Pleiotropic Action of Renal Cell Carcinoma-Dysregulated miRNAs on Hypoxia-Related Signaling Pathways
Pleiotropic Action of Renal Cell Carcinoma-Dysregulated miRNAs on Hypoxia-Related Signaling Pathways
复制标题
DOI：
10.1016/j.ajpath.2011.12.030
复制
发表时间：
2012-04-01
影响因子：
6
通讯作者：
Yousef, George M.
中科院分区：
文献类型：
--
作者：
Lichner, Zsuzsanna;Mejia-Guerrero, Salvador;Yousef, George M.
大约 70% 的肾细胞癌 (RCC) 中 von Hippel-Lindau (VHL) 基因丢失；然而，越来越多的证据支持 VHL 表达调节中涉及替代机制，包括 microRNA (miRNA) 的抑制。 miRNA 是小的非编码 RNA 分子，通过与目标 mRNA 结合来调节基因表达。在这项研究中，我们发现在 RCC 病例中失调的 miRNA 可以靶向 RCC 相关信号通路的多个成员。重要的是，VHL 和缺氧诱导因子 1-α 基因均经过实验验证，并且如荧光素酶测定和蛋白质印迹分析所示，很可能是 miR-17-5p 和 miR-224 的直接靶标。我们发现 RCC 标本中 miR-17-5p 与其两个预测靶标 VEGF-A 和 EGLN3 之间以及 miR-224 与其靶标 SMAD4 和 SMAD5 之间呈负相关，这表明下游信号通路也受到透明细胞 RCC 失调 miR 的调节。我们的生物信息学分析结果表明，单个 miRNA 分子可以靶向同一途径的多个成分，并且多个 miRNA 可以靶向同一分子。我们的结果还表明，miRNA 代表了 RCC 病例中 VHL 失活的一种机制，并且可以阐明癌症发病机制的新维度。因此，miRNA 体现了新的潜在治疗靶点，对肿瘤生长和转移潜力均具有显着影响。 （Am J Pathol 2012，180：1675-1687；DOI：10.1016/j.ajpath.2011.12.030）
The von Hippel-Lindau (VHL) gene is lost in similar to 70% of all renal cell carcinomas (RCCs); however, increasing evidence supports the involvement of alternative mechanisms in the regulation of VHL expression, including suppression by microRNAs (miRNAs). miRNAs are small, noncoding RNA molecules that regulate gene expression through binding to target mRNAs. In this study, we found that miRNAs, which are dysregulated in cases of RCC, can target multiple members of RCC-related signaling pathways. Importantly, both VHL and the hypoxia-inducible factor 1-alpha gene are experimentally validated and are likely direct targets of miR-17-5p and miR-224, as shown by both luciferase assay and Western blot analysis. We found a negative correlation between miR-17-5p and its two predicted targets, VEGF-A and EGLN3, and between miR-224 and its targets SMAD4 and SMAD5 in RCC specimens, suggesting that downstream signaling pathways are also modulated by clear cell RCC-dysregulated miRs. Results from our bioinformatics analysis show that a single miRNA molecule can target multiple components of the same pathway and that multiple miRNAs can target the same molecule. Our results also indicate that miRNAs represent a mechanism for the inactivation of VHL in cases of RCC and can elucidate a new dimension in cancer pathogenesis. As such, miRNAs exemplify new potential therapeutic targets with a significant effect on both tumor growth and metastatic potential. (Am J Pathol 2012, 180:1675-1687; DOI: 10.1016/j.ajpath.2011.12.030)