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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Inhibition of Wntless/GPR177 suppresses gastric tumorigenesis

  • Seo, Jaesung (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Kee, Hyun Jung (Department of Surgery, Yonsei University College of Medicine) ;
  • Choi, Hye Ji (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Lee, Jae Eun (Department of Surgery, Yonsei University College of Medicine) ;
  • Park, Soo-Yeon (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Lee, Seung-Hyun (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Jeong, Mi-Hyeon (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Guk, Garam (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Lee, SooYeon (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Choi, Kyung-Chul (Department of Biomedical Sciences, University of Ulsan College of Medicine) ;
  • Choi, Yoon Young (Department of Surgery, Yonsei University College of Medicine) ;
  • Kim, Hyunki (Department of Pathology, Yonsei University College of Medicine) ;
  • Noh, Sung Hoon (Department of Surgery, Yonsei University College of Medicine) ;
  • Yoon, Ho-Geun (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Cheong, Jae-Ho (Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)
  • Received : 2018.02.26
  • Accepted : 2018.03.20
  • Published : 2018.05.31
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Abstract

Wntless/GPR177 functions as WNT ligand carrier protein and activator of $WNT/{\beta}$-catenin signaling, however, its molecular role in gastric cancer (GC) has remained elusive. We investigated the role of GPR177 in gastric tumorigenesis and provided the therapeutic potential of a clinical development of anti-GPR177 monoclonal antibodies. GPR177 mRNA expression was assessed in GC transcriptome data sets (GSE15459, n = 184; GSE66229, n = 300); protein expression was assessed in independent patient tumor tissues (Yonsei TMA, n = 909). GPR177 expression were associated with unfavorable prognosis [log-rank test, GSE15459 (P = 0.00736), GSE66229 (P = 0.0142), and Yonsei TMA (P = 0.0334)] and identified as an independent risk predictor of clinical outcomes: GSE15459 [hazard ratio (HR) 1.731 (95% confidence interval; CI; 1.103-2.715), P = 0.017], GSE66229 [HR 1.54 (95% CI, 1.10-2.151), P = 0.011], and Yonsei TMA [HR 1.254 (95% CI, 1.049-1.500), P = 0.013]. Either antibody treatment or GPR177 knockdown suppressed proliferation of GC cells and sensitized cells to apoptosis. And also inhibition of GPR177 suppresses in vitro and in vivo tumorogenesis in GC cells and inhibits $WNT/{\beta}$-catenin signaling. Finally, targeting and inhibition of GPR177 with antibody suppressed tumorigenesis in PDX model. Together, these results suggest GPR177 as a novel candidate for prognostic marker as well as a promising target for treatment of GC patients.

Keywords

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