S100A4 mediates endometrial cancer invasion and is a target of TGF-β1 signaling

• Published in: Laboratory investigation Vol. 89; no. 8; pp. 937 - 947
• Main Authors: Xie, Ran, Schlumbrecht, Matthew P, Shipley, Gregory L, Xie, Susu, Bassett, Roland L, Broaddus, Russell R
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.08.2009; Nature Publishing Group US; Nature Publishing Group
• Subjects: Biological and medical sciences; Biotechnology; cancer invasion; endometrial cancer; epithelial-to-mesenchymal transition; Female genital diseases; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Medical sciences; Medicine; Medicine & Public Health; Pathology; research-article; S100A family genes; S100A4; Tumors; endometrial cancer; S100A4; S100A family genes; cancer invasion; epithelial-to-mesenchymal transition; Biotechnology; Endometrium cancer; Targeting; Mesenchyma; Tumorous infiltration; Metastasis; Signal transduction; Gene; Clinical biology; Uterine diseases; Family environment; Genetics; S100 calcium binding protein A4; Family study; Mesenchymal cell; Malignant tumor; Invasion; Female genital diseases; Transforming growth factor β1; Cancer
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2009.52

The molecular mechanisms of endometrial cancer invasion are poorly understood. S100A4, also known as FSP1 (fibroblast-specific protein 1), has long been known to be a molecular marker of fibrosis in a variety of different fibrotic diseases of the lungs, liver, kidney, and heart. We demonstrate here that increased expression of S100A4 is associated with advanced stage endometrial cancer and decreased recurrence free survival. To verify the essential role of S100A4 in invasiveness of endometrial cancer, S100A4 expression was downregulated by RNAi in HEC-1A cells, which resulted in undetectable S100A4 protein and significantly decreased migration and invasion. Owing to the established connection between TGF-β1 and S100A4 induction in experimental models of kidney and liver fibrosis, we next examined whether TGF-β1 could also regulate S100A4 in endometrial cancer cells. TGF-β1 stimulated endometrial cancer cell migration and invasion with a concomitant increase in S100A4 protein. Induction of S100A4 was associated with the activation of Smads. TGF-β1-mediated endometrial cancer cell motility was inhibited by S100A4 siRNA. In aggregate, these results suggest that S100A4 is a critical mediator of invasion in endometrial cancer and is upregulated by the TGF-β1 signaling pathway. These results also suggest that endometrial cancer cell invasion and fibrosis share common molecular mechanisms.