ROR2 inhibits the proliferation of gastric carcinoma cells via activation of non‑canonical Wnt signaling

Yan,Likun; Du,Qingguo; Yao,Jianfeng; Liu,Ruiting

doi:10.3892/etm.2016.3883

ROR2 inhibits the proliferation of gastric carcinoma cells via activation of non‑canonical Wnt signaling

Authors:
- Likun Yan
- Qingguo Du
- Jianfeng Yao
- Ruiting Liu
View Affiliations

Affiliations: Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
Published online on: November 8, 2016 https://doi.org/10.3892/etm.2016.3883
Pages: 4128-4134

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gastric carcinoma is one of the most common human cancers and has a poor prognosis. Receptor tyrosine kinase‑like orphan receptor 2 (ROR2), which is a non‑canonical receptor of the Wnt signaling pathway, has been reported to be deregulated in numerous types of human cancers, including gastric carcinoma. However, the exact role of ROR2 in the regulation of the malignant phenotypes of gastric carcinoma, as well as the underlying molecular mechanism, remains largely unclear. The present study demonstrated that ROR2 was recurrently downregulated in gastric carcinoma tissues, as compared with their matched adjacent normal tissues. Furthermore, the expression levels of ROR2 were reduced in several common gastric carcinoma cell lines, as compared with normal gastric epithelial cells. Gastric carcinoma cells were transfected with ROR2 plasmids, and it was demonstrated that restoration of ROR2 expression significantly inhibited the proliferation and induced the apoptosis of gastric carcinoma cells by a Wnt5a‑independent mechanism. In addition, it was observed that ROR2‑overexpressing cells accumulated in the G0/G1 phase; thus suggesting that overexpression of ROR2 induced cell cycle arrest at the G0/G1 phase. An investigation of the underlying mechanism demonstrated that activation of the non‑canonical Wnt signaling pathway inhibited canonical Wnt signal transduction, as demonstrated by the decreased level of β‑catenin in nuclei, as well as the reduced expression levels of c‑Myc. The results of the present study indicated a tumor suppressive role for ROR2 in gastric carcinoma growth in vitro, and suggested that ROR2 may be used as a molecular target for the treatment of gastric carcinoma.

