pVHL / HIF调节的CD70表达与透明细胞肾细胞癌中CD27 +淋巴细胞的浸润和可溶性CD27的血清水平升高有关。,Clinical Cancer Research

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pVHL / HIF调节的CD70表达与透明细胞肾细胞癌中CD27 +淋巴细胞的浸润和可溶性CD27的血清水平升高有关。
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2015 Feb 15 , DOI: 10.1158/1078-0432.ccr-14-1425
Melanie Ruf ₁ , Christiane Mittmann ₁ , Anna M. Nowicka ₁ , Arndt Hartmann ₂ , Thomas Hermanns ₃ , Cédric Poyet ₃ , Maries van den Broek ₄ , Tullio Sulser ₃ , Holger Moch ₁ , Peter Schraml ₁

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用途：CD70是TNF配体超家族的成员，已显示在透明细胞肾细胞癌（ccRCC）中经常过表达。CD70上调的机制及其在ccRCC中的作用尚不清楚。实验设计：免疫组化分析了667个RCC和RCC转移中的CD70表达。在组织和细胞系中研究了Von Hippel-Lindau基因（VHL）突变，VHL蛋白（pVHL）的表达模式，缺氧诱导因子（HIF）α和几个HIF靶标，并与CD70过表达相关。进行基因启动子分析以确认CD70为HIF靶基因。对连续的组织切片进行免疫染色，以揭示表达CD70的RCC与对CD70受体（CD27）呈阳性的肿瘤浸润淋巴细胞之间的关系。通过RCC患者的共培养实验和血清分析评估了CD70介导的RCC中可溶性CD27的释放。结果：在80％的ccRCC原发性肿瘤和转移中可见CD70表达升高，并且与pVHL / HIF通路的失调有关。体外分析表明，CD70上调是由HIF驱动的。此外，CD27（+）淋巴细胞优先渗透表达CD70的ccRCC。共培养物中可溶性CD27的CD70依赖性释放可能解释了在表达CD70的ccRCC患者的血清中观察到高的CD27水平。RCC中淋巴细胞浸润和CD70表达的结合与患者预后较差有关。结论：我们的发现表明在ccRCC中，由于pVHL失活，CD70的表达受HIF调节。

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pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma.

PURPOSE: CD70, a member of the TNF ligand superfamily, has been shown frequently overexpressed in clear cell renal cell carcinoma (ccRCC). The mechanisms of CD70's upregulation and its role in ccRCC are unknown. EXPERIMENTAL DESIGN: CD70 expression was immunohistochemically analyzed in 667 RCCs and RCC metastases. Von Hippel-Lindau gene (VHL) mutations, expression patterns of VHL protein (pVHL), hypoxia-inducible factor (HIF) alpha, and several HIF targets were studied in tissues and cell lines and correlated with CD70 overexpression. Gene promoter analysis was performed to confirm CD70 as HIF target gene. Consecutive tissue sections were immunostained to reveal the relation between CD70-expressing RCCs and tumor-infiltrating lymphocytes positive for the CD70 receptor (CD27). CD70-mediated release of soluble CD27 in RCC was assessed by coculture experiments and sera analysis of patients with RCC. RESULTS: Elevated CD70 expression was seen in 80% of primary tumors and metastases of ccRCC and correlated with dysregulation of the pVHL/HIF pathway. In vitro analyses demonstrated that CD70 upregulation is driven by HIF. Furthermore, CD27(+) lymphocytes preferentially infiltrate CD70-expressing ccRCCs. CD70-dependent release of soluble CD27 in cocultures may explain the high CD27 levels observed in sera of patients with CD70-expressing ccRCC. The combination of lymphocyte infiltration and CD70 expression in RCC was associated with worse patient outcome. CONCLUSION: Our findings demonstrate that in ccRCC, CD70 expression is regulated by HIF as a consequence of pVHL inactivation. Increased serum levels of CD27 suggest the existence of CD70-expressing ccRCC, thus representing a potential serum marker for patients suffering from this disease.

更新日期：2017-01-31

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