title: Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization.
abstract: Cholangiocarcinoma (CCA) carries a severe prognosis because of its strong invasiveness and early metastasization. In several patients, otherwise eligible for surgical resection, micrometastasis are already present at the time of surgery. The mechanisms responsible for CCA invasiveness are unclear. S100A4, a member of the S100 family of small Ca(2+)-binding proteins, is expressed in mesenchymal cells, regulates cell motility in several cell types, and is expressed in some epithelial cancers. Thus, we aimed to study the role of S100A4 in CCA invasiveness and metastasization. The expression of S100A4 was studied by immunohistochemistry in 93 human liver samples of CCA patients undergoing surgical resection and correlated with metastases development (67 cases) and patient survival following surgery using log rank tests and multivariate analysis. S100A4 expression was studied in EGI-1 and TFK-1, human CCA cell lines with and without nuclear S100A4 expression, respectively. Metastatic properties of CCA cells were assessed by xenotransplantation in severe combined immunodeficiency (SCID) mice after transduction with lentiviral vectors encoding firefly luciferase gene. Proliferation, motility (wound healing), invasiveness (Boyden chamber), and metalloproteinases (MMPs) secretion were studied in CCA cells, with or without lentiviral silencing of S100A4. Nuclear expression of S100A4 by neoplastic ducts was a strong predictor of metastasization and reduced survival after resection (P < 0.01). EGI-1 CCA cells showed stronger metastatic properties than TFK-1 when xenotransplanted in SCID mice. S100A4-silenced EGI-1 cells showed significantly reduced motility, invasiveness, and MMP-9 secretion in vitro, without changes in cell proliferation.
  
  
  CONCLUSIONS
  Nuclear S100A4 identifies a subset of CCA patients with a poor prognosis after surgical resection. Nuclear expression of S100A4 increases CCA cells invasiveness and metastasization, indicating that S100A4 may also represent a potential therapeutic target.
authors: Department of Surgical and Gastroenterological Sciences, University of Padova, Italy.
authors: Luca
authors: L
authors: Fabris
authors: Massimiliano
authors: M
authors: Cadamuro
authors: Lidia
authors: L
authors: Moserle
authors: James
authors: J
authors: Dziura
authors: Xiangyu
authors: X
authors: Cong
authors: Luisa
authors: L
authors: Sambado
authors: Giorgia
authors: G
authors: Nardo
authors: Aurelio
authors: A
authors: Sonzogni
authors: Michele
authors: M
authors: Colledan
authors: Alberto
authors: A
authors: Furlanetto
authors: Nicolò
authors: N
authors: Bassi
authors: Marco
authors: M
authors: Massani
authors: Umberto
authors: U
authors: Cillo
authors: Claudia
authors: C
authors: Mescoli
authors: Stefano
authors: S
authors: Indraccolo
authors: Massimo
authors: M
authors: Rugge
authors: Lajos
authors: L
authors: Okolicsanyi
authors: Mario
authors: M
authors: Strazzabosco
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