Inhibition of Wntless/GPR177 suppresses gastric tumorigenesis
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Wntless/GPR177 functions as WNT ligand carrier protein and activator of WNT/-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/-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
Wntless/GPR177 functions as WNT ligand carrier protein and activator of WNT/-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/-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.
참고문헌 (30)
- Tan P, "Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma", Gastroenterology, 149, pp.1153~1162 (2015)[DOI]
- Tan IB, "Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy", Gastroenterology, 141, pp.476~485 (2011)[DOI]
- Corso S, "How Can Gastric Cancer Molecular Profiling Guide Future Therapies?", Trends Mol Med, 22, pp.534~544 (2016)[DOI]
- Bang Y-J, "Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial", The Lancet, 376, pp.687~697 (2010)[DOI]
- Sartore-Bianchi A, "Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12", 13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial, 2016, pp.17, 738~746
- Wilke H, "Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastrooesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial", Lancet Oncol, 15, pp.1224~1235 (2014)[DOI]
- Kahn M, "Can we safely target the WNT pathway?", Nat Rev Drug Discov, 13, pp.513~532 (2014)[DOI]
- Lu D, "Wls promotes the proliferation of breast cancer cells via Wnt signaling", Med Oncol, 32, pp.140~ (2015)[DOI]
- Mao J, "Roles of Wnt", betacatenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment, 2014, pp.5, e1039~
- Clevers H, "Wnt", beta-catenin signaling and disease, 2012, pp.149, 1192~1205
- Anastas JN, "WNT signalling pathways as therapeutic targets in cancer", Nat Rev Cancer, 13, pp.11~26 (2013)[DOI]
- Proffitt KD, "Precise regulation of porcupine activity is required for physiological Wnt signaling", J Biol Chem, 287, pp.34167~34178 (2012)[DOI]
- Voloshanenko O, "Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells", Nat Commun, 4, pp.2610~ (2013)[DOI]
- Banziger C, "Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells", Cell, 125, pp.509~522 (2006)[DOI]
- Bartscherer K, "Secretion of Wnt ligands requires Evi, a conserved transmembrane protein", Cell, 125, pp.523~533 (2006)[DOI]
- Yu J, "WLS retrograde transport to the endoplasmic reticulum during Wnt secretion", Dev Cell, 29, pp.277~291 (2014)[DOI]
- Maruyama EO, "Gpr177 deficiency impairs mammary development and prohibits Wnt-induced tumorigenesis", PLoS One, 8, pp.e56644~ (2013)[DOI]
- Augustin I, "The Wnt secretion protein Evi", Gpr177 promotes glioma tumourigenesis, 2012, pp.4, 38~51
- Barrott J, "Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia", Goltz syndrome, 2011, pp.108, 12752~12757
- Liu J, "Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974", Proc Natl Acad Sci U S A, 110, pp.20224~20229 (2013)[DOI]
- Minn YK, "MicroRNA-200 family members and ZEB2 are associated with brain metastasis in gastric adenocarcinoma", Int J Oncol, 45, pp.2403~2410 (2014)[DOI]
- Lee E, "Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition", Cell Death Dis, 6, pp.e1805~ (2015)[DOI]
- Choi YY, "Establishment and characterisation of patient-derived xenografts as paraclinical models for gastric cancer", Sci Rep, 6, pp.22172~ (2016)[DOI]
- Kim W, "Wnt", beta-catenin signalling: from plasma membrane to nucleus, 2013, pp.450, 9~21
- Fu J, "Gpr177", mouse Wntless is essential for Wnt-mediated craniofacial and brain development, 2011, pp.240, 365~371
- Jin J, "Expression of GPR177 (Wntless", Evi, Dev Dyn, pp.2010, 239[DOI]
- Yu HM, "Expression of Gpr177, a Wnt trafficking regulator, in mouse embryogenesis", Dev Dyn, 239, pp.2102~2109 (2010)[DOI]
- Carpenter AC, "Wnt ligands from the embryonic surface ectoderm regulate 'bimetallic strip' optic cup morphogenesis in mouse", Development, 142, pp.972~982 (2015)[DOI]
- Jiang M, "Gpr177 regulates pulmonary vasculature development", Development, 140, pp.3589~3594 (2013)[DOI]
- Park SY, "Protein serine", threonine phosphatase PPEF-1 suppresses genotoxic stress response via dephosphorylation of PDCD5, 2017, pp.7, 39222~