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It is well known that S100A4 is overexpressed in many tumors and involved in tumor invasion and metastasis. But the regualtion of it is ill understood. We previously found that hypoxia mimicking cobalt chloride (CoCl 2 ) enhanced the mRNA and protein expressions of the S100A4 gene in the gastric cancer cell line BGC823. In this study we found that S100A4 also displayed increased expression in BGC823 cells after exposure to real hypoxia (2.5% O 2 ) as that by CoCl 2 treatment. Moreover, S100A4 protein showed different subcellular distribution under real hypoxia compared with that by CoCl 2 treatment or in normoxic conditions. To investigate the underlying molecular mechanism by which hypoxia regulates the expression of S100A4, we analyzed the regulatory sequences of the genes by bioinformatics and found a putative hypoxia responsive element (HRE) motif in the first intron of S1004. Furthermore, luciferase reporter assay showed that it is responsive to hypoxia. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrated that hypoxia-inducible factor 1 (HIF-1) binds to the functional HRE in vitro and in vivo. The results provide evidence that S100A4 is a hypoxia-inducible gene, whose transcription is stimulated at least partly through the interaction of HIF-1 and HRE located at +329 to +334 of S100A4. (Cancer Sci 2010; 101: 1141-1146 S 100A4 protein is a member of the S100 family of calciumbinding proteins involved in the invasiveness and metastasis of tumors.(1-4) S100A4 expression has been associated with metastasis in animal studies, and a number of studies have examined the utility of S100A4 expression as a prognostic marker in human cancers. Expression of S100A4 is significantly increased in tumors, such as thyroid, ovarian, lung, colorectal, pancreatic, and gastric cancers.(5-12) It plays a key role in the process of metastasis by stimulating angiogenesis; (13) promoting the migration of tumor cells, (14) adhesion of cells to matrix, and escape of tumor cells from primary tumors; and inducing expression of protein hydrolase. (15,16) However, the regulation of S100A4 gene expression is not well understood.Hypoxia occurs in solid tumors due to uncoordinated tumor growth and angiogenesis. It was reported that hypoxia promoted tumor progression, invasion, metastasis, and resistance to chemotherapy, leading to poor patient prognosis.(17) Whether S100A4 is regulated by hypoxia and mediates the effects of hypoxia in promoting the progression of cancer should be an interesting issue. In a previous study, we treated the gastric cancer cell line BGC823 with CoCl 2 to mimic hypoxia and found that CoCl 2 could up-regulate S100A4 expression, (18) but the effect of real hypoxia on S100A4 expression and underlying molecular mechanism are less well understood.It is well known that hypoxia-inducible factor 1 (HIF-1) plays a critical role in cell response to hypoxia. HIF-1 is a heterodimeric transcription factor which activates a wide range of genes encoding important proteins involved in the ph...

Many studies have revealed that S100A4 is involved in cancer progression by affecting a variety of biological functions. Our previous study showed that S100A4 influences many biological properties of gastric cancer cells; however, the underlying mechanisms are far from clear. In this study, we used cDNA microarray analysis to investigate the global alterations in gene expression in MGC803 gastric cancer cells after siRNA-mediated S100A4 inhibition. Among the total genes investigated, 179 differentially expressed genes (38 upregulated and 141 downregulated) were detected in S100A4-siRNA transfected MGC803 cells compared with NC-siRNA transfected cells. We focused on the GDF15 gene, which was significantly downregulated after S100A4 inhibition. ChIP studies showed that the S100A4 protein binds to the GDF15 promoter, implicating S100A4 in GDF15 regulation at the transcriptional level. GDF15 overexpression promoted CSC-like properties of MGC803 cells, such as spheroid and soft-agar colony forming abilities. S100A4 inhibition suppressed the CSC-like properties of the cells, whereas, GV141-GDF15 vector transfection reversed these effects. Our results suggest that S100A4 influences the CSC-like properties of MGC803 gastric cancer cells by regulating GDF15 expression.