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Objective: To investigate the effects and mechanisms of exogenous calcium-binding protein S100A4 on proliferation, survival and migration functions of glioma cells. Methods: Pan-cancer dataset was downloaded from UCSC database for the analysis of S100A4 expression and prognosis in pan-cancer, and transcriptome and clinical data of glioma patients were downloaded from CGGA database. Prognosis and progression of S100A4 expression in glioma patients were analyzed by R software. S100A4 protein network interaction of glioma patients were addressed by online analytical tools GEPIA and STRING. Human glioma cell lines (U87 and U251) were cultured in vitro, and the experiment was divided into 3 groups: PBS group, S100A4 group and S100A4+TAK242 group [Resatorvid (TAK242) was a specific inhibitor of Toll-like receptors 4 (TLR4)]. Flow cytometry was used to detect proliferation and apoptosis of glioma cells. Wound healing assay, Transwell assay and clone formation assay were used to detect migration and proliferation ability of U87 and U251 cells, and Western blot was used to detect levels of TLR4 protein and NF-κB related signaling proteins. Results: Bioinformatics results showed that S100A4 was significantly upregulated in multiple tumours (P<0.05), which included glioblastoma (GBM), lower grade glioma (LGG), stomach adenocarcinoma (STAD), liver hepatocellular carcinoma (LIHC), etc, with poorer prognosis in GBM and LGG. Compared with glioma patients with low expression of S1004, high expression S100A4 in glioma patients had shorter survival and higher degree of WHO classification. In addition, S100A4 protein in glioma patients may interact with Annexin A2 (ANXA2), TLR4 and advanced glycosylation end product-specific receptor (AGER) proteins. In cellular experiments, U87 and U251 cells showed enhanced proliferation and migration, and significantly up-regulated levels of TLR4, p-ERK1/2, p-p38 and p-p65 proteins after exogenous S100A4 treatment compared to PBS group (P<0.05), while glioma cells in S100A4+TAK242 group showed weaker proliferation and migration, and lower TLR4, p-p38 and p-p65 protein levels than those in S100A4 group, TLR4, p-ERK1/2, p-p38, p-p65 protein levels were significantly down-regulated (P<0.05). Conclusion: S100A4 may regulate function of glioma proliferation, migration and survival through TLR4/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]