High ROR2 expression in tumor cells and stroma is correlated with poor prognosis in pancreatic ductal adenocarcinoma.

Jianfei Huang,Shu Zhang,Huijun Zhu,Wei Wang,Zhiwei Wang,Yuhua Lu,Xudong Wang,Xiangjun Fan

doi:10.1038/srep12991

Jianfei Huang, Shu Zhang + Show 6 more

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https://doi.org/10.1038/srep12991

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Abstract

RTK-like orphan receptor 2 (ROR2) is overexpressed in several cancers and has tumorigenic activity. However, the expression of ROR2 and its functional and prognostic significance have yet to be evaluated in pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time polymerase chain reaction was used to characterize the expression of ROR2 mRNA in PDAC, corresponding peritumoral tissues, and PDAC cell lines. Immunohistochemical analysis with tissue microarrays was used to evaluate ROR2 expression in PDAC and to investigate the relationship of this expression to clinicopathological factors and prognosis. The expression of ROR2 mRNA and protein was significantly higher in PDAC than in normal pancreatic tissues. High cytoplasmic ROR2 expression in cancer cells was significantly associated with a primary tumor, distant metastasis, and TNM stage, and high stromal ROR2 expression was significantly associated with regional lymph node metastasis and TNM stage. The Kaplan–Meier method and Cox regression analyses showed that high ROR2 expression in tumor cytoplasm or stromal cells was significantly associated with malignant attributes and reduced survival in PDAC. We present strong evidence that ROR2 could be used as an indicator of poor prognosis and could represent a novel therapeutic target for PDAC.

Highlights

Receptor tyrosine kinases (RTKs) are cell surface receptors that modulate normal cellular processes through ligand-controlled tyrosine kinase activity
It is well known that Wnt signaling is essential for embryonic development and cellular processes, including differentiation, polarity, migration, invasion, adhesion, and survival, all of which are crucial components of tumorigenesis and metastasis
It has been reported that genetic and epigenetic alterations of components of the canonical Wnt signaling pathway are a primary mechanism of cancer development[30]

Summary

Introduction

Receptor tyrosine kinases (RTKs) are cell surface receptors that modulate normal cellular processes through ligand-controlled tyrosine kinase activity. RTKs have been reported to play a significant role in cancer development, and RTKs have been identified as therapeutic targets for certain types of cancer[13]. Several studies have demonstrated that ROR2 acts as a receptor that regulates canonical and noncanonical Wnt signaling and plays a pivotal role in Wnt5a-induced filopodia outgrowth and cell metastasis[16,17,18]. The expression of ROR2 and its clinical characteristics, especially its prognostic role, have yet to be investigated in PDAC. Some authors have reported that ROR2 expression might serve as a convenient prognostic biomarker and a potential therapeutic target for malignant tumors[21,22,23,24], they may have ignored ROR2 protein expression in tumor stromal cells. We further analyzed the clinicopathological attributes of ROR2, including its prognostic significance in PDAC patient survival

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