Abstract
In renal cell carcinoma (RCC), single members of the Wnt/β-catenin signaling cascade were recently identified to contribute to cancer progression. However, the role of Wnt1, one of the key ligands in β-catenin regulation, is currently unknown in RCC. Therefore, alterations of the Wnt1/β-catenin axis in clear cell RCC (ccRCC) were examined with regard to clinicopathology, overall survival (OS) and cancer specific survival (CSS). Corresponding ccRCCs and benign renal tissue were analyzed in 278 patients for Wnt1 and β-catenin expression by immunohistochemistry in tissue microarrays. Expression scores, including intensity and percentage of stained cells, were compared between normal kidney and ccRCCs. Data was categorized according to mean expression scores and correlated to tumor and patients’ characteristics. Survival was analyzed according to the Kaplan-Meier and log-rank test. Univariable and multivariable Cox proportional hazard regression models were used to explore the independent prognostic value of Wnt1 and β-catenin. In ccRCCs, high Wnt1 was associated with increased tumor diameter, stage and vascular invasion (p ≤ 0.02). High membranous β-catenin was associated with advanced stage, vascular invasion and tumor necrosis (p ≤ 0.01). Higher diameter, stage, node involvement, grade, vascular invasion and sarcomatoid differentiation (p ≤ 0.01) were found in patients with high cytoplasmic β-catenin. Patients with a high cytoplasmic β-catenin had a significantly reduced OS (hazard ratio (HR) 1.75) and CSS (HR 2.26), which was not independently associated with OS and CSS after adjustment in the multivariable model. Increased ccRCC aggressiveness was reflected by an altered Wnt1/β-catenin signaling. Cytoplasmic β-catenin was identified as the most promising candidate associated with unfavorable clinicopathology and impaired survival. Nevertheless, the shift of membranous β-catenin to the cytoplasm with a subsequently increased nuclear expression, as shown for other malignancies, could not be demonstrated to be present in ccRCC.
Highlights
64,770 new diagnoses of kidney cancer are made each year, resulting in over13,570 deaths reported in the United States, with a growing trend in 2012 [1]
Lymph node involvement was present in 13 patients (4.7%), and 39 (14.0%) patients had evidence of distant metastatic disease
The Tissue Microarray (TMA) slides were prepared with a core size of 1.0 mm; all patient probes were assembled as triplets, as previously described [40]
Summary
64,770 new diagnoses of kidney cancer are made each year, resulting in over. Comprehensive investigations using genetic, epigenetic, transcriptomic or proteomic profiling elucidated β-catenin activation via canonical Wnt signaling as the central effector of cancer progression and metastasis, the significance of oncogenic signaling via Wnt ligands and β-catenin remains controversial in renal cancer [11]. In this context, the Wnt ligand, the first member of Wnt family proteins, does play a key role in the induction of kidney morphogenesis, and seems to participate in renal tumorigenesis [16,17]. This study addresses alterations in the Wnt1/β-catenin signal axis for potential future diagnostic and therapeutic approaches in ccRCC
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