Department of Obstetrics and Gynecology, Medical Center - University of Freiburg, Freiburg, Germany.
Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Freiburg, Germany.
Oncol Rep. 2017 Aug;38(2):993-1004. doi: 10.3892/or.2017.5717. Epub 2017 Jun 13.
Due to their post-transcriptional regulatory impact on gene expression, microRNAs (miRNA, miRs) influence decisively cellular processes of differentiation, proliferation and apoptosis. In oncogenic pathways various miRNAs exert either oncogenic or tumor suppressor activities in a stage-specific manner. Dysregulation of miRNA expression pattern has been associated with several human cancers including endometrial cancer (EC). In the present study, expression profile alterations of EC associated secreted miRNAs were determined under the microenvironmental stress situations hypoxia and acidosis occurring in tumor progression and metastasis. The potential influence of hypoxia and acidosis vs. control conditions on the expression levels of 24 EC-relevant miRNA types was quantitatively accessed via real-time PCR in three established EC in vitro models. Expression data were analyzed statistically. In vitro application of hypoxia resulted in downregulation of miR-15a, miR-20a, miR-20b and miR-128-1 in Ishikawa cells (type I EC) and upregulation of miR-21 in EFE-184 cells (type I EC). Acidosis triggered upregulation of tumor promoting miR-125b in AN3-CA cell (type II EC), whereas in Ishikawa cells (type I EC) miRNAs with tumor suppressive function were found altered in divergent directions, both up- (let-7a) and down- (miR-22) regulated. Our current findings emphasize the functional importance of secreted miRNAs in the immediate response of EC cells to exogenic stress situations such as the typical tumor epiphenomena hypoxia and acidosis. Focusing on the specific potential of secreted, thus circulating miRNA molecules, alterations in expression levels not only influence intracellular gene expression and signaling cascades, but also transfer the induction of (tumor)biological cellular changes to adjacent cells.
由于它们对基因表达的转录后调节作用，microRNAs（miRNA，miRs）决定性地影响细胞的分化、增殖和凋亡过程。在致癌途径中，各种 miRNA 以特定阶段特异性的方式发挥致癌或肿瘤抑制活性。miRNA 表达谱的失调与包括子宫内膜癌（EC）在内的几种人类癌症有关。在本研究中，在肿瘤进展和转移中发生的微环境应激情况下缺氧和酸中毒下，确定了与 EC 相关的分泌 miRNA 的表达谱改变。通过实时 PCR 在三种已建立的 EC 体外模型中定量评估缺氧和酸中毒与对照条件对 24 种 EC 相关 miRNA 类型表达水平的潜在影响。对表达数据进行了统计学分析。体外应用缺氧导致 Ishikawa 细胞（I 型 EC）中 miR-15a、miR-20a、miR-20b 和 miR-128-1 的下调和 EFE-184