Impact of an Altered Wnt1/β-Catenin Expression on Clinicopathology and Prognosis in Clear Cell Renal Cell Carcinoma

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.

The epigenetic landscape of renal cancer

“…The Wnt/β-catenin pathway is frequently disrupted in RCC by promoter methylation of key pathway regulators (FIG. 3a), and unregulated β-catenin activation increases the tumourgenicity of renal cells 74 . In addition, VHL is inactivated in ~11-30% of ccRCC and pRCC by promoter methylation [75][76][77] or by loss of chromosome 3.…”

Impact of E-Cadherin and β-Catenin as Prognostic Factor in Renal Cell Carcinoma with Tumor Thrombus of the Vena Cava

“…Several studies indicate that high β-Catenin- expression is associated with worse clinical and pathological features. It could be shown that high β-Cateninexpression is associated with higher grading [15] and advanced stage, vascular invasion, and tumor necrosis [21]. However, other studies could not prove the correlation with adverse clinical and pathological parameters [18,26,28].…”

“…Krabbe et al [18] could identify an association between reduced β-Catenin-expression and worse RFS and CSS, whereas there are several studies showing no association between β-Catenin-expression and survival [26,28]. Furthermore, there are several studies suggesting a worse prognostic effect of high cytoplasmic β-Catenin expression and worse survival [15,21,22].…”

“…There is evidence that a decreased β-Cateninexpression is associated with worse outcome, displaying the epithelial-mesenchymal transition-process [18]. However, a stabilization and preservation of β-Catenin also promotes proliferation, migration, and invasion in RCC [19,20] and thus is associated with worse survival [15,21,22].…”

miR-124 represses FZD5 to attenuate P-glycoprotein-mediated chemo-resistance in renal cell carcinoma

“…A compelling clinical study validated that the Wnt ligand receptors Frizzled 5 (FZD5) and FZD8 were markedly increased in renal carcinoma samples [13]. Enhanced RCC aggressiveness was reflected in altered Wnt1/β-catenin canonical signaling, and β-catenin was determined to be related to unfavorable clinicopathology and impaired survival [14]. Moreover, the Wnt/β-catenin pathway was identified as exerting functions in inducing P-gp overexpression in chronic myeloid leukemia [15].…”