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Platelet-derived growth factor may be a potential diagnostic and prognostic marker for cholangiocarcinoma

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Tumor Biology

Abstract

Our previous report showed that platelet-derived growth factor (PDGF) and related genes were upregulated in a Syrian hamster model and could be detected in all human cholangiocarcinoma (CCA) tissues. We therefore hoped that PDGF could be used as a diagnostic and prognostic marker. We analyzed 78 samples of human CCA and adjacent tissues for PDGF and related gene expression, and localized PDGF protein expression. The mechanism of anti-cancer drugs on PDGF and related genes or proteins in CCA cell lines (OCA17, M156, and KKU100) was studied through MTT cell viability assay, quantitative real-time PCR, and immunoblotting. Mutagenesis of the PDGFRA coding region was analyzed. Moreover, the PDGFRA in sera of CCA patients and healthy controls was investigated. PDGFA was found to be upregulated in CCA tissue (84.6 %). Positive PDGFA immunohistochemical staining was significantly correlated with status (P = 0.000), stage of CCA (P = 0.013), metastasis (P = 0.017), and short survival rate (P = 0.005), and the multivariate analysis confirmed that PDGFA positive immunostaining had a higher likelihood of the risk of death (HR = 2.907, P = 0.016). For DNA point mutation of the PDGFRA sequence, silent mutations were found at tyrosine kinase 2 V824V (exon 18) and A603A (exon 13), and a missense mutation in S478P (exon 10); there was only a missense mutation in S478P (29 %) that has significant correlation with the histopathological grading (P = 0.037) and positive immunoreactive PDGFA (P = 0.021). In vitro cell line study by immunowestern blotting found that sunitinib malate had an inhibitory effect on the PDGFA pathway by decreasing p-PDGFRA, AKT, and p-AKT expression. The serum level of PDGFA in CCA patients was significantly higher than those of healthy control by 1.4-fold (P = 0.014). The present results suggest that PDGFA and PDGFRA may be used for CCA prognosis and/or as diagnostic candidate markers.

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Acknowledgements

This work was supported by a grant from the Thailand Research Fund through the Royal Golden Jubilee PhD program (Grant No. PHD/0139/2551) to Miss Sirintip Boonjaraspinyo and Associate Professor Thidarut Boonmars; a Grant-in-Aid for Scientific Research (24590504) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and a grant from the Office of the Higher Education Commission and the National Research University Project, Faculty of Medicine (Grant No. I54325), Khon Kaen University, Thailand. We also are grateful to the Department of Parasitology, the Liver Fluke and Cholangiocarcinoma Research Center, the Animal Experimental Unit, the Department of Research Affairs (AS54301), and the Faculty of Medicine, Khon Kaen University. We would also like to thank the Department of Parasitology, Graduate School of Medicine, Gifu University, for their support.

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Authors and Affiliations

  1. Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Sirintip Boonjaraspinyo, Thidarut Boonmars, Paiboon Sithithaworn & Somchai Pinlaor

  2. Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, 40002, Thailand

    Sirintip Boonjaraspinyo, Thidarut Boonmars, Watcharin Loilome, Paiboon Sithithaworn, Somchai Pinlaor, Puangrat Yongvanit, Chawalit Pairojkul & Narong Khuntikeo

  3. Department of Parasitology, Graduate School of Medicine, Gifu University, Gifu, 501-1194, Japan

    Sirintip Boonjaraspinyo, Zhiliang Wu & Isao Nagano

  4. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Watcharin Loilome & Puangrat Yongvanit

  5. Division of Clinical Immunology, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Phuangphaka Sadee Nielsen

  6. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Chawalit Pairojkul

  7. Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Narong Khuntikeo

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  1. Sirintip Boonjaraspinyo
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Correspondence to Thidarut Boonmars or Zhiliang Wu.

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Boonjaraspinyo, S., Boonmars, T., Wu, Z. et al. Platelet-derived growth factor may be a potential diagnostic and prognostic marker for cholangiocarcinoma. Tumor Biol. 33, 1785–1802 (2012). https://doi.org/10.1007/s13277-012-0438-8

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