S100A4/non-muscle myosin II signaling regulates epithelial-mesenchymal transition and stemness in uterine carcinosarcoma
S100A4/non-muscle myosin II signaling regulates epithelial-mesenchymal transition and stemness in uterine carcinosarcoma
复制标题
DOI：
10.1038/s41374-019-0359-x
复制
发表时间：
2020-05-01
影响因子：
5
通讯作者：
Saegusa, Makoto
中科院分区：
文献类型：
--
作者：
Tochimoto, Masataka;Oguri, Yasuko;Saegusa, Makoto
子宫癌肉瘤（UCS）代表了与上皮-间质转化（EMT）相关的癌症的真实例子，其表现出癌症干细胞（CSC）样特征。尽管S100 A4是EMT的诱导物，但关于其参与UCS肿瘤发生的情况知之甚少。在此，我们重点讨论了S100 A4在UCS开发过程中的功能作用。同时检测35例UCS中S100 A4及其功能相关分子的表达。在子宫内膜癌细胞系中，NF-κ B B/p65的转染显著增加了S100 A4启动子的活性和mRNA水平，而不依赖于启动子中假定的κ B结合位点。稳定过表达S100 A4的细胞表现出CSC性质的增强，沿着细胞增殖的降低和细胞迁移的加速。这些表型在S100 A4敲减细胞中被废除。S100 A4抗体介导的免疫共沉淀和鸟枪蛋白质组学分析的组合显示，S100 A4与非肌肉肌球蛋白II（NMII）重链，包括肌球蛋白9和肌球蛋白14强烈相互作用。通过blebbistatin特异性抑制NMII，表型化S100 A4过表达并诱导成纤维细胞样形态。在临床样本中，肉瘤的S100 A4评分显著高于UCS的癌性成分，与ALDH 1、Slug和波形蛋白评分呈正相关，与Ki-67标记指数呈负相关。这些发现表明，S100 A4/匪II相关的信号级联可能有助于EMT/CSC特性的建立和维持，沿着细胞增殖和迁移能力的变化。S100 A4/非肌肉肌球蛋白II相关的信号级联可能有助于上皮间质转化/癌干细胞特性的建立和维持，沿着细胞增殖和迁移能力的变化。这些事件可能起始于子宫癌肉瘤的癌性成分，并导致不同的肉瘤分化。
Uterine carcinosarcoma (UCS) represents a true example of cancer associated with epithelial-mesenchymal transition (EMT), which exhibits cancer stem cell (CSC)-like traits. Although S100A4 is an inducer of EMT, little is known about its involvement in UCS tumorigenesis. Herein, we focused on the functional role of S100A4 during development of UCS. Expression of S100A4 and molecules associated with its function were also examined in 35 UCS cases. In endometrial carcinoma cell lines, S100A4 promoter activity and mRNA levels were significantly increased by the transfection of NF-kappa B/p65, independent of a putative kappa B-binding site in the promoter. Cells stably overexpressing S100A4 showed enhancement of CSC properties, along with decreased cell proliferation and acceleration of cell migration. These phenotypes were abrogated in S100A4-knockdown cells. A combination of S100A4 antibody-mediated co-immunoprecipitation and shotgun proteomics analysis revealed that S100A4 strongly interacted with non-muscle myosin II (NMII) heavy chains, including myosin 9 and myosin 14. Specific inhibition of NMII by blebbistatin phenocopied S100A4 overexpression and induced a fibroblast-like morphology. In clinical samples, S100A4 score was significantly higher in sarcomatous as compared with carcinomatous components of UCS, and was positively correlated with ALDH1, Slug, and vimentin scores, and inversely with Ki-67 labeling indices. These findings suggest that an S100A4/NMII-related signaling cascade may contribute to the establishment and maintenance of EMT/CSC properties, along with changes in cell proliferation and migration capability. These events may be initiated in carcinomatous components in UCS and lead to divergent sarcomatous differentiation.The S100A4/non-muscle myosin II-related signal cascade may contribute to the establishment and maintenance of epithelial mesenchymal transition/cancer stem cell properties, along with changes in cell proliferation and migration capability. These events may be initiated in carcinomatous components in uterine carcinosarcoma and lead to divergent sarcomatous differentiation.