乳腺癌中ZNF217通过激活上皮间质转化通路分子对骨转移的促进作用

ZNF217 promotes bone metastasis by activating epithelial-mesenchymal transition pathway molecules in breast cancer

目的:ZNF217是否通过激活上皮间质转化(EMT)的分子,参与促进恶性肿瘤细胞的迁徙,导致骨转移。方法:培养不同生物学行为的SUM-159和MDA-MB231乳腺癌细胞,以及移植瘤小鼠。检测ZNF217过表达与EMT相关基因(Snail1和Twist)表达的关系,探索ZNF217过表达癌细胞骨转移的发生率,随访49例Ⅳ期(或复发)乳腺癌中发生骨转移患者,进一步验证ZNF217过表达与骨转移的关系。结果:乳腺癌SUM-159细胞较MDA-MB231细胞的ZNF217表达水平高,并对阿霉素耐药,且高表达ZNF217的SUM-159侵袭性更高。SUM-159和MDA-MB231移植瘤小鼠中,前者的骨转移发生率更高,骨转移组织检测显示ZNF217过表达,而且EMT相关基因表达(Snail1和Twist)也存在明显上调。随访乳腺癌患者中,ZNF217过表达患者骨转移发生率更高(31%vs 18%,χ2=4.3,P=0.038),而且生存时间更短,无进展生存时间(PFS)为10.7个月(9.5~11.8月),ZNF217低表达患者PFS为12.7个月(11.7~13.6月)(Log Rank=4.8,P=0.029)。结论:ZNF217可能通过促进EMT通路相关基因的激活,增加细胞迁徙能力,导致乳腺癌骨转移,可能是预测乳腺癌患者骨转移和预后的生物标志物。

Objectives:To determine whether ZNF217 is involved in promoting the migration of malignant cells and leading to bone metastasis by activating the molecules of epithelial-mesenchymal transition(EMT).Methods:We cultured SUM-159 and MDA-MB231 breast cancer cells with different biologi-cal behaviors,and transplanted them into mice.Then we detected the relationship between overex-pression of ZNF217 and EMTrelated gene(Snail1 and Twist)expression,to explore the incidence of bone metastasis of ZNF217 overexpression cells.In addition,forty-nine advanced breast cancer pa-tients were followed up to further verify the relationship between the overexpression of ZNF217 and bone metastasis.Results:Compared with that in MDA-MB231 breast cancer cells,the expression of ZNF217 was higher in SUM-159 breast cancer cells,which was insensitive to adriamycin.Moreover,SUM-159 with overexpression of ZNF217 was more invasive.In SUM-159 and MDA-MB231 trans-planted tumor mice,the incidence of bone metastasis was higher in the former.Overexpression of ZNF217 was detected in metastasis bone tissues,and the expression of EMT-related genes(Snail1 and Twist)was also significantly up-regulated.According to the follow up study of breast cancer pa-tients,patients with overexpression of ZNF217 had higher incidence of bone metastasis(31%vs18%,χ2=4.3,P=0.038),shorter survival time of 10.7 months(9.5-11.8 months),while patients with lower expression of ZNF217 was 12.7 months(11.7-13.6 months)(Log Rank=4.8,P=0.029)of survival time.Conclusion:ZNF217 may promote the activation of genes related to EMT pathway,increase cell migration ability and lead to bone metastasis of breast cancer.Therefore,ZNF217 may be a biomarker for predicting bone metastasis and prognosis of breast cancer patients.