S100A4 mediates endometrial cancer invasion and is a target of TGF-beta1 signaling.
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-beta1 and S100A4 induction in experimental models of kidney and liver fibrosis, we next examined whether TGF-beta1 could also regulate S100A4 in endometrial cancer cells. TGF-beta1 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-beta1-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-beta1 signaling pathway. These results also suggest that endometrial cancer cell invasion and fibrosis share common molecular mechanisms.
Xie
Ran
R
Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Schlumbrecht
Matthew P
MP
Shipley
Gregory L
GL
Xie
Susu
S
Bassett
Roland L
RL
Broaddus
Russell R
RR
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing; D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C077591:S100A4 protein, human