Expression of Ror2 Mediates Invasive Phenotypes in Renal Cell Carcinoma

Neal R Rasmussen,Pheroze Tamboli,Samira A Brooks,James J Hsieh,Adam B Sendor,Toni K Choueiri,Eric M Wallen,Zufan Debebe,A Ari Hakimi,Peter Hinds,Catherine Simpson,Tricia M Wright,A Rose Brannon,Jacqueline L Norris,William P Janzen,W Kimryn Rathmell,Jodi K Maranchie,Daotai Nie

doi:10.1371/journal.pone.0116101

Abstract

Ror2 is a Wnt ligand receptor that is overexpressed in a variety of tumors including clear cell renal cell carcinoma (ccRCC). Here we demonstrate that expression of wild type Ror2 results in increased tumorigenic properties in in vitro cell culture and in vivo xenograft models. In addition, Ror2 expression produced positive changes in both cell migration and invasion, which were dependent on matrix metalloprotease 2 (MMP2) activity. Mutations in key regions of the kinase domain of Ror2 resulted in the abrogation of increased tumor growth, cell migration, and cell invasion observed with expression of wild-type Ror2. Finally, we examined Ror2 expression as a prognostic biomarker for ccRCC utilizing the TCGA ccRCC dataset. High expression of Ror2 showed a significant correlation with higher clinical stage, nuclear grade, and tumor stage. Furthermore, high expression of Ror2 in ccRCC patients correlated with significant lower overall survival, cancer specific survival, and recurrence free survival. Together, these findings suggest that Ror2 plays a central role in influencing the ccRCC phenotype, and can be considered as a negative prognostic biomarker and potential therapeutic target in this cancer.

Highlights

Renal cell carcinoma (RCC) remains a growing problem worldwide, as its incidence and mortality rate continue to climb steadily at,2–3% per decade [1]
We explored the effects of receptor 2 (Ror2) overexpression in tumor xenograft growth, and in The Cancer Genome Atlas (TCGA) clear cell renal cell carcinoma (ccRCC) tumor datasets to determine how Ror2 expression related to clinical outcomes
Prior work in RCC has shown that suppression of Ror2 with shRNA in RCC cells orthotopically injected into the kidney resulted in a dramatic reduction of tumor growth in vivo [4]

Summary

Introduction

Renal cell carcinoma (RCC) remains a growing problem worldwide, as its incidence and mortality rate continue to climb steadily at ,2–3% per decade [1]. In the United States in 2013, it is estimated there will be over 65,000 new cases and 13,000 deaths, with nearly one-third of these patients presenting with metastatic RCC [2]. For those patients with metastases upon diagnosis, the 5-year survival rate remains only 5–10% [1, 3]. RCC consists of several subtypes, the most prevalent being clear cell renal cell carcinoma (ccRCC), which accounts for ,70% of cases. The advent of targeted therapeutics have improved the outlook for ccRCC patients, yet their efficacy remains limited mainly to improvements in progression free survival as opposed to overall survival. There is an urgent necessity to identify novel therapeutic targets that contribute to tumor progression and have the potential to serve as prognostic biomarkers in ccRCC

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Results

Conclusion