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Milk fat globule epidermal growth factor 8 serves a novel biomarker of opisthorchiasis-associated cholangiocarcinoma

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Tumor Biology

Abstract

Milk fat globule epidermal growth factor 8 (MFG-E8) is a pleiotropic secreted glycoprotein to play roles in mediating immune tolerance and homeostasis maintenance and enhancing angiogenesis. To evaluate its value as a biomarker in opisthorchiasis-associated cholangiocarcinoma (CCA), the present study investigated MFG-E8 expression kinetics during the tumorigenesis in Opisthorchis viverrini infection-induced CCA, and demonstrated its expression in the tumor tissues of CCA patients and its serum level among them. During the tumorigenesis of CCA, MFG-E8 expression was increased in a time-dependent manner with the pathological processes. Absolutely higher expression of MFG-E8 messenger RNA was detected in the tumor tissues from CCA patients, compared with those in adjacent tissues. Immunobiochemical analysis showed that more than 90 % CCA cases were positive and the positive reaction located in the membrane and cytoplasm of the tumor cells. Moreover, the average serum level in the CCA patients was significantly higher than that in healthy individuals and those with O. viverrini infection or other parasitosis. Correlation analysis of MFG-E8 expression with CCA clinicopathology revealed that a high expression of MFG-E8 protein was significantly bound with a poor differentiation, pathological advanced stage, and metastasis of CCA. The multivariation analysis indicated that MFG-E8 was an independent prognostic factor. In addition, short hairpin RNA-mediated MFG-E8 knockdown in CCA cell line obviously suppressed the cell proliferation. Our results strongly suggested that MFG-E8 is a promising biomarker for the diagnosis, prognosis, and therapy target of opisthorchiasis-associated CCA.

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Acknowledgments

This research was supported by the Grant-in-Aid for Scientific Research (24590504) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Khon Kaen University and the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, through the Health Cluster (SHep-GMS). The authors are thankful to Dr Jianxin Sun, an epidemiologist at Connecticut Department of Public Health, for his critical reading and editing of this manuscript.

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Authors and Affiliations

  1. Department of Parasitology, Gifu University Graduate School of Medicine, Yanagido1-1, Gifu, 501-1194, Japan

    Zhiliang Wu, Thidarut Boonmars, Isao Nagano, Yuzo Takahashi & Yoichi Maekawa

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

    Thidarut Boonmars

  3. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Thidarut Boonmars

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

    Watcharin Loilome & Puangrat Yongvanit

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

    Narong Khuntikeo

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

    Phuangphaka Sadee Nielsen

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

    Chawalit Paorojkul

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

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Wu, Z., Boonmars, T., Nagano, I. et al. Milk fat globule epidermal growth factor 8 serves a novel biomarker of opisthorchiasis-associated cholangiocarcinoma. Tumor Biol. 35, 1985–1995 (2014). https://doi.org/10.1007/s13277-013-1264-3

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