title: Milk fat globule epidermal growth factor 8 serves a novel  biomarker of opisthorchiasis-associated cholangiocarcinoma.
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.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wu
authors.forename: Thidarut
authors.initials: T
authors.lastname: Boonmars
authors.forename: Isao
authors.initials: I
authors.lastname: Nagano
authors.forename: Watcharin
authors.initials: W
authors.lastname: Loilome
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
authors.forename: Narong
authors.initials: N
authors.lastname: Khuntikeo
authors.forename: Phuangphaka Sadee
authors.initials: PS
authors.lastname: Nielsen
authors.forename: Chawalit
authors.initials: C
authors.lastname: Paorojkul
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Maekawa
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000032:analysis / Q000096:biosynthesis*; D001650:Bile Duct Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D018281:Cholangiocarcinoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D008894:Milk Proteins / Q000032:analysis / Q000096:biosynthesis*; D009889:Opisthorchiasis / Q000150:complications*; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000954:Antigens, Surface; D014408:Biomarkers, Tumor; C098942:MFGE8 protein, human; D008894:Milk Proteins; D034741:RNA, Small Interfering