Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer
Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer
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DOI：
10.1038/onc.2013.335
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发表时间：
2014-07-10
期刊：
影响因子：
8
通讯作者：
Chu, T-Y
中科院分区：
文献类型：
--
作者：
Huang, T-H;Chu, T-Y
MIR-126是一种内皮特异的microRNA，在发育过程中维持血管完整性是必不可少的。它在肿瘤间质中的血管生成作用尚不清楚。本研究探讨miR-126在宫颈癌发生过程中的时空表达及其作用。MIR-126主要表达于宫颈间质内皮细胞。在细胞共培养模型中，宫颈癌细胞和成纤维细胞的串扰诱导了人脐静脉内皮细胞miR-126的下调，从而增加了管道的形成。共注射人宫颈癌相关成纤维细胞可增强宫颈癌细胞的致瘤性，增加肿瘤血管中的微血管密度和染料滞留量。与血管生成相关的是，宿主来源的miR-126在这些异种移植瘤中逐渐下调，而在共注射中补充miR-126前体抑制了血管生成和肿瘤生长。促血管生成基因肾上腺髓质素(adrenomedullin，ADM)在宫颈癌间质中表达上调，主要定位于血管和淋巴管，被认为是miR-126在原位癌向侵袭期的抑制靶点。这项研究表明，癌间质串扰诱导miR-126的抑制和ADM的上调，可能还有其他促血管生成因子，以促进宫颈癌的血管生成和侵袭性生长。
miR-126 is an endothelial-specific microRNA essential for maintaining vessel integrity during development. Its role of tumor angiogenesis in cancer stroma is unclear. This study investigated the temporal and spatial expression and the role of miR-126 in the course of cervical carcinogenesis. miR-126 was found to be mainly expressed in the stromal endothelium of the uterine cervix. This downregulation was recapitulated in a cell coculture model, wherein cross talk of cervical cancer cells and fibroblasts induced a downregulation of miR-126 in human umbilical vein endothelial cells, with consequent increase of tube formation. Coinjection of cancer-associated fibroblasts of human cervix enhanced tumorigenesis of cervical cancer cells, with an increase of microvessel density and dye retention in the tumor vasculature. In association with angiogenesis, host-originated miR-126 in these xenograft tumors was progressively downregulated, whereas supplement of the miR-126 precursor in the coinjection suppressed angiogenesis and tumor growth. A proangiogenic gene adrenomedullin (ADM), which was found to be upregulated in the stroma of cervical cancer and which localized mainly in the blood and lymphatic vessels, was identified as a target of inhibition by miR-126 at the carcinoma in situ-to-invasion stage. The study suggests a cancer stroma cross talk induced repression of miR-126 and upregulation of ADM, and probably other proangiogenic factors, to facilitate angiogenesis and invasion growth of cervical cancer.