Abstract
The function of the extracellular matrix (ECM) in the tumor microenvironment is not limited to forming a barrier against tumor invasion. As demonstrated in pathological specimens, cholangiocarcinoma samples exhibit an enrichment of the ECM surrounding the tumor cells. In this study, we examined involvement of the ECM in the regulation of the invasiveness of cholangiocarcinoma cells. The RMCCA1 cholangiocarcinoma cell line was cultured in culture plates either with or without a coating of reconstituted ECM basement membrane preparation (BD Matrigel matrix). In vitro invasion assays were then performed. In addition, the protein expression profile of the cell line was examined using two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry. The proteins expressed and their functional associations with cancer progression were determined. Culturing the RMCCA1 cell line in the BD Matrigel matrix induced cell invasion. Numerous proteins were induced by culturing the RMCCA1 cells in the matrix gel. The expression of L-plastin, an actin-binding protein, was significantly upregulated. The knockdown of L-plastin expression by siRNA silencing significantly suppressed the cellular response to matrix gel-stimulated cancer cell invasion. The ECM promotes the invasiveness of cholangiocarcinoma cells by upregulating L-plastin. These findings suggest the potential exploitation of this mechanism as a means of inhibiting the invasiveness of cholangiocarcinoma cells.
Highlights
Cholangiocarcinoma, an aggressive malignant tumor that develops from the bile duct epithelium, is associated with local invasiveness and a high rate of metastasis [1,2]
We report for the first time that the extracellular matrix (ECM) plays a major role in the regulation of cholangiocarcinoma cell invasion
Based on 2D electrophoresis results, we identified the proteins that were upregulated when cholangiocarcinoma cells were cultured in matrix gel for 24 h
Summary
Cholangiocarcinoma, an aggressive malignant tumor that develops from the bile duct epithelium, is associated with local invasiveness and a high rate of metastasis [1,2]. The worldwide incidence and mortality rates associated with cholangiocarcinoma have risen over the past three decades. In Thailand, the annual incidence of cholangiocarcinoma is 87 per 100,000 inhabitants [3]. In Southeast Asia and in Thailand, infection with hepatobiliary flukes (Opisthorchis viverrini) is the most common risk factor for cholangiocarcinoma [5]. Therapeutic options for cholangiocarcinoma patients are limited, as this type of cancer responds poorly to chemotherapy and radiation therapy. The understanding of the mechanisms involved in cancer cell invasion and metastasis may be useful in developing new therapeutic options for cholangiocarcinoma patients
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