飞燕草素通过Wnt/β-catenin信号通路抑制乳腺癌的机制研究
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摘要
为研究飞燕草素对乳腺癌MDA-MB-231细胞Wnt/β-catenin信号通路的影响。免疫组化检测裸鼠乳腺肿瘤组织和肺组织转移瘤Ki-67及乳腺肿瘤组织蛋白水解酶超家族基质金属蛋白酶-7(matrix metallopeptidase 7,MMP-7)的表达水平;Western blot检测移植瘤Wnt/β-catenin通路β-联蛋白(β-catenin)、磷酸糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)及通路下游细胞周期相关蛋白cyclinD1、原癌基因c-myc和MMP-7的蛋白水平表达,体内外实验发现飞燕草素不仅能抑制裸鼠异种移植瘤生长及乳腺癌肿瘤组织和肺组织转移瘤Ki-67表达还可以明显降低乳腺癌MDA-MB-231细胞Wnt/β-catenin信号通路β-catenin和p-GSK-3β下游靶基因c-myc、cyclin D1和MMP-7蛋白的表达。本研究证实飞燕草素能通过抑制Wnt/β-catenin信号通路,发挥抑制乳腺癌的作用。
In order to investigate the effect of delphinidin on Wnt/β-catenin signaling pathway in breast cancer cells MDA-MB-231.Ki-67 and MMP-7 expression was detected in breast tumors and lung tissues by immunohistochemistry.Expression of β-catenin,glycogen synthase kinase(GSK)-3β(GSK-3β),cyclinD1,c-myc and MMP-7 was tested by Western blot,Results showed that delphinidin inhibited the protein expression of GSK-3β,cyclinD1,c-myc and MMP-7.The in vivo finding revealed that administration of delphinidin significantly decreased the tumor volume and Ki-67 expression of tumour metastasis in MDA-MB-231 xenograft model by inhibiting tumour proliferation and Wnt/β-catenin Signaling Pathway.Taken together,our study demonstrated that delphinidin could against tumour in vitro and in vivo by inhibiting the proliferation and metastasis of tumour via Wnt/β-catenin signaling pathway.
In order to investigate the effect of delphinidin on Wnt/β-catenin signaling pathway in breast cancer cells MDA-MB-231.Ki-67 and MMP-7 expression was detected in breast tumors and lung tissues by immunohistochemistry.Expression of β-catenin,glycogen synthase kinase(GSK)-3β(GSK-3β),cyclinD1,c-myc and MMP-7 was tested by Western blot,Results showed that delphinidin inhibited the protein expression of GSK-3β,cyclinD1,c-myc and MMP-7.The in vivo finding revealed that administration of delphinidin significantly decreased the tumor volume and Ki-67 expression of tumour metastasis in MDA-MB-231 xenograft model by inhibiting tumour proliferation and Wnt/β-catenin Signaling Pathway.Taken together,our study demonstrated that delphinidin could against tumour in vitro and in vivo by inhibiting the proliferation and metastasis of tumour via Wnt/β-catenin signaling pathway.
引文
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4 Hui C,Bin Y,Xiaoping Y,et al.Anticancer activities of an anthocyanin-rich extract from black rice against breast cancer cells in vitro and in vivo[J].Nutr Cancer,2010,62:1128-1136.
5 Eghbaliferiz S,Iranshahi M.Prooxidant activity of polyphenols,flavonoids,anthocyanins and carotenoids:updated review of mechanisms and catalyzing metals[J].Phytother Res,2016,30:1379-1391.
6 Yang X,Luo E,Liu X,et al.Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway[J].BMC Cancer,2016,16:423.
7 Chen J,Zhu Y,Zhang W,et al.Delphinidin induced protective autophagy via mTOR pathway suppression and AMPK pathway activation in HER-2 positive breast cancer cells[J].BMC Cancer,2018,27:342.
8 Khalaf AM,Fuentes D,Morshid AI,et al.Role of Wnt/β-catenin signaling in hepatocellular carcinoma,pathogenesis,and clinical significance[J].J Hepato Cell Carcinoma,2018,5:61-73.
9 Kwon YJ,Ye DJ,Baek HS,et al.7,12-Dimethylbenz[α]anthracene increases cell proliferation and invasion through induction of Wnt/β-catenin signaling and EMT process[J].Environ Toxicol,2018,33:729-742.
10 Ayad E,Soliman A,Anis SE,et al.Ki-67 assessment in breast cancer in an egyptian population:a comparative study between manual assessment on optical microscopy and digital quantitative assessment[J].Diagn Pathol,2018,13:63.
11 Abdel-Salam IM,Ashmawy AM,Hilal AM,et al.Chemical composition of aqueous ethanolextract of luffa cylindrica leaves and Its effect on representation of caspase-8,caspase-3,and the proliferation marker Ki-67 in intrinsic molecular subtypes of breast cancer in vitro[J].Chem Biodivers,2018,15:e1800045.
12 Liang X,Wang S,Wang X,et al.Leptin promotes the growth of breast cancer by upregulating the Wnt/β-catenin pathway[J].Exp Ther Med,2018,16:767-771.
13 Bagheri M,Fazli M,Saeednia S,et al.Pomegranate peel extract inhibits expression of β-catenin,epithelial mesenchymal transition,and metastasis in triple negative breast cancer cells[J].Cell MolBiol(Noisy-le-grand),2018,64:86-91.
14 Zhang W,Cui Y,Gao J,et al.Recombinant osteopontin improves neurological functional recovery and protects against apoptosis via PI3K/Akt/GSK-3β pathway following intracerebral hemorrhage[J].Med Sci Monit,2018,24:1588-1596.
15 Wan XY,Yang Z,LI Y,et al.Research progress of Wnt signal pathway and malignant tumors[J].Chin Med Herald(中国医药导报),2016,13:71-73.
16 YuanH,Wei R,Xiao Y,et al.RHBDF1 regulates APC-mediated stimulation of the epithelial-to-mesenchymal transition and proliferation of colorectal cancer cells in part via the Wnt/β-catenin signalling pathway[J].Exp Cell Res,2018,368:24-36.
17 Bobustuc GC,Kassam AB,Rovin RA,et al.MGMT inhibition in ER positive breast cancer leads to CDC2,TOP2A,AURKB,CDC20,KIF20A,cyclin A2,cyclin B2,cyclin D1,ERα and Survivin inhibition and enhances response to temozolomide[J].Oncotarget,2018,9:29727-29742.
18 Azarnezhad A,Tabrizi M,Javan F,et al.Detection of CCND1,C-MYC and FGFR1 amplification using modified SYBR Green qPCR and FISH in breast cancer[J].Turk J Med Sci,2018,48:759-767.
19 Chou AK,Hsiao CL,Shih TC,et al.The contribution of Matrix Metalloproteinase-7 promoter genotypes in breast cancer in Taiwan[J].Anticancer Res,2017,37:4973-4977.