Open Access

ARTICLE

Activation of Vimentin Is Critical to Promote a Metastatic Potential of Cholangiocarcinoma Cells

Waraporn Saentaweesuk^*†‡, Norie Araki^‡, Kulthida Vaeteewoottacharn^*†, Atit Silsirivanit^*†‡, Wunchana Seubwai^†§, Chutima Talabnin^¶, Kanha Muisuk^§, Banchob Sripa^†#, Sopit Wongkham^*†, Seiji Okada^**, Chaisiri Wongkham^*†

* Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
† Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
‡ Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
§ Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
¶ School of Biochemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, Thailand
# Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
** Division of Hematopoiesis, Center of AIDS Research, Kumamoto University, Kumamoto, Japan

Oncology Research 2018, 26(4), 605-616. https://doi.org/10.3727/096504017X15009778205068

Abstract

Cholangiocarcinoma (CCA) is a highly metastatic tumor, and the majority of patients with CCA have a short survival time because there are no available effective treatments. Hence, a better understanding regarding CCA metastasis may provide an opportunity to improve the strategies for treatment. A comparison study between the highly metastatic cells and their parental cells is an approach to uncover the molecular mechanisms underlying the metastatic process. In the present study, a lung metastatic CCA cell line, KKU-214L5, was established by the in vivo selection of the tail vein-injected mouse model. KKU-214L5 cells possessed mesenchymal spindle-like morphology with higher migration and invasion abilities in vitro than the parental cells (KKU-214). KKU-214L5 also exhibited extremely aggressive lung colonization in the tail vein-injected metastatic model. Epithelial–mesenchymal transition (EMT) was clearly observed in KKU-214L5 cells. Significant downregulation of epithelial markers (ZO-1 and claudin-1), with unique upregulation of E-cadherin and mesenchymal markers (vimentin, b-catenin, and slug), was observed in KKU-214L5. Increasing MMP-2 and MMP-9 activities and CD147 expression reflected the high invasion activity in KKU-214L5 cells. Suppression of vimentin using siRNA significantly decreased the migration and invasion capabilities of KKU-214L5 to almost the basal levels of the parental cells without any change on the expression levels of other EMT markers and the activities of MMPs. These results suggest that vimentin activation is essential to potentiate the metastatic characters of CCA cells, and suppression of vimentin expression could be a potential strategy to improve the treatment of CCA, a highly metastatic cancer.

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