218)。
高脂饲料配比:蛋白质20%,糖类20%,脂肪60%;由帆泊生物技术有限公司提供(批号:FB-D12492)。
普通饲料配比:蛋白质20%,糖类70%,脂肪10%;由上海中医药大学实验动物中心提供。
1.1.4 主要仪器
电子分析天平,美国Ohaus公司(型号:PR423ZH/E);CO2恒温培养箱,美国Thermo Fisher Scientific公司(型号:BB150);多功能酶标仪,瑞士Tecan公司(型号:Spark®);全自动密封式组织脱水机,美国Thermo Fisher Scientific公司(型号:Shandon Excelsior);组织包埋机,美国Thermo Fisher Scientific公司(型号:Shandon Histostar);病理切片扫描仪,德国Precipoint公司(型号:M8);实时荧光定量PCR仪,美国Thermo Fisher Scientific公司(型号:AB StepOne);台式高速低温离心机,德国Eppendorf公司(型号:5810R)。
本实验共使用25只C57BL/6J小鼠,其中1只作为供瘤鼠,使用正常饮食饲喂。其余24只小鼠随机分为4组,每组6只,分别为正常饮食组、高脂饮食组、黄芩苷低剂量组和黄芩苷高剂量组。24只小鼠接受正常饮食或高脂饮食喂养4周后,参照文献[
正常饮食组:正常饮食饲喂4周后构建结直肠癌肝转移模型,术后第3天起灌胃100 μL磷酸盐缓冲液(PBS),1次/d,共4周。
高脂饮食组:高脂饮食饲喂4周后构建结直肠癌肝转移模型,术后第3天起灌胃100 μL PBS,1次/d,共4周。
黄芩苷低剂量组:高脂饮食饲喂4周后构建结直肠癌肝转移模型,术后第3天起灌胃100 μL低剂量黄芩苷(50 mg/kg),1次/d,共4周。
黄芩苷高剂量组:高脂饮食饲喂4周后构建结直肠癌肝转移模型,术后第3天起灌胃100 μL高剂量黄芩苷(200 mg/kg),1次/d,共4周。
1.4.1 体质量
每周记录小鼠体质量直至实验结束,比较各组小鼠体质量变化情况。
1.4.2 血清TC、TG、LDL-C及HDL-C水平
实验结束后,收集小鼠血清,根据试剂盒说明书检测小鼠血清中的TC、TG、LDL-C和HDL-C水平。
1.4.3 脂肪质量
实验结束后,称量小鼠腹股沟白色脂肪组织(iWAT)、附睾白色脂肪组织(eWAT)和背部棕色脂肪组织(BAT)的质量。
1.4.4 原位肿瘤质量、肝脏质量及肝转移灶数量
实验结束后,观察各组小鼠盲肠及肝脏成瘤情况,分离盲肠肿瘤及肝脏,记录原位肿瘤质量、肝脏质量、肝转移灶数量,计算肝脏指数(肝质量/体质量)和肝转移率。
1.4.5 肝脏组织形态观察
实验结束后,将小鼠肝脏用4%多聚甲醛固定48 h,采用乙醇和二甲苯进行脱水、透明,然后采用石蜡包埋,将包埋好的组织块切割成5 µm厚度的切片,根据HE染色试剂盒说明书对肝组织切片进行染色,采用病理切片扫描仪观察肝脏组织形态。
1.4.6 肠道菌群检测
提前备好高压灭菌的1.5 mL离心管和手术镊,待取材前一天收集小鼠粪便,避免粪便接触尿液或掉落至地面,保存于-80 ℃冰箱。按照QIAamp DNA Stool Mini Kit试剂盒说明书提取粪便微生物DNA;采用琼脂糖凝胶电泳和NanoDrop® ND-2000分光光度计检测DNA的纯度和浓度;利用PCR扩增合格的DNA样本16S rRNA中V3-V4可变区,引物为338F(5'-ACTCCTACGGGAGGCAGAG-3')和806R(5'-GGAC TACHVGGGTWTCTAAT-3');对扩增子进行纯化、量化、标准化,然后构建合格的Miseq文库,后续用Illumina Miseq PE300平台进行测序;16S rRNA扩增建库及测序工作由上海美吉生物医药科技有限公司协助完成。
1.4.7 肝转移灶中上皮间质转化(EMT)基因的表达
