Nuclear Expression of S100A4 Calcium-Binding Protein Increases Cholangiocarcinoma Invasiveness and Metastasization

被引：80

作者：

Fabris, Luca ^{[2
,3
,4
]}

Cadamuro, Massimiliano ^{[2
,4
]}

Moserle, Lidia ^{[5
]}

Dziura, James ^{[6
]}

Cong, Xiangyu ^{[6
]}

Sambado, Luisa ^{[4
]}

Nardo, Giorgia ^{[5
]}

Sonzogni, Aurelio ^{[4
]}

Colledan, Michele ^{[4
]}

Furlanetto, Alberto ^{[7
]}

Bassi, Nicolo ^{[2
,8
]}

Massani, Marco ^{[8
]}

Clio, Umberto ^{[2
]}

Mescoli, Claudia ^{[9
]}

Indraccolo, Stefano ^{[10
]}

Rugge, Massimo ^{[9
]}

Okolicsanyi, Lajos ^{[2
,3
]}

Strazzabosco, Mario ^{[1
,4
,11
]}

机构：

[1] Yale Univ, Sch Med, Sect Digest Dis, New Haven, CT 06520 USA

[2] Univ Padua, Dept Surg & Gastroenterol Sci, Padua, Italy

[3] Reg Hosp, Div Gastroenterol, Treviso, Italy

[4] Osped Riuniti Bergamo, CeLiveR, I-24100 Bergamo, Italy

[5] Univ Padua, Dept Oncol & Surg Sci, Padua, Italy

[6] Yale Univ, Yale Ctr Analyt Sci, New Haven, CT USA

[7] Reg Hosp, Dept Pathol, Treviso, Italy

[8] Reg Hosp, Surg Div 4, Treviso, Italy

[9] Univ Padua, Dept Pathol, Padua, Italy

[10] IRCCS, Ist Oncol Veneto, Padua, Italy

[11] Univ Milano Bicocca, Dept Clin Med, Milan, Italy

来源：

HEPATOLOGY | 2011年 / 54卷 / 03期

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; PROGNOSTIC-SIGNIFICANCE; CANCER; CALMODULIN; GROWTH;

D O I：

10.1002/hep.24466

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 Ca2+-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. (HEPATOLOGY 2011;54:890-899)

引用

页码：890 / 899

页数：10

共 25 条

[1]

INTERACTIONS OF MYOGENIC BHLH TRANSCRIPTION FACTORS WITH CALCIUM-BINDING CALMODULIN AND S100A (ALPHA-ALPHA) PROTEINS [J].