S100A4 Regulates the Migration and Invasion of Polyploid Giant Cancer Cells with Their Daughter Cells in Human Colorectal Cancer

Background: 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. Methods: Cell functional experiment, co-immunoprecipitation combined with mass spectroscopy, immunocytochemical staining, animal experiment and human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4 regulating the invasion and metastasis of PGCCs. Findings: PGCCs and their daughter cells had high migration, invasion, and proliferation abilities compared to control cells before CoCl2 treatment; these were significantly inhibited after S100A4i. After S100A4 and TRIM21 were knocked down in PGCCs and the daughter cells, the expressions of S100A4, cathepsin B, cyclin B1, TRIM21, and the complex of Annexin A2/S100A10 decreased based on the results of co-immunoprecipitation combined with mass spectroscopy. Moreover, the results of animal experiments and analysis of human CRC samples indicated that S100A4 and its interacting proteins contributed to the invasion and metastasis of PGCCs and their daughter cells. Interpretations: S100A4 and TRIM21 may regulate each other and adjust the Annexin A2/S100A10 complex to affect the expression of downstream proteins including cathepsin B and cyclin B1. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs and their daughter cells via cytoskeletal constructions with S100A4.   Funding Statement: National Natural Science Foundation of China (81472729 and 81672426), and the foundation of committee on science and technology of Tianjin (17ZXMFSY00120 and 17YFZCSY00700), and foundation of Tianjin Union Medical Center (2017YJ018). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was approved by the Institutional Animal Care and Use Committee of the Tianjin Union Medicine Center. The use of these human tissue samples was approved by the Hospital Review Board and the confidentiality of patient information was maintained.