1] Center for Cervical Cancer Prevention, Department of Research, Tzu Chi General Hospital, Hualien, Taiwan, ROC [2] Institute of Medical Science, Tzu Chi University, Hualien, Taiwan, ROC.
1] Center for Cervical Cancer Prevention, Department of Research, Tzu Chi General Hospital, Hualien, Taiwan, ROC [2] Institute of Medical Science, Tzu Chi University, Hualien, Taiwan, ROC [3] Department of Obstetrics and Gynecology, Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC.
Oncogene. 2014 Jul 10;33(28):3636-47. doi: 10.1038/onc.2013.335. Epub 2013 Sep 16.
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.
miR-126 是一种内皮细胞特异性 microRNA，对于胚胎发育过程中维持血管完整性至关重要。其在肿瘤血管生成中的作用在癌症基质中尚不清楚。本研究探讨了 miR-126 在宫颈癌发生过程中的时空表达及其作用。研究发现，miR-126 主要在子宫颈的基质内皮细胞中表达。在细胞共培养模型中，这种下调被重现，即宫颈癌细胞和成纤维细胞的相互作用诱导人脐静脉内皮细胞中 miR-126 的下调，导致管形成增加。共注射人宫颈的癌症相关成纤维细胞增强了宫颈癌细胞的致瘤性，增加了肿瘤血管中的微血管密度和染料保留。与血管生成相关的是，这些异种移植瘤中宿主来源的 miR-126 逐渐下调，而在共注射中补充 miR-126 前体则抑制了血管生成和肿瘤生长。一种促血管生成基因肾上腺髓质素（ADM）在宫颈癌基质中被发现上调，主要定位于血管和淋巴管中，被鉴定为 miR-126 在原位癌到侵袭阶段抑制的靶基因。该研究表明，癌症基质的相互作用诱导了 miR-126 的抑制和 ADM 的上调，以及可能的其他促血管生成因子的上调，从而促进了宫颈癌的血管生成和侵袭生长。
