1. ¹Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
2. ²Department of Internal Medicine, Gastroenterology Section, Hokkaido University Graduate School of Medicine, Sapporo, Japan
3. ³Department of Diagnostic Pathology, Kanazawa University Hospital, Kanazawa, Japan
4. ⁴Department of Surgical Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
5. ⁵Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
6. ⁶Division of Cancer Medicine, Department of Gastroenterologic Surgery, Kanazawa University Graduate School of Medicine, Kanazawa, Japan

Correspondence: Dr Y Nakanuma, MD, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan. E-mail: pbcpsc@kenroku.kanazawa-u.ac.jp

Received 29 December 2008; Revised 28 April 2009; Accepted 27 May 2009; Published online 31 August 2009.

Abstract

Fascin is an actin-binding protein involved in the cell motility. Recently, aberrant expression of fascin in carcinoma cells was reported to participate in their invasive growth in cooperation with proteinases such as matrix metalloproteinases (MMPs). This study examined the participation of fascin in the progression of cholangiocarcinoma (CC) with reference to MMPs and tumor necrosis factor- (TNF-). Expression levels of fascin and MMP2 and 9 were examined immunohistochemically in human non-neoplastic biliary epithelium (13 cases) and CC (87 cases). The relationship between fascin and MMP9-expression levels was examined using two CC cell lines (CCKS-1 and HuCCT1). It was also examined whether or not fascin was involved in TNF--induced overproduction of MMP9 in CC. Fascin and MMP9 were expressed in 49 and 53% of CC samples, respectively, and the expression of these genes was frequent in intrahepatic CC. Fascin expression was correlated significantly with MMP9 expression. In particular, these two molecules were expressed more intensely at the invasive fronts of CC. Fascin expression was an unfavorable prognostic factor for patients with intrahepatic CC. In vitro studies showed that TNF- could induce the overexpression of fascin and MMP9 in two CC cell lines. A knockdown study of fascin by siRNA showed that TNF- induced the overproduction of fascin, which in turn upregulated MMP9 expression. Overexpression of fascin may have an important function in the progression of CC, and fascin expression might be involved in the signaling pathway in TNF--dependent production of MMP9 in CC.