取30 mg小鼠肝转移灶并置于1.5 mL离心管中,加入1 mL预冷的TRIzol试剂充分匀浆,然后按照TRIzol∶氯仿为5∶1的比例加入氯仿提取总RNA,应用HiScript Ⅱ Q RT SuperMix for qPCR(+gDNA wiper)试剂盒制备cDNA。以GAPDH为内参进行荧光定量PCR扩增,以检测各组小鼠肝转移灶中Vimentin、N⁃cadherin、E‑cadherin和Occludin mRNA的表达水平。引物由生工生物工程(上海)股份有限公司合成,引物序列见
基因名称 | 引物序列 | 引物长度/bp |
---|---|---|
GAPDH | 上游:5'-CGACTTCAACAGCAACTCCCACTCTTCC-3' | 28 |
下游:5'-TGGGTGGTCCAGGGTTTCTTACTCCTT-3' | 27 | |
E⁃cadherin | 上游:5'-TCGACACCCGATTCAAAGTGG-3' | 21 |
下游:5'-TTCCAGAAACGGAGGCCTGAT-3' | 21 | |
N⁃cadherin | 上游:5'-CCCAAGTCCAACATTTCCATCC-3' | 22 |
下游:5'-AAAGCCTCCAGCAAGCACG-3' | 19 | |
Vimentin | 上游:5'-CCAACCTTTTCTTCCCTGAA-3' | 20 |
下游:5'-TTGAGTGGGTGTCAACCAGA-3' | 20 | |
Occludin | 上游:5'-CCTCCAATGGCAAAGTGAAT-3' | 20 |
下游:5'-CTCCCCACCTGTCGTGTAGT-3' | 20 |
注: GAPDH为甘油醛⁃3⁃磷酸脱氢酶基因,E⁃cadherin为E⁃钙黏蛋白基因,N⁃cadherin为N⁃钙黏蛋白基因,Vimentin为波形蛋白基因,Occludin为闭合蛋白基因。
采用GraphPad 9.4软件进行数据分析。计量资料以ˉx±s表示。两组间比较采用t检验,多组间比较采用one-way ANOVA分析,菌群多组间比较采用Kruskal-Wallis秩和检验;采用皮尔森(Pearson)相关性分析衡量肝转移灶中EMT相关基因表达与厚壁菌门细菌丰度的相关性。以P<0.05为差异有统计学意义。
第8周实验结束时,与正常饮食组比较,高脂饮食组小鼠体质量显著增加,差异有统计学意义(P<0.05)。与高脂饮食组比较,黄芩苷高、低剂量组小鼠体质量均呈下降趋势,其中黄芩苷高剂量组差异有统计学意义(P<0.05),黄芩苷低剂量组差异无统计学意义(P>0.05)。见
图1 各组小鼠体质量折线图
注: 与正常饮食组比较,*P<0.05;与高脂饮食组比较,#P<0.05;n=6,ˉx±s。
与正常饮食组比较,高脂饮食组小鼠TC和LDL-C水平显著升高(P<0.05);TG和HDL-C呈上升趋势,但差异无统计学意义(P>0.05)。与高脂饮食组比较,黄芩苷高、低剂量组小鼠TC和LDL-C水平显著降低(P<0.05),其中黄芩苷高剂量组的干预效果更佳;黄芩苷各剂量组小鼠TG水平呈下降趋势,但差异无统计学意义(P>0.05);黄芩苷低剂量组小鼠HDL-C水平呈上升趋势,但差异无统计学意义(P>0.05)。见
图2 各组小鼠血清TC、TG、LDL-C和HDL-C水平比较
注: TC为总胆固醇,TG为三酰甘油,LDL-C为低密度脂蛋白胆固醇,HDL-C为高密度脂蛋白胆固醇。与正常饮食组比较,*P<0.05;与高脂饮食组比较,#P<0.05;n=6,ˉx±s。
与正常饮食组比较,高脂饮食组小鼠iWAT、eWAT和BAT质量均明显增加(P<0.05)。与高脂饮食组比较,黄芩苷高、低剂量组小鼠iWAT和eWAT质量均显著下降(P<0.05),且黄芩苷高剂量组iWAT质量较黄芩苷低剂量组明显降低(P<0.05);黄芩苷高剂量组小鼠BAT质量明显降低(P<0.05);黄芩苷低剂量组小鼠BAT质量呈下降趋势,但差异无统计学意义(P>0.05)。见
图3 各组小鼠iWAT、eWAT和BAT质量比较
注: iWAT为腹股沟白色脂肪组织,eWAT为附睾白色脂肪组织,BAT为背部棕色脂肪组织。与正常饮食组比较,*P<0.05;与高脂饮食组比较,#P<0.05;与黄芩苷低剂量组比较,△P<0.05;n=6,ˉx±s。
与正常饮食组比较,高脂饮食组小鼠原位肿瘤质量、肝脏质量、肝质量/体质量、肝转移灶数量及总转移率均明显增加(P<0.05)。与高脂饮食组比较,黄芩苷各剂量组小鼠原位肿瘤质量、肝脏质量、肝质量/体质量、肝转移灶数量及总转移率均呈下降趋势,其中黄芩苷高剂量组的干预效果最佳(P<0.05)。见
图4 各组小鼠原位肿瘤质量、肝脏质量、肝质量/体质量、肝转移灶数量及总转移率比较
注: 与正常饮食组比较,*P<0.05;与高脂饮食组比较,#P<0.05;n=6,ˉx±s。
HE染色可见各组小鼠肝脏均有明显的肿瘤细胞浸润,表现为细胞排列无序、核大且着色较深。与正常饮食组比较,高脂饮食组小鼠肝脏表面转移灶较多,呈团块状;与高脂饮食组比较,黄芩苷高、低剂量组小鼠肝脏转移灶数量减少且体积较小,其中黄芩苷高剂量组小鼠肝脏转移瘤体积大幅缩小,呈局限性生长。见
图5 各组小鼠结直肠癌肝转移灶组织形态(HE染色,×200)
利用16S rRNA测序分析正常饮食组、高脂饮食组和黄芩苷组(选取黄芩苷最有效剂量组即黄芩苷高剂量组进行分析)小鼠肠道菌群的变化,各组小鼠香农(Shannon)指数无明显变化(P>0.05),表明3组小鼠肠道物种多样性无差异。
在门水平上,与正常饮食组比较,高脂饮食组小鼠厚壁菌门(Firmicutes)相对丰度增加(P<0.05),拟杆菌门(Bacteroidetes)相对丰度下降(P<0.05),厚壁菌门/拟杆菌门比值(F/B比值)升高(P<0.05);经高剂量黄芩苷干预后,小鼠厚壁菌门相对丰度降低(P<0.05),F/B比值降低(P<0.05)。
在属水平上,组间差异显著性检验分析显示,丰度均值总和在前15的物种包括:鼠杆菌科未定义菌属(norank_f_muribaculaceae),异杆菌属(Allobaculum),回肠杆菌属(Ileibacterium),布劳特氏菌属(Blautia),毛螺菌科未定义菌属(unclassified_f_Lachnospiraceae),苏黎世杆菌属(Turicibacter),颤杆菌属(Oscillibacter),肠杆菌属(Enterorhabdus),链球菌属(Streptococcus),梭菌属(Tuzzerella),候选单胞生糖菌属(Candidatus_Saccharimonas),拟普雷沃菌属(Alloprevotella),阴性杆菌属(Negativibacillu),消化球菌属(Peptococcus)等。与正常饮食组相比,高脂饮食组和黄芩苷组小鼠肠道内异杆菌属、回肠杆菌属、链球菌属和拟普雷沃菌属相对丰度呈下降趋势;高脂饮食组小鼠布劳特氏菌属、颤杆菌属、梭菌属、阴性杆菌属和消化球菌属的相对丰度呈上升趋势,而黄芩苷可有效下调以上细菌的丰度;高脂饮食组小鼠牧斯皮氏菌属、苏黎世杆菌属和肠杆菌属的相对丰度下降,而黄芩苷可显著增加这些细菌的丰度。见
图6 各组小鼠肠道菌群组成比较
注: A为香农(Shannon)指数,B为门水平的物种分类,C为厚壁菌门/拟杆菌门(F/B)比值比较,D为属水平的物种差异分析。Deferribacterota为脱铁杆菌门,Cyanobacteria为蓝细菌门,Patescibacteria为髌骨细菌门,Desulfobacteria为脱硫菌门,Verrucomicrobia为疣微菌门,Proteobacteria为变形菌门,Actinobacteriota为放线菌门,Bacteroidetes为拟杆菌门,Firmicutes为厚壁菌门,norank_ f_muribaculaceae为鼠杆菌科未定义菌属,Allobaculum为异杆菌属,Ileibacterium为回肠杆菌属,Blautia为布劳特氏菌属,unclassified_ f_Lachnospiraceae为毛螺菌科未定义菌属,Turicibacter为苏黎世杆菌属,Oscillibacter为颤杆菌属,Enterorhabdus为肠杆菌属,Streptococcus为链球菌属,Tuzzerella为梭菌属,Candidatus_Saccharimonas为候选单胞生糖菌属,Alloprevotella为拟普雷沃菌属,Negativibacillu为阴性杆菌属,Peptococcus为消化球菌属。与正常饮食组比较,*P<0.05;与高脂饮食组比较,#P<0.05;n=3,ˉx±s。
与正常饮食组比较,高脂饮食组小鼠肝转移灶Vimentin和N‑cadherin mRNA表达水平明显升高(P<0.05),E‑cadherin和Occludin mRNA表达水平明显降低(P<0.05)。与高脂饮食组比较,黄芩苷组(即黄芩苷高剂量组)小鼠肝转移灶Vimentin和N‑cadherin mRNA表达水平明显降低(P<0.05),E‑cadherin和Occludin mRNA表达水平明显升高(P<0.05)。见
图7 各组小鼠肝转移灶中Vimentin、N⁃cadherin、E⁃cadherin和Occludin的mRNA表达比较
注: Vimentin为波形蛋白基因,N-cadherin为N-钙黏蛋白基因,E-cadherin为E-钙黏蛋白基因,Occludin为闭合蛋白基因。与正常饮食组比较,*P<0.05;与高脂饮食组比较,#P<0.05;n=6,ˉx±s。
已有研究[
图8 肝转移灶中EMT相关mRNA表达与厚壁菌门细菌丰度相关性分析
注: Vimentin为波形蛋白基因,N⁃cadherin为N-钙黏蛋白基因,E⁃cadherin为E-钙黏蛋白基因,Occludin为闭合蛋白基因,Anaerovorax为厌氧菌属,Anaerotruncus为厌氧棍状菌属,Blautia为布劳特氏菌属,unclassified_ f_Lachnospiraceae为毛螺菌科未定义菌属,Dubosiella为杜氏杆菌属,Oscillibacter为颤杆菌属,Erysipelatoclostridium为丹毒杆菌属,unclassified_ f_Christensenellaceae为克里斯滕森菌科未定义菌属,Tuzzerella为梭菌属,UCG⁃009为疣微菌属,Negativibacillu为阴性杆菌属,Peptococcus为消化球菌属,unclassified_ f_Ruminococcaceae、norank_ f_Ruminococcaceae均为瘤胃菌科未定义菌属,Roseburia为罗氏菌属。两变量存在相关关系,*P<0.05。
有研究[
近年来,中药及其有效成分因多靶点、多途径、高疗效和低毒副作用等优点,被广泛用于肿瘤的治疗。黄芩苷是中药黄芩的主要黄酮类化合物成分,可通过诱导凋亡、抑制侵袭和迁移、阻滞细胞周期及诱导自噬等途径发挥抗肿瘤作用[
研究[
EMT是肿瘤转移过程中的重要环节,肠道致病菌可通过直接与靶细胞接触或产生毒性代谢产物,激活信号转导及转录激活蛋白3(STAT3)、Wnt/β-连环蛋白(Wnt/β-catenin)和核因子-κB(NF-κB)等信号通路,进而诱导EMT[
本研究还存在一定的局限性,即仅考虑了黄芩苷在高脂饮食状态下能抑制CRLM的发生发展,而黄芩苷在正常饮食条件下对CRLM是否同样具有保护作用尚有待进一步明确。
综上所述,本研究初步探讨了黄芩苷抗肿瘤转移的作用及潜在机制,证实了黄芩苷可明显抑制高脂饮食诱发的CRLM及转移灶EMT水平,同时对肠道菌群具有明显的调节作用,尤其可降低厚壁菌门丰度,抑制F/B比值,进而有利于重塑肠道菌群结构。
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