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Inhibition of Wntless/GPR177 suppresses gastric tumorigenesis
Jaesung Seo1,#, Hyun Jung Kee2,#, Hae-Ji Choi2, Jae Eun Lee2, Soo-Yeon Park1, Seung-Hyun Lee1, Mi-Hyeon Jung1, Garam Guk1, SooYeon Lee1, Kyung-Chul Choi3, Yoon Young Choi2, Hyunki Kim4, Sung Hoon Noh2, Ho-Geun Yoon1,*, Jae-Ho Cheong1,2
1Department of Biochemistry and Molecular Biology and 2Department of Surgery, Yonsei University College of Medicine,
3Department of Biomedical Sciences, University of Ulsan College of Medicine,
4Department of Pathology, Yonsei University College of Medicine
Abstract
Wntless/GPR177 functions as WNT ligand carrier protein and activator of WNT/モ-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/モ-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.
Abstract, Accepted Manuscript(in press) [Submitted on February 26, 2018, Accepted on March 20, 2018]
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