Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization

Luca Fabris, Massimiliano Cadamuro, Lidia Moserle, James Dziura, Xiangyu Cong, Luisa Sambado, Giorgia Nardo, Aurelio Sonzogni, Michele Colledan, Alberto Furlanetto, Nicolò Bassi, Marco Massani, Umberto Cillo, Claudia Mescoli, Stefano Indraccolo, Massimo Rugge, Lajos Okolicsanyi, Mario Strazzabosco

Research output: Contribution to journalArticlepeer-review


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. Conclusion: 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.

Original languageEnglish
Pages (from-to)890-899
Number of pages10
Issue number3
Publication statusPublished - Sep 2 2011

ASJC Scopus subject areas

  • Hepatology


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