title: Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients.
abstract: Chronic inflammation of gastric mucosa by Helicobacter pylori infection can initiate gastric carcinogenesis. As angiopoietin-like protein 2 (ANGPTL2) mediates inflammation and inflammation-associated carcinogenesis, we investigated the functional and clinical significance of ANGPTL2 in human gastric cancer (GC). SiRNA knockdown studies were performed for the functional assessment of ANGPTL2 in GC cell lines. ANGPTL2 expression was evaluated immunohistochemically in 192 tissue specimens from GC patients. In addition, we screened serum ANGPTL2 levels from 32 GC patients and 23 healthy controls; and validated these results in 194 serum samples from GC patients and 45 healthy controls by ELISA. ANGPTL2 knockdown caused anoikis and inhibited proliferation, invasion and migration in GC cells. ANGPTL2 expression was upregulated in GC tissues compared to normal gastric mucosa; and high ANGPTL2 expression was significantly associated with tumor progression, early recurrence (P = 0.003) and poor prognosis (P = 0.007). Serum ANGPTL2 in GC patients was significantly higher than for healthy controls (P < 0.05), and accurately distinguished GC patients from healthy control (AUC = 0.865). The validation step confirmed significantly higher serum ANGPTL2 levels in GC patients than healthy controls (P < 0.0001). Receiver operating characteristic curves yielded robust AUC value (0.831) accompanied by high sensitivity (73.0%) and specificity (82.2%) in distinguishing GC patients from healthy controls. High serum ANGPTL2, rather than its expression in matched tissues, was significantly associated with tumor progression, and emerged as an independent marker for recurrence (HR: 5.05, P = 0.0004) and prognosis (HR: 3.6, P = 0.01). Serum ANGPTL2 expression is a potential noninvasive biomarker for diagnosis, early recurrence and prognosis of GC patients.
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and Center for Gastrointestinal Research and Center for Epigenetics, Cancer Preventino and Cancer genomics, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246-2017, USA ytoi0725@clin.medic.mie-u.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Takahito
authors.initials: T
authors.lastname: Kitajima
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Shimura
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Imaoka
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Mori
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Masato
authors.initials: M
authors.lastname: Okigami
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and Center for Gastrointestinal Research and Center for Epigenetics, Cancer Preventino and Cancer genomics, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246-2017, USA.
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Okugawa
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Susumu
authors.initials: S
authors.lastname: Saigusa
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohi
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Mohri
authors.affiliation: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Preventino and Cancer genomics, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246-2017, USA ytoi0725@clin.medic.mie-u.ac.jp ajay.goel@baylorhealth.edu.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie 514-8507, Japan and.
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000097:blood* / Q000235:genetics; D023102:Anoikis; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D055088:Early Detection of Cancer; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000097:blood* / Q000175:diagnosis; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D013274:Stomach Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000401:mortality; D055815:Young Adult
chemical_list: C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D014408:Biomarkers, Tumor