The chromosome 11q13.3 amplification associated lymph node metastasis is driven by miR-548k through modulating tumor microenvironment.
The chromosome 11q13.3 amplification associated lymph node metastasis is driven by miR-548k through modulating tumor microenvironment.
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DOI：
10.1186/s12943-018-0871-4
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发表时间：
2018-08-21
期刊：
影响因子：
37.3
通讯作者：
Zhan Q
中科院分区：
文献类型：
--
作者：
Zhang W;Hong R;Li L;Wang Y;Du P;Ou Y;Zhao Z;Liu X;Xiao W;Dong D;Wu Q;Chen J;Song Y;Zhan Q
食管鳞状细胞癌淋巴结转移患者的预后仍然很差。阐明LNM相关的基因组改变和潜在的分子机制可能为ESCC治疗提供临床治疗策略。通过对ESCC测序数据的联合分析，全面调查SCNAs，并确定与LNM显著相关的驱动基因。miR-548 k在淋巴管生成和淋巴转移中的作用在体外和体内都得到了验证。分析ESCC组织和血液样本中miR-548 k表达与患者临床病理特征以及预后和诊断之间的关联。在314例ESCC患者的合并队列中，我们发现了76个显著的聚焦区域，包括43个扩增和33个缺失。临床意义分析揭示了一组与LNM相关的基因，其中最常扩增的基因是11q13.3扩增子中的MIR 548 K。miR-548 k过表达可显著促进淋巴管生成和淋巴道转移。此外，我们证明miR-548 k通过ADAMTS 1/VEGFC/VEGFR 3途径促进VEGFC分泌和刺激淋巴管生成来调节肿瘤微环境，同时通过调节KLF 10/EGFR轴来促进转移。更重要的是，我们发现早期ESCC患者血清中miR-548 k和VEGFC的水平显著高于健康献血员，提示miR-548 k和VEGFC作为生物标志物在ESCC早期诊断中有很好的应用前景。我们的研究全面表征了ESCC中的SCNAs，并强调了miR-548 k在促进淋巴转移中的关键作用，其可能被用作ESCC的新诊断和预后标志物。本文的在线版本（10.1186/s12943-018-0871-4）包含补充材料，可供授权用户使用。
The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal. Elucidation of the LNM associated genomic alteration and underlying molecular mechanisms may provide clinical therapeutic strategies for ESCC treatment. Joint analysis of ESCC sequencing data were conducted to comprehensively survey SCNAs and identify driver genes which significantly associated with LNM. The roles of miR-548k in lymphangiogensis and lymphatic metastasis were validated both in vitro and in vivo. ESCC tissue and blood samples were analyzed for association between miR-548k expression and patient clinicopathological features and prognosis and diagnosis. In the pooled cohort of 314 ESCC patients, we found 76 significant focused regions including 43 amplifications and 33 deletions. Clinical implication analysis revealed a panel of genes associated with LNM with the most frequently amplified gene being MIR548K harbored in the 11q13.3 amplicon. Overexpression of miR-548k remarkably promotes lymphangiogenesis and lymphatic metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-548k modulating the tumor microenvironment by promoting VEGFC secretion and stimulating lymphangiogenesis through ADAMTS1/VEGFC/VEGFR3 pathways, while promoting metastasis by regulating KLF10/EGFR axis. Importantly, we found that serum miR-548k and VEGFC of early stage ESCC patients were significantly higher than that in healthy donators, suggesting a promising application of miR-548k and VEGFC as biomarkers in early diagnosis of ESCC. Our study comprehensively characterized SCNAs in ESCC and highlighted the crucial role of miR-548k in promoting lymphatic metastasis, which might be employed as a new diagnostic and prognostic marker for ESCC. The online version of this article (10.1186/s12943-018-0871-4) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
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通讯作者：
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