Zhou Xinyue, Ning Yidi, Wang Xiaorui, Xu Jing, Liu Yandi, Zhang Mingqing, Zhang Shiwu
Department of Pathology, Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao, Tianjin, 300071, People's Republic of China.
Nankai University Medical College, Tianjin, 300071, People's Republic of China.
Hum Cell. 2025 Jul 28;38(5):136. doi: 10.1007/s13577-025-01252-5.
The abundance of polyploid giant cancer cells (PGCCs) is correlated with malignant tumor progression. PGCCs divide asymmetrically to generate daughter cells with high invasive and migratory capacities. The objective of this study was to investigate the mechanism by which the overexpression of polo-like kinase 1 (PLK1) regulates the migration and invasion of PGCCs and their daughter cells (PDCs). In the present study, PGCC formation was induced by CoCl in Hct116 and LoVo cells. The mRNA expression and protein levels were detected using reverse transcription‒quantitative PCR and western blotting, respectively. The regulatory relationships among related proteins were determined via small molecule inhibitors, transient small interfering RNA (siRNA) transfection, and coimmunoprecipitation. Our findings indicated that CoCl induces PGCC formation and produces progeny cells with increased invasive and metastatic abilities. PLK1 was expressed in PDCs and showed altered subcellular localization. In addition, aurora kinase A (AURKA) activated PLK1 by phosphorylating it at serine 137 and threonine 210. Activated PLK1 first stabilizes β-catenin accumulation in the cytoplasm and subsequently promotes its entry into the nucleus. After entering the nucleus, β-catenin promotes the accumulation of the tyrosine 705 site of signal transducer and activator of transcription 3 (pSTAT3-Tyr705), which promotes the downstream expression of target proteins, such as cyclin D1, matrix metallopeptidase 2 (MMP2) and c-MYC, and EMT-associated proteins as transcription factors. Furthermore, STAT3 and PLK1 form a feedback loop, allowing STAT3 to regulate PLK1 expression. In conclusion, PLK1 phosphorylation at different sites regulates the transcriptional function of pSTAT3-Tyr705 by promoting β-catenin nuclear translocation. Furthermore, AURKA and STAT3 affected PLK1 expression.
多倍体巨癌细胞（PGCCs）的丰度与恶性肿瘤进展相关。PGCCs进行不对称分裂以产生具有高侵袭和迁移能力的子细胞。本研究的目的是探究polo样激酶1（PLK1）过表达调节PGCCs及其子细胞（PDCs）迁移和侵袭的机制。在本研究中，用氯化钴在Hct116和LoVo细胞中诱导PGCC形成。分别使用逆转录定量PCR和蛋白质印迹法检测mRNA表达和蛋白质水平。通过小分子抑制剂、瞬时小干扰RNA（siRNA）转染和免疫共沉淀确定相关蛋白质之间的调控关系。我们的研究结果表明，氯化钴诱导PGCC形成并产生具有增强侵袭和转移能力的子代细胞。PLK1在PDCs中表达并表现出亚细胞定位改变。此外，极光激酶A（AURKA）通过在丝氨酸137和苏氨酸210位点磷酸化激活PLK1。激活的PLK1首先稳定细胞质中β-连环蛋白的积累，随后促进其进入细胞核。进入细胞核后，β-连环蛋白促进信号转导和转录激活因子3（pSTAT3-Tyr705）酪氨酸705位点的积累，从而促进细胞周期蛋白D1、基质金属肽酶2（MMP2）和c-MYC等靶蛋白以及作为转录因子的EMT相关蛋白的下游表达。此外，STAT3和PLK1形成一个反馈环，使STAT3能够调节PLK1表达。总之，PLK1在不同位点的磷酸化通过促进β-连环蛋白核转位调节pSTAT3-Tyr705的转录功能。此外，AURKA和STAT3影响PLK1表达。
