title: Clonorchis sinensis excretory-secretory products promote the migration and invasion of cholangiocarcinoma cells by activating the integrin β4-FAK/Src signaling pathway.
abstract: Cholangiocarcinoma (CCA) is a slow-growing but highly metastatic cancer. Its metastatic potential largely explains its high mortality rate. A recognized risk factor for CCA development is infection with the liver flukes Opisthorchis viverrini and Clonorchis sinensis. We previously reported that the excretory-secretory products (ESPs) of C. sinensis promoted the three-dimensional aggregation and invasion of CCA cells. In the present study, a quantitative real-time PCR array of extracellular matrix (ECM) and adhesion molecules was used to examine the regulatory mechanism of ESP-mediated CCA cell migration and invasion. In particular, the expression levels of integrin α isoforms and β4 were upregulated in response to ESPs. Increased expression of integrin β4 was probably correlated with activation of focal adhesion kinase (FAK) and the steroid receptor coactivator (Src) family kinase and the subsequent activation of two downstream focal adhesion molecules, paxillin and vinculin. Moreover, inhibition of FAK/Src activation reduced paxillin and vinculin phosphorylation and attenuated ESP-induced CCA cell migration and invasion. These findings suggest that the integrin β4-FAK/Src signaling axis may play a crucial role in clonorchiasis-associated CCA metastasis during tumor progression.
authors.affiliation: Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea. Electronic address: jhpak@amc.seoul.kr.
authors.forename: Jhang Ho
authors.initials: JH
authors.lastname: Pak
authors.affiliation: Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Qudsia
authors.initials: Q
authors.lastname: Bashir
authors.affiliation: Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: In Ki
authors.initials: IK
authors.lastname: Kim
authors.affiliation: Department of Medical Environmental Biology and Research Center for Biomolecules and Biosystems, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
authors.forename: Sung-Jong
authors.initials: SJ
authors.lastname: Hong
authors.affiliation: Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Sejung
authors.initials: S
authors.lastname: Maeng
authors.affiliation: Department of Biotechnology, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Young Yil
authors.initials: YY
authors.lastname: Bahk
authors.affiliation: Department of Parasitology, Inha University School of Medicine, Incheon 400-103, Republic of Korea.
authors.forename: Tong-Soo
authors.initials: TS
authors.lastname: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003004:Clonorchis sinensis / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D020869:Gene Expression Profiling; D015801:Helminth Proteins / Q000378:metabolism*; D006801:Humans; D039663:Integrin beta4 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D015801:Helminth Proteins; D039663:Integrin beta4; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases
keywords: Cholangiocarcinoma; Clonorchis sinensis; Excretory-secretory products; Integrin-mediated signaling pathway; Invasion; Migration