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KMID : 0624620180510050255
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BMB Reports
2018 Volume.51 No. 5 p.255 ~ p.260
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Inhibition of Wntless/GPR177 suppresses gastric tumorigenesis
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Seo Jae-Sung
Kee Hyun-Jung
Choi Hye-Ji
Lee Jae-Eun
Park Soo-Yeon
Lee Seung-Hyun
Jeong Mi-Hyeon
Guk Ga-Ram
Lee Soo-Yeon
Choi Kyung-Chul
Choi Yoon-Young
Kim Hyun-Ki
Noh Sung-Hoon
Yoon Ho-Geun
Cheong Jae-Ho
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Abstract
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Wntless/GPR177 functions as WNT ligand carrier protein and activator of WNT/β-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/β-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.
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KEYWORD
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Gastric cancer, GPR177, Monoclonal antibody, PDX, WNT signaling
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