Down-Regulated miR-30a in Clear Cell Renal Cell Carcinoma Correlated with Tumor Hematogenous Metastasis by Targeting Angiogenesis-Specific DLL4.
Down-Regulated miR-30a in Clear Cell Renal Cell Carcinoma Correlated with Tumor Hematogenous Metastasis by Targeting Angiogenesis-Specific DLL4.
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通过靶向血管生成特异性 DLL4 下调透明细胞肾细胞癌中的 miR-30a 与肿瘤血行转移相关
DOI：
10.1371/journal.pone.0067294
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zheng T
中科院分区：
文献类型：
--
作者：
Huang QB;Ma X;Zhang X;Liu SW;Ai Q;Shi TP;Zhang Y;Gao Y;Fan Y;Ni D;Wang BJ;Li HZ;Zheng T
背景内皮细胞DLL 4在肿瘤血管生成中起重要作用，是肿瘤侵袭性生长和转移所必需的。然而，DLL 4在透明细胞肾细胞癌（ccRCC）中的调节尚未被系统地阐明。方法我们进行生物信息学分析以探索靶向DLL 4的miRNAs。选择miR-30 a作为代表以验证其在内皮细胞中的功能关联。采用实时荧光定量PCR检测90例ccRCC和28例非癌旁组织中DLL 4和成熟miR-30 a的表达。最后，miR-30 a的表达与DLL 4表达、肿瘤特征（转移状况和微血管密度）和患者无转移生存期相关。分别进行单因素和多因素分析，筛选与血行转移相关的危险因素。主要发现miR-30 a负调控DLL 4并抑制内皮细胞的增殖和迁移。DLL 4在ccRCC中上调，并且在血行转移病例中进一步增加，而miR-30 a在肿瘤组织中下调，并且在血行转移ccRCC中进一步降低（学生t检验，所有p<0.05）。此外，miR-30 a的表达与DLL 4的表达和微血管密度呈负相关（线性相关分析，均p<0.05）。低水平的miR-30 a也表明发生转移的可能性更高（对数秩检验，p = 0.010）。 最重要的是，通过单变量分析和二元逻辑回归模型，miR-30 a表达是ccRCC血行转移的独立预测因子（均p<0.05）。结论miR-30 a在ccRCC中表达下调，可能通过靶向血管生成特异性DLL 4增加微血管密度，从而促进肿瘤血行转移。
Background Endothelial DLL4 plays an important role in controlling of tumor angiogenesis, which is required for tumor invasive growth and metastasis. However, the regulation of DLL4 in clear cell renal cell carcinoma (ccRCC) has not yet been systematically elucidated. Methodology We performed bioinformatical analysis to explore miRNAs targeting DLL4. miR-30a was selected as a representative to validate its functional association in endothelial cell. Then, the expressions of DLL4 and mature miR-30a from 90 cases of ccRCC and 28 cases of nonmatched adjacent non-tumor tissues were measured by quantitative real-time PCR. Finally, the expression of miR-30a was correlated with DLL4 expression, tumor features (metastatic condition and microvessel density), and patient metastasis-free survival. The univariate and multivariate analyses were performed to select the risk factors associated with hematogenous metastasis, respectively. Principal Findings miR-30a negatively regulated DLL4 and inhibited the proliferation and migration of endothelial cells. DLL4 was up-regulated in ccRCC and further increased in hematogenous metastatic cases, while miR-30a was down-regulated in tumor tissues and further decreased in hematogenous metastatic ccRCC (student t test, all p<0.05). Additionally, expression of miR-30a was inversely correlated with expression of DLL4 and microvessel density (linear correlation analysis, both p<0.05). Low-level miR-30a also indicated a higher probability of developing metastasis (log-rank test, p = 0.010). Most importantly, miR-30a expression was an independent predictor of ccRCC hematogenous metastasis by the univariate analysis and binary logistic regression model (both p<0.05). Conclusions Down-regulated miR-30a in ccRCC was associated with tumor hematogenous metastasis through increasing microvessel density by targeting angiogenesis-specific DLL4.
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影响因子：
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作者：
Ai Q;Ma X;Huang Q;Liu S;Shi T;Zhang C;Zhu M;Zhang Y;Wang B;Ni D;Li H;Zheng T;Zhang X
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