title: Serum Dickkopf-1 as a Biomarker for the Diagnosis of Hepatocellular Carcinoma.
abstract: Dickkopf-1 (DKK-1) is a Wnt/β-catenin signaling pathway inhibitor. We investigated whether DKK-1 is related to progression in hepatocellular carcinoma (HCC) cells and HCC patients.
  
  
  
  In vitro reverse-transcription polymerase chain reaction (RT-PCR), wound healing assays, invasion assays, and ELISAs of patient serum samples were employed. The diagnostic accuracy of the serum DKK-1 ELISA was assessed using receiver operating characteristic (ROC) curves and area under ROC (AUC) analyses.
  
  
  
  RT-PCR showed high DKK-1 expression in Hep3B and low in 293 cells. Similarly, the secreted DKK-1 concentration in the culture media was high in Hep3B and low in 293 cells. Wound healing and invasion assays using 293, Huh7, and Hep3B cells showed that DKK-1 overexpression promoted cell migration and invasion, whereas DKK-1 knock-down inhibited them. When serum DKK-1 levels were assessed in 370 participants (217 with HCC and 153 without), it was significantly higher in HCC patients than in control groups (median 1.48 ng/mL vs. 0.90 ng/mL, p<0.001). The optimum DKK-1 cutoff level was 1.01 ng/mL (AUC=0.829; sensitivity 90.7%; specificity 62.0%). Although DKK-1 had a higher AUC than alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) (AUC=0.829 vs. 0.794 and 0.815, respectively), they were statistically similar (all p>0.05). When three biomarkers were combined (DKK-1 plus AFP plus DCP), they showed significantly higher AUC (AUC=0.952) than single marker, DKK-1 plus AFP, or DKK-1 plus DCP (all p<0.001).
  
  
  
  DKK-1 might be a key regulator in HCC progression and a potential therapeutic target in HCC. Serum DKK-1 could complement the diagnostic accuracy of AFP and DCP.
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.
authors.forename: Seung Up
authors.initials: SU
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea. jhpark5277@yuhs.ac.|Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyon-Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.|Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyemi
authors.initials: H
authors.lastname: Kim
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.
authors.forename: Shinhwa
authors.initials: S
authors.lastname: Baek
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.
authors.forename: Beom Kyung
authors.initials: BK
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jong Doo
authors.initials: JD
authors.lastname: Lee
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.|Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. gihankhys@yuhs.ac.
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
mesh_terms: D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000175:diagnosis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000378:metabolism*; D008113:Liver Neoplasms / Q000097:blood / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods*; D012680:Sensitivity and Specificity; D000509:alpha-Fetoproteins / Q000032:analysis / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011498:Protein Precursors; D000509:alpha-Fetoproteins; C008208:acarboxyprothrombin; D011516:Prothrombin
keywords: Dickkopf-1; biomarker; hepatocellular carcinoma