Research Center Anatomopathology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
Hum Reprod. 2012 Oct;27(10):3036-45. doi: 10.1093/humrep/des292. Epub 2012 Aug 17.
Which is the role of microRNAs (miRNAs) related to several angiogenesis regulators such as VEGF-A (Vascular endothelial growth factor-A) and TSP-1 (Thrombospondin-1) in endometrial cancer?
A dysregulated expression of miRNAs related to angiogenesis and an increase in the VEGF-A levels were observed in endometrial cancer in comparison with control. The different expression of miRNAs could modulate the expression of angiogenic and antiangiogenic factors, which may play an important role in the pathogenesis of endometrial cancer.
Dysregulated miRNA expression has been previously evaluated in endometrial adenocarcinoma. To the best of our knowledge, there are no studies on the relationship between angiogenic factors and miRNAs in endometrial cancer.
STUDY DESIGN, SIZE, DURATION: Case-control study: 41 patients with histologically proven endometrioid endometrial cancer and 56 women without endometrial cancer.
PARTICIPANTS/MATERIALS, SETTING, METHODS: RNAs isolated from tissue samples were analyzed using the GeneChip miRNA 2.0 Array platform (Affymetrix). TaqMan qRT-PCR was used to assess the expression of the selected miRNAs related to angiogenesis (miR-15b, -16, -17-5p, -20a, -21, -125a, -200b, -210, -214*, -221, -222 and -424), and VEGF-A and TSP-1 mRNAs were assessed by qRT-PCR using SYBR Green. Protein levels were quantified by ELISAs.
Compared with the miRNAs in the control endometrium, eight miRNAs (miR-15b, -17-5p, -20a, -125a, -214*, -221, -222 and -424) were significantly down-regulated and two miRNAs (miR-200b and -210) were significantly up-regulated in the cancerous endometrium. A significant increase in VEGF-A mRNA and protein expression and in TSP-1 protein levels (P <0.01) was observed in endometrial cancer. Moreover, significant inverse correlations between VEGF-A protein levels and miR-20a, -125a, -214*, -221, -222 and -424 were detected. In contrast, a positive correlation was observed between VEGF-A and miR-200b and -210. Furthermore, stage IB endometrial cancer was associated with a higher VEGF-A protein/mRNA ratio and lower miR-214*, -221 and -222 expression in comparison with stage IA.
LIMITATIONS, REASONS FOR CAUTION: Future functional studies (e.g. miRNA inhibition or ectopic overexpression) in cell culture models are needed to confirm the VEGF targeting by the miRNAs found in the present study.
The findings of the present study have potential implications for diagnostics and therapeutics of endometrial carcinoma.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants from the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, PI080185, PI0110091) and Red RECAVA (RD06/0014/0004), by Consellería de Sanidad (AP-141/11) and Consellería de Educación (PROMETEO/2011/027), Generalitat Valenciana, by Beca Fibrinolisis 2009 and Becario 2010, 2011 from Fundación Española de Trombosis y Hemostasia and by the Fundación Investigación Hospital La Fe, Spain. None of the authors have any conflicts of interest.
哪些与血管生成调节剂（如 VEGF-A（血管内皮生长因子-A）和 TSP-1（血栓调节蛋白-1）相关的 microRNAs（miRNAs）在子宫内膜癌中发挥作用？
与对照组相比，子宫内膜癌中观察到 miRNAs 与血管生成相关的表达失调和 VEGF-A 水平增加。miRNAs 的不同表达可能调节血管生成和抗血管生成因子的表达，这可能在子宫内膜癌的发病机制中发挥重要作用。
以前已经评估了子宫内膜腺癌中 miRNA 表达失调。据我们所知，目前尚无关于血管生成因子与子宫内膜癌中 miRNAs 之间关系的研究。
研究设计、规模、持续时间：病例对照研究：41 例组织学证实的子宫内膜样子宫内膜癌患者和 56 例无子宫内膜癌的女性。
参与者/材料、设置、方法：使用 GeneChip miRNA 2.0 Array 平台（Affymetrix）分析从组织样本中分离出的 RNA。使用 TaqMan qRT-PCR 评估与血管生成相关的选定 miRNAs（miR-15b、-16、-17-5p、-20a、-21、-125a、-200b、-210、-214*、-221、-222 和 -424）的表达，并使用 SYBR Green 通过 qRT-PCR 评估 VEGF-A 和 TSP-1 mRNA 的表达。通过 ELISA 定量蛋白质水平。
与对照组子宫内膜中的 miRNA 相比，八种 miRNA（miR-15b、-17-5p、-20a、-125a、-214*、-221、-222 和 -424）在癌症子宫内膜中明显下调，两种 miRNA（miR-200b 和 -210）明显上调。在子宫内膜癌中观察到 VEGF-A mRNA 和蛋白表达显著增加和 TSP-1 蛋白水平增加（P <0.01）。此外，还检测到 VEGF-A 蛋白水平与 miR-20a、-125a、-214*、-221、-222 和 -424 之间存在显著的负相关。相反，VEGF-A 与 miR-200b 和 -210 之间存在正相关。此外，与 IA 期相比，IB 期子宫内膜癌与更高的 VEGF-A 蛋白/RNA 比值和更低的 miR-214*、-221 和 -222 表达相关。
局限性、谨慎的原因：未来需要在细胞培养模型中进行 miRNA 抑制或异位过表达等功能研究，以证实本研究中发现的 miRNAs 对 VEGF 的靶向作用。
本研究的结果对子宫内膜癌的诊断和治疗具有潜在意义。
研究资金/竞争利益：本工作得到了国家科学研究、发展和创新计划（西班牙卡洛斯三世健康研究所、健康研究基金、PI080185、PI0110091）和 RECAVA 网络（RD06/0014/0004）、西班牙瓦伦西亚自治区政府（AP-141/11）和教育部（PROMETEO/2011/027）、西班牙国家血栓和止血基金会的 2009 年纤维蛋白溶解奖学金和 2010 年和 2011 年的 2011 年研究员奖学金以及拉费医院研究基金会的资助。所有作者均无利益冲突。
