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Arctigenin inhibits cholangiocarcinoma progression by regulating cell migration and cell viability via the N-cadherin and apoptosis pathway

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Abstract

Northeast Thailand has the highest incidence of cholangiocarcinoma (CCA) in the world. The lack of promising diagnostic markers and appropriate therapeutic drugs is the main problem for metastatic stage CCA patients who have a poor prognosis. N-cadherin, a cell adhesion molecule, is usually upregulated in cancers and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT), one of the metastasis processes. Additionally, it has been shown that arctigenin, a seed isolated compound from Arctium lappa, can inhibit cancer cell progression via suppression of N-cadherin pathway. In this study, we investigated the protein expression of N-cadherin and its correlation with clinicopathological data of CCA patients, as well as the impact of arctigenin on KKU-213A and KKU-100 CCA cell lines and its underlying mechanisms. Immunohistochemistry results demonstrated that high expression of N-cadherin was significantly associated with severe CCA stage (p = 0.027), and shorter survival time (p = 0.002) of CCA patients. The mean overall survival times between low and high expression of N-cadherin were 31.6 and 14.8 months, respectively. Wound healing assays showed that arctigenin significantly inhibited CCA cell migration by downregulating N-cadherin whereas upregulating E-cadherin expression. Immunocytochemical staining revealed that arctigenin suppressed the expression of N-cadherin in both CCA cell lines. Furthermore, flow cytometry and western blot analysis revealed that arctigenin significantly reduced CCA cell viability and induced apoptosis via the Bax/Bcl-2/caspase-3 pathway. This research supports the use of N-cadherin as a prognostic marker for CCA and arctigenin as a potential alternative therapy for improving CCA treatment outcomes.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to acknowledge Prof. Ross H Andrews for editing the MS via Publication Clinic KKU, Thailand.

Funding

This research was supported by the Program Management Unit for Human Resources & Institutional Development, Research and Innovation (grant number B05F630053), and grant from Khon Kaen University to A.T. (KKU63).

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Authors and Affiliations

  1. Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand

    Sutthiwan Janthamala & Phongsaran Kimawaha

  2. Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand

    Sutthiwan Janthamala, Apinya Jusakul, Sarinya Kongpetch, Phongsaran Kimawaha, Poramate Klanrit, Watcharin Loilome, Nisana Namwat & Anchalee Techasen

  3. Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand

    Apinya Jusakul

  4. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Sarinya Kongpetch

  5. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Poramate Klanrit, Watcharin Loilome & Nisana Namwat

  6. Department of Clinical Microbiology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand

    Anchalee Techasen

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  1. Sutthiwan Janthamala
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Contributions

SJ, AJ, SK, and AT contribute to the concept and design of the research. SJ performed experiments and procedures. SJ and PhK performed data analysis. AJ, SK, PoK, WL, NN, and AT provided procedures and laboratory techniques. SJ and AT prepared the initial manuscript and figures. AT provided project leadership. All authors read and approved the manuscript, and all data were generated in-house and that no paper mill was used.

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Correspondence to Anchalee Techasen.

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All human specimens and the protocols in this study were approved by the Human Ethics Committee of Khon Kaen University, based on the ethics of human specimen experimentation of the National Research Council of Thailand (HE631304), and informed consents were obtained from each subject before surgery.

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Janthamala, S., Jusakul, A., Kongpetch, S. et al. Arctigenin inhibits cholangiocarcinoma progression by regulating cell migration and cell viability via the N-cadherin and apoptosis pathway. Naunyn-Schmiedeberg's Arch Pharmacol 394, 2049–2059 (2021). https://doi.org/10.1007/s00210-021-02123-0

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