Research

Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker

Kusumawadee Utispan^1,7 , Peti Thuwajit^2,7 , Yoshimitsu Abiko³ , Komgrid Charngkaew⁴ , Anucha Paupairoj^5,7 , Siri Chau-in^6,7 and Chanitra Thuwajit^2,7

¹  Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Road, Muang, Khon Kaen 40002, Thailand

²  Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok Noi, Bangkok 10700, Thailand

³  Department of Biochemistry and Molecular Biology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba 2718587, Japan

⁴  Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand

⁵  Department of Pathology, Faculty of Medicine, Khon Kaen University, Thailand

⁶  Department of Surgery, Faculty of Medicine, Khon Kaen University, Thailand

⁷  Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Thailand

author email corresponding author email

Molecular Cancer 2010, 9:13doi:10.1186/1476-4598-9-13

Published:	24 January 2010

Abstract

Background

Fibroblasts play important roles in several cancers. It was hypothesized that cholangiocarcinoma (CCA)-associated fibroblasts (Cfs) differ from non-tumorigenic liver fibroblasts (Lfs) in their gene expression profiles resulting in the capability to promote cancer. Periostin (PN) is a multi-functional protein and has emerged as a promising marker for tumor progression. The role of PN in CCA, however, has not yet been explored.

Results

In this study, the gene expression profile of Cfs in comparison to Lfs was performed using oligonucleotide microarrays. The common- and unique-expressed genes in Cfs and the promising roles in cancer promotion and progression were determined. PN was markedly over-expressed in Cfs confirmed by real time RT-PCR and western blot analysis. Immunohistochemistry examination of a number of patients with intrahepatic CCA showed the expression of PN solely in stromal fibroblasts, but was expressed neither in cancer cells nor immune cells. Low to no expression of PN was observed in tissues of benign liver disease and hepatocellular carcinoma. CCA patients with high levels of PN had significantly shorter survival time than those with low levels (P = 0.026). Multivariate analysis revealed high levels of PN (P = 0.045) and presence of lymph node metastasis (P = 0.002) as independent poor prognostic factors. The in vitro study revealed that recombinant PN induced CCA cell proliferation and invasion. Interestingly, interference RNA against integrin α₅ significantly reduced the cellular response to PN-stimulated proliferation and invasion.

Conclusion

The gene expression profile of fibroblasts in CCA is apparently explored for the first time and has determined the genes involving in induction of this cancer progression. High PN can be used to distinguish CCA from other related liver diseases and is proposed as a prognostic factor of poor survival. Regulation of fibroblast-derived PN in CCA proliferation and invasion may be considered as an alternative therapeutic approach.