Bladder cancer is the fourth most common cancer in men and the most common malignancy of the urinary tract. Bladder cancers detected at an early stage have a very high five-year survival rate, but when detected after local metastasis the rate is only about 50%. Our group recently reported a positive correlation between the expression of Wnt5a, a member of the Wnt proteins family, and histopathological grade and stage of urothelial carcinoma (UC). The objective of this study was to analyze UC cases reported in Athens, Ohio and investigate the major components of Wnt5a / planar cell polarity (PCP) signaling pathway in UC human tissue samples and UC cell lines.Formalin fixed and paraffin embedded transurethral resection tissues were immunostained for Wnt5a, Ror-2, CTHRC1 and E-cadherin. In addition, in vitro studies using UC cell lines were investigated for Wnt5a/PCP signaling and epithelial mesenchymal transition (EMT) gene expression. The IHC results showed a correlation between the expression of Wnt5a, Ror2 and CTHRC1 with high histological grade of the tumor, while E-cadherin showed an opposite trend of expression. Real time RT-PCR results showed that RNA expression of the Wnt5a/ PCP pathway genes vary in low and high grade UC cell lines and that the high grade cell lines exhibited signs of EMT.These findings support that Wnt5a-Ror2 signaling plays a role in UC, support the potential use of Wnt5a as a prognostic marker and provide evidence that Wnt5a signaling may be used as an effective molecular target for novel therapeutic tools.

Bladder cancer is the fourth most common cancer in males and the most common malignancy of the urinary tract. According to American Cancer Society 74,690 new cases and 15,580 deaths from bladder cancer are expected for 2014 in the US. Our group recently reported a positive correlation between the expression of Wnt5a, a member of the Wnt proteins family, and histopathological grade and stage of urothelial carcinoma (UC). The objective of the study was to analyze the correlation between the expression of Wnt5a, E‐cadherin, and β‐catenin and histopathological grade of the UC in human tissue samples. The expression of the receptor tyrosine kinase‐like orphan receptor 2 (Ror2) in the tumor as a mechanism of Wnt5a in the metastatic process was also exploredTissue samples were obtained via transurethral resection for diagnostic purposes, formalin fixed and paraffin embedded. Wnt5a, E‐cadherin, β‐catenin, and Ror‐2 expression was characterized in UC samples using immunohistochemistry (IHC). The histopathological grade of each sample was determined using H&E stained sections and applying International Society of Urological Pathology (ISUP) criteria.The IHC results show that low grade tumors show strong staining for E‐cadherin and β‐catenin and weak staining for Wnt5a while, high grade tumors show opposite result. Interestingly, high grade tumors that show invasion into the muscularis propria show strong immunostaining for both Wnt5a and Ror2 while in noninvasive tumors a weak staining for Ror2 was detected.These results are in agreement with previous reports from our laboratory and support the potential application of Wnt5a as a prognostic marker for UC. Based on our results, Wnt5a‐Ror2 signaling may play a role in the invasiveness of UC.