髓样锌指蛋白 1 调节乳腺癌中与癌症相关的成纤维细胞和癌症干细胞特征的表达。

Myeloid zinc finger-1 regulates expression of cancer-associated fibroblast and cancer stemness profiles in breast cancer.

机构信息

Emory University School of Medicine, Atlanta, GA.

Department of Surgery, University of South Florida, Tampa, FL.

出版信息

Surgery. 2019 Oct;166(4):515-523. doi: 10.1016/j.surg.2019.05.042. Epub 2019 Jul 10.

DOI:10.1016/j.surg.2019.05.042

PMID:31301870

Abstract

BACKGROUND

Osteopontin acts thru myeloid zinc finger-1 and transforming growth factor-β to drive the adoption of a cancer-associated fibroblast phenotype by local mesenchymal stem cells. Cancer-associated fibroblasts increase cancer cell stemness.

METHODS

Mesenchymal stem cells were exposed to osteopontin or were cocultured with MB231 human breast cancer cells (high osteopontin producer) in the presence or absence of aptamer (inactivates extracellular osteopontin). Myeloid zinc finger-1 phosphorylation sites were identified, and phosphomutants of T134 (SCAN domain) and S453 (zinc finger DNA binding domain) were constructed. Transforming growth factor-β F and cancer-associated fibroblast markers (smooth muscle actin, vimentin, and tenascin-c) were measured in mesenchymal stem cells. In MB231, stemness markers Sox2, Nanog, and Oct4 were measured.

RESULTS

Mesenchymal stem cells plus osteopontin increased transforming growth factor-β and cancer-associated fibroblast markers (P < .05 vs mesenchymal stem cells alone); this was abolished by aptamer inactivation of osteopontin. In mesenchymal stem cells transfected with phosphoresistant myeloid zinc finger-1, osteopontin did not increase cancer-associated fibroblast markers or transforming growth factor-β. In contrast, phosphomimetic myeloid zinc finger-1 increased cancer-associated fibroblast markers and transforming growth factor-β (P < .05 vs mesenchymal stem cells alone). In mesenchymal stem cells plus MB231, MB231 stemness markers were increased (P < .05 vs MB231 alone). In MB231 plus mesenchymal stem cells expressing phosphoresistant myeloid zinc finger-1, MB231 stemness markers were not increased in comparison with MB231 plus mesenchymal stem cells.

CONCLUSION

Myeloid zinc finger-1 phosphorylation in mesenchymal stem cells drives the osteopontin-mediated cancer-associated fibroblast phenotype, which then increases the cancer cell stemness profile.

摘要

背景

骨桥蛋白通过髓样锌指 1 和转化生长因子-β 作用于局部间充质干细胞，使其获得癌症相关成纤维细胞表型。癌症相关成纤维细胞增加了癌细胞的干性。

方法

将间充质干细胞暴露于骨桥蛋白或与 MB231 人乳腺癌细胞（高骨桥蛋白产生者）共培养，同时存在或不存在适体（使细胞外骨桥蛋白失活）。鉴定髓样锌指 1 的磷酸化位点，并构建 T134（SCAN 结构域）和 S453（锌指 DNA 结合域）的磷酸化突变体。测量间充质干细胞中的转化生长因子-β F 和癌症相关成纤维细胞标志物（平滑肌肌动蛋白、波形蛋白和 tenascin-c）。在 MB231 中，测量干性标志物 Sox2、Nanog 和 Oct4。

结果

间充质干细胞加骨桥蛋白增加了转化生长因子-β 和癌症相关成纤维细胞标志物（P<0.05 与单独的间充质干细胞相比）；这一作用被骨桥蛋白适体失活所消除。在转染了磷酸化抗性髓样锌指-1 的间充质干细胞中，骨桥蛋白不会增加癌症相关成纤维细胞标志物或转化生长因子-β。相比之下，磷酸化模拟的髓样锌指-1 增加了癌症相关成纤维细胞标志物和转化生长因子-β（P<0.05 与单独的间充质干细胞相比）。在间充质干细胞加 MB231 中，MB231 干性标志物增加（P<0.05 与单独的 MB231 相比）。在表达磷酸化抗性髓样锌指-1 的间充质干细胞加 MB231 中，与间充质干细胞加 MB231 相比，MB231 干性标志物没有增加。