Fei Fei, Liu Kai, Li Chunyuan, Du Jiaxing, Wei Zhen, Li Bo, Li Yuwei, Zhang Yi, Zhang Shiwu
Department of Pathology, Tianjin Union Medical Center, Tianjin, China.
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Front Oncol. 2020 Feb 21;10:182. doi: 10.3389/fonc.2020.00182. eCollection 2020.
Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. and experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.
最近，越来越多的证据表明，多倍体巨癌细胞（PGCCs）能够产生具有强大迁移和侵袭能力的子细胞，这与癌症复发和转移有关。然而，PGCCs及其子细胞的潜在分子机制仍不清楚。本研究结合222例人类结直肠癌（CRC）样本进行实验，以确定S100A4相关蛋白调控PGCCs及其子细胞侵袭和转移的分子机制。与对照细胞相比，PGCCs及其子细胞具有较高的迁移、侵袭和增殖能力；S100A4敲低后，这些能力受到显著抑制。组织蛋白酶B、细胞周期蛋白B1、TRIM21和膜联蛋白A2的高表达在S100A4敲低后显著下调，而在PGCCs及其子细胞中，TRIM21敲低后S100A4、组织蛋白酶B、细胞周期蛋白B1和S100A10的过表达显著下调。与未处理的细胞相比，PGCCs及其子细胞的致瘤和转移能力显著更强，S100A4敲低后显著降低。此外，S100A4相关蛋白的表达与人类CRC的恶性程度呈正相关，在淋巴结转移中维持在高水平。S100A4和TRIM21可能相互调节，影响细胞周期蛋白B1的表达和亚细胞定位，并参与调节膜联蛋白A2/S100A10复合物的结构和功能，影响下游组织蛋白酶B，导致PGCCs及其子细胞的侵袭和转移。此外，14-3-3ζ/δ和埃兹蛋白可能通过与S100A4的细胞骨架构建参与PGCCs及其子细胞的运动和侵袭。
