The subcellular location of cyclin B1 and CDC25 associated with the formation of polyploid giant cancer cells and their clinicopathological significance
The subcellular location of cyclin B1 and CDC25 associated with the formation of polyploid giant cancer cells and their clinicopathological significance
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cyclin B1和CDC25与多倍体巨癌细胞形成相关的亚细胞定位及其临床病理意义
DOI：
10.1038/s41374-018-0157-x
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发表时间：
2019-04-01
影响因子：
5
通讯作者：
Zhang, Shiwu
中科院分区：
文献类型：
--
作者：
Fei, Fei;Qu, Jie;Zhang, Shiwu
多倍体巨癌细胞（PGCC）是癌症异质性的关键因素，PGCC的形成与细胞周期相关蛋白表达的变化有关。本研究探讨了多种细胞周期相关蛋白在BT-549和HEY细胞PGCC中的细胞内定位和表达水平。此外，PGCC的形成和细胞周期相关蛋白在人乳腺癌和卵巢癌中的临床病理意义进行了研究。细胞周期相关蛋白的表达水平，包括细胞周期蛋白B1，CDC 25 B，CDC 25 C，和其他细胞周期磷蛋白，包括Chk 2，和Aurora-A激酶，使用免疫染色和蛋白质印迹法测定在体外和体内。在对照细胞，细胞周期蛋白B1敲低细胞和他们的PGCC CoCl 2处理后的迁移，侵袭和增殖进行了比较。此外，收集人乳腺癌和卵巢癌样本，以确定PGCC数量、细胞周期相关蛋白表达与肿瘤病理分级和转移的相关性。我们的研究结果证实，细胞周期蛋白B1定位于PGCC的细胞质和其出芽的子细胞的细胞核中。磷酸化蛋白Chk 2和Aurora-A激酶调节细胞周期蛋白B1、CDC 25 B和CDC 25 C的表达和亚细胞定位。随着肿瘤分级和淋巴结转移的增加，cyclin B1在胞浆中的阳性表达率及CDC 25 B和CDC 25 C在胞核中的阳性表达率均增加。细胞周期相关蛋白包括cyclin B1、CDC 25 B和CDC 25 C在PGCC的形成过程中起着重要的调控作用。抑制cyclinB 1和CoCl 2处理显著促进细胞增殖、侵袭和迁移能力。这些细胞周期相关蛋白的亚细胞定位受到其他细胞周期磷蛋白的调节，并与人类乳腺癌和卵巢癌的病理分级和肿瘤转移有关。
Polyploid giant cancer cells (PGCCs) are key contributors to cancer heterogeneity, and the formation of PGCCs is associated with changes in the expression of cell-cycle-related proteins. This study investigated the intracellular localization and expression level of multiple cell-cycle-related proteins in PGCCs derived from BT-549 and HEY cells. In addition, the formation of PGCCs and the clinicopathological significance of cell-cycle-related proteins in human breast and ovarian cancer were examined. The expression levels of cell-cycle-related proteins, including cyclin B1, CDC25B, CDC25C, and other cell cycle phosphoproteins, including Chk2, and Aurora-A kinase, were determined using immunostaining and western blotting both in vitro and in vivo. Migration, invasion, and proliferation in control cells, cyclin B1 knockdown cells and their PGCCs following CoCl2 treatment were compared. In addition, human breast and ovarian cancer samples were collected to determine the correlation of number of PGCCs, expression of cell-cycle-related proteins, and tumor pathologic grade and metastasis. Our results confirm that cyclin B1 was localized in the cytoplasm of PGCCs and in the nuclei of their budding daughter cells. The phosphorylated proteins Chk2 and Aurora-A kinase regulated the expression and subcellular localization of cyclin B1, CDC25B, and CDC25C. The rate of positive cytoplasmic staining of cyclin B1 and positive nuclear staining of both CDC25B and CDC25C increased with increase in tumor grade and lymph node metastasis. Cell-cycle-related proteins, including cyclin B1, CDC25B, and CDC25C play an important role in regulating the formation of PGCCs. The inhibition of cyclinB1 and CoCl2 treatment significantly promoted cell proliferation, invasion, and migration abilities. The subcellular localization of these cell-cycle-related proteins was regulated by other cell cycle phosphoproteins, and was associated with pathologic grade and metastasis of tumors in cases of human breast and ovarian cancer.