TGFβ1对三阴性乳腺癌间质样干细胞表型及肝转移的作用研究

目的探讨转化生长因子β1（TGFβ1）对三阴性乳腺癌间质样干细胞表型的作用及其机制。方法TGFβ1处理乳腺癌细胞系SUMl59、MDA及SCP2，光镜下观察细胞形态；RT-PCR检测KRT8、KRT18、KRT14及a-MSA表达；Western blot检测NANOG、cvclinD1、CDK4及RB的表达；建立原位乳腺癌肝转移模型，肉眼及HE染色检测肝脏转移灶，免疫组化法检测cyclinDl蛋白表达。结果TGFβ1组细胞呈现长梭样改变。TGFβ1组细胞KRT8及KRT18表达下降，KRT14及ACTA2表达上调。TGFp1组NANOG表达上调。TGFβ1组cyclinD1、CDK4及RB表达上调。TGFβ1提高KRT14及ACTA2表达，而降低KRT8及KRT18表达的作用可以被CDK4激酶抑制剂阻断。结论TGFβ1通过上调cyclinD1／CDK4通路促进三阴性乳腺癌间质样干细胞表型发生进一步改变。同时，TGFβ1诱导的三阴性乳腺癌间质样干细胞表型的改变促进了裸鼠乳腺癌肝脏转移。

Objective To investigate the effect and mechanism of TGF β1 on the phenotype of mesenchymal stern cells in three negative breast cancer. Methods The expressions of KRTS, KRT18, KRT14 and a-MSA were detected by RT-PCR. The expressions of NANOG, cyclinDl, CDK4 and RB were detected by Western-blot. Breast cancer liver metastasis model was established in nude mice and liver metastases in control group and TGF β1 group were accessed by HE staining. The expression ofcyclinD1 protein was detected by immunohistochemistry. Results TGF β1 treated cells showed a long shuttle-like changes. The expressions of KRT8 and KRT18 were decreased in TGF β1 group and the expressions of KRT14 and ACTA2 were up-regulated. The NANOG expression was upregulated by TGF β1 stimulation. Fnrthermore, the expressions of cyclinD1, CDK4 and RB in TGF β1 group were upregulated. TGF β1 function was blocked by CDK4 kinase inhibitors. In vivo study, TGF β1-induced mesenchymal stem cell phenoWpe was we found increased breast cancer liver metastases in nude mice. Conclusion TGF β1 proinotes the mesenchymal stern cell phenotype of TNBC by upregulating cyclinD1/CDK4 pathway. Meanwhile, TGF β1-induced TNBC mesenchymal stem cell phenotype changes promotes breast cancer liver metastasis.