View Figures

View References

1	Shi J, Qu YP and Hou P: Pathogenetic mechanisms in gastric cancer. World J Gastroenterol. 20:13804–13819. 2014. View Article : Google Scholar : PubMed/NCBI
2	Piazuelo MB and Correa P: Gastric cancer: Overview. Colomb Med (Cali). 44:192–201. 2013.PubMed/NCBI
3	Li Z, Lei H, Luo M, Wang Y, Dong L, Ma Y, Liu C, Song W, Wang F, Zhang J, et al: DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer. Gastric Cancer. 18:43–54. 2014. View Article : Google Scholar : PubMed/NCBI
4	Qiu T, Zhou X, Wang J, Du Y, Xu J, Huang Z, Zhu W, Shu Y and Liu P: MiR-145, miR-133a and miR-133b inhibit proliferation, migration, invasion and cell cycle progression via targeting transcription factor Sp1 in gastric cancer. FEBS Lett. 588:1168–1177. 2014. View Article : Google Scholar : PubMed/NCBI
5	Ford CE, Ma SS Qian, Quadir A and Ward RL: The dual role of the novel Wnt receptor tyrosine kinase, ROR2, in human carcinogenesis. Int J Cancer. 133:779–787. 2013. View Article : Google Scholar : PubMed/NCBI
6	Sundaram MV: Canonical RTK-Ras-ERK signaling and related alternative pathways. WormBook. 1–38. 2013. View Article : Google Scholar : PubMed/NCBI
7	Jimenez G, Shvartsman SY and Paroush Z: The Capicua repressor-a general sensor of RTK signaling in development and disease. J Cell Sci. 125:1383–1391. 2012. View Article : Google Scholar : PubMed/NCBI
8	Batchu SN and Korshunov VA: Novel tyrosine kinase signaling pathways: Implications in vascular remodeling. Curr Opin Nephrol Hypertens. 21:122–127. 2012. View Article : Google Scholar : PubMed/NCBI
9	Enomoto M, Hayakawa S, Itsukushima S, Ren DY, Matsuo M, Tamada K, Oneyama C, Okada M, Takumi T, Nishita M and Minami Y: Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling. Oncogene. 28:3197–3208. 2009. View Article : Google Scholar : PubMed/NCBI
10	Li L, Ying J, Tong X, Zhong L, Su X, Xiang T, Shu X, Rong R, Xiong L, Li H, et al: Epigenetic identification of receptor tyrosine kinase-like orphan receptor 2 as a functional tumor suppressor inhibiting β-catenin and AKT signaling but frequently methylated in common carcinomas. Cell Mol Life Sci. 71:2179–2192. 2014. View Article : Google Scholar : PubMed/NCBI
11	Lu BJ, Wang YQ, Wei XJ, Rong LQ, Wei D, Yan CM, Wang DJ and Sun JY: Expression of WNT-5a and ROR2 correlates with disease severity in osteosarcoma. Mol Med Rep. 5:1033–1036. 2012.PubMed/NCBI
12	Wright TM, Brannon AR, Gordan JD, Mikels AJ, Mitchell C, Chen S, Espinosa I, van de Rijn M, Pruthi R, Wallen E, et al: Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma. Oncogene. 28:2513–2523. 2009. View Article : Google Scholar : PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
14	Katoh M: WNT signaling pathway and stem cell signaling network. Clin Cancer Res. 13:4042–4045. 2007. View Article : Google Scholar : PubMed/NCBI
15	O'Connell MP, Fiori JL, Xu M, Carter AD, Frank BP, Camilli TC, French AD, Dissanayake SK, Indig FE, Bernier M, et al: The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma. Oncogene. 29:34–44. 2010. View Article : Google Scholar : PubMed/NCBI
16	Green J, Nusse R and van Amerongen R: The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harb Perspect Biol. 6:2014. View Article : Google Scholar : PubMed/NCBI
17	Heo SH, Jeong ES, Lee KS, Seo JH, Jeong DG, Won YS, Kwon HJ, Kim HC, Kim DY and Choi YK: Canonical Wnt signaling pathway plays an essential role in N-methyl-N-nitrosurea induced gastric tumorigenesis of mice. J Vet Med Sci. 75:299–307. 2013. View Article : Google Scholar : PubMed/NCBI
18	Stricker S and Mundlos S: FGF and ROR2 receptor tyrosine kinase signaling in human skeletal development. Curr Top Dev Biol. 97:179–206. 2011. View Article : Google Scholar : PubMed/NCBI
19	Kobayashi M, Shibuya Y, Takeuchi J, Murata M, Suzuki H, Yokoo S, Umeda M, Minami Y and Komori T: Ror2 expression in squamous cell carcinoma and epithelial dysplasia of the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 107:398–406. 2009. View Article : Google Scholar : PubMed/NCBI
20	Lerner UH and Ohlsson C: The WNT system: Background and its role in bone. J Intern Med. 277:630–649. 2015. View Article : Google Scholar : PubMed/NCBI
21	Jones AE, Price FD, Le Grand F, Soleimani VD, Dick SA, Megeney LA and Rudnicki MA: Wnt/β-catenin controls follistatin signalling to regulate satellite cell myogenic potential. Skelet Muscle. 5:142015. View Article : Google Scholar : PubMed/NCBI
22	He H, Chen K, Wang F, Zhao L, Wan X, Wang L and Mo Z: miR204-5p promotes the adipogenic differentiation of human adipose-derived mesenchymal stem cells by modulating DVL3 expression and suppressing Wnt/beta-catenin signaling. Int J Mol Med. 35:1587–1595. 2015.PubMed/NCBI
23	Chang B, Tessneer KL, McManus J, Liu X, Hahn S, Pasula S, Wu H, Song H, Chen Y, Cai X, et al: Epsin is required for dishevelled stability and Wnt signalling activation in colon cancer development. Nat Commun. 6:63802015. View Article : Google Scholar : PubMed/NCBI
24	Xie J, Zhang Y, Hu X, Lv R, Xiao D, Jiang L and Bao Q: Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer. Med Oncol. 32:1452015. View Article : Google Scholar : PubMed/NCBI
25	Ashihara E, Takada T and Maekawa T: Targeting the canonical Wnt/β-catenin pathway in hematological malignancies. Cancer Sci. 106:665–671. 2015. View Article : Google Scholar : PubMed/NCBI
26	Ilmer M, Boiles AR, Regel I, Yokoi K, Michalski CW, Wistuba II, Rodriguez J, Alt E and Vykoukal J: RSPO2 enhances canonical wnt signaling to confer stemness-associated traits to susceptible pancreatic cancer cells. Cancer Res. 75:1883–1896. 2015. View Article : Google Scholar : PubMed/NCBI
27	Fang F, Zhao WY, Li RK, Yang XM, Li J, Ao JP, Jiang SH, Kong FZ, Tu L, Zhuang C, et al: Silencing of WISP3 suppresses gastric cancer cell proliferation and metastasis and inhibits Wnt/β-catenin signaling. Int J Clin Exp Pathol. 7:6447–6461. 2014.PubMed/NCBI
28	Geng M, Cao YC, Chen YJ, Jiang H, Bi LQ and Liu XH: Loss of Wnt5a and Ror2 protein in hepatocellular carcinoma associated with poor prognosis. World J Gastroenterol. 18:1328–1338. 2012. View Article : Google Scholar : PubMed/NCBI