Impact of an altered Wnt1/β-catenin expression on clinicopathology and prognosis in clear cell renal cell carcinoma.
Impact of an altered Wnt1/β-catenin expression on clinicopathology and prognosis in clear cell renal cell carcinoma.
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DOI：
10.3390/ijms140610944
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发表时间：
2013-05-24
影响因子：
5.6
通讯作者：
Bedke J
中科院分区：
文献类型：
--
作者：
Kruck S;Eyrich C;Scharpf M;Sievert KD;Fend F;Stenzl A;Bedke J
在肾细胞癌中，Wnt/β-catenin信号通路中的单个成员最近被发现与肿瘤的进展有关。然而，作为β-连环蛋白调控的关键配体之一，WNT1在肾癌中的作用目前尚不清楚。因此，我们从临床病理、总生存期(OS)和肿瘤特异性生存期(CS)三个方面研究了透明细胞肾癌(CCRCC)中WNT1/β-连环素轴的变化。应用组织芯片免疫组织化学方法检测2 78例肾良性病变及相应的癌旁肾癌组织中WNT1和β-catenin的表达。比较正常肾和肾小管上皮细胞癌的表达积分，包括染色细胞的强度和百分比。数据根据平均表达分数进行分类，并与肿瘤和患者特征相关。生存分析采用Kaplan-Meier和LOG-RANK检验。采用单因素和多因素COX比例风险回归模型，探讨WNT1和β-catenin的独立预后价值。在CCRCC中，高WNT1与肿瘤直径、分期和血管侵犯增加相关(p≤0.02)。β-连环蛋白高表达与晚期、血管侵犯和肿瘤坏死有关(p≤0.0 1)。胞浆≤-连环素水平高的患者肿瘤直径、分期、淋巴结转移、分级、血管侵犯和肉瘤样分化程度较高(pβ0.0 1)。在多变量模型中调整后，胞浆β-连环蛋白升高的患者OS(危险比(HR)1.75)和CSS值(HR 2.26)显著降低，但与OS和CSS值无关。CcRCC侵袭性的增加反映在WNT1/β-catenin信号的改变上。细胞质β-连环蛋白被认为是与不良临床病理和生存不良相关的最有希望的候选基因。然而，与其他恶性肿瘤一样，细胞膜β-连环蛋白向细胞质转移，随后核表达增加，不能证明在肾细胞癌中存在这种现象。
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.
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