Abstract
BackgroundUrothelial carcinoma (UC) patients often bear clinical and genetic heterogeneity, which may differ in management and prognosis. Especially, patients with advanced/metastatic UC generally have a poor prognosis and survive for only few months. The Wnt/β-catenin signaling is found to be highly activated in several cancers, including UC. However, accumulated evidence has shown discordance between the Wnt/β-catenin signaling and UC carcinogenesis. Accordingly, we aim to get a better understanding of the molecular characterization of UC, focusing on the Wnt signaling, which may add value to guiding management more precisely.Patients and MethodsClinical data and pathological features were retrospectively surveyed. The correlations of secreted Frizzled-related protein 2 (SFRP2) immunoexpression with clinicopathological features were analyzed by Pearson’s chi-square test. The Kaplan–Meier method with a log-rank test was employed to plot survival curves. All significant features from the univariate analysis were incorporated into the Cox regression model for multivariate analysis.ResultsFollowing data mining on a transcriptome dataset (GSE31684), we identified that 8 transcripts in relation to the Wnt signaling pathway (GO: 0016055) were significantly upregulated in advanced/metastatic bladder tumors. Among these transcripts, the SFRP2 level showed the most significant upregulation. Additionally, as SFRP2 is a putative Wnt inhibitor and may be expressed by stroma, we were interested in examining the immunoexpression and clinical relevance of stromal and tumoral SFRP2 in our urothelial carcinoma cohorts containing 295 urinary bladder UC (UBUC) and 340 upper urinary tract UC (UTUC) patients. We observed that high SFRP2 expression in stroma but not in tumors is significantly linked to aggressive UC features, including high tumor stage and histological grade, positive nodal metastasis, the presence of vascular and perineural invasion, and high mitotic activity in UBUC and UTUC. Moreover, high stromal SFRP2 expression significantly and independently predicted worse clinical outcomes in UBUC and UTUC. Utilizing bioinformatic analysis, we further noticed that stromal SFRP2 may link epithelial–mesenchymal transition (EMT) to UC progression.ConclusionCollectively, these results imply that stromal SFRP2 may exert oncogenic function beyond its Wnt antagonistic ability, and stromal SFRP2 expression can provide prognostic and therapeutic implications for UC patients.
Highlights
Urothelial carcinoma (UC) is a malignancy derived from the transitional epithelium of the urinary tract, which is known as transitional cell carcinoma
To identify promising genes related to UC progression, a public dataset (GSE31684), incorporating 93 bladder cancer patients who were managed by radical cystectomy, was used for data mining
SFRP1, secreted Frizzled-related protein 2 (SFRP2), and SFRP5 belong to the same subfamily, whose members share homology in their cysteine-rich domain [25]. We found that both the SFRP1 and SFRP2 transcripts are significantly increased in tumors with muscle invasiveness and distal metastasis, but the SFRP2 level showed the most prominent upregulation among all identified transcripts
Summary
Urothelial carcinoma (UC) is a malignancy derived from the transitional epithelium of the urinary tract, which is known as transitional cell carcinoma. UC patients often bear clinical and genetic heterogeneity, which may differ in management and prognosis. For UBUC, 70–80% of patients are non-muscle-invasive bladder cancer (NMIBC) at initial diagnosis, and the standard treatment is transurethral resection of bladder tumor (TURBT) with subsequent intravesical instillation [2]. 20–30% of UBUC patients are initially diagnosed with muscle-invasive bladder cancer (MIBC) or metastatic disease, and radical cystectomy is indicated as the standard therapy [4]. Cisplatin-based postoperative adjuvant chemotherapy is given for advanced/metastatic UBUC or UTUC patients, but the clinical outcomes remain disappointing due to chemoresistance [6]. Since UBUC and UTUC are featured by clinical heterogeneity, the addition of genetic information may improve management and prognosis. Urothelial carcinoma (UC) patients often bear clinical and genetic heterogeneity, which may differ in management and prognosis. The Wnt/b-catenin signaling is found to be highly activated in several cancers, including UC. We aim to get a better understanding of the molecular characterization of UC, focusing on the Wnt signaling, which may add value to guiding management more precisely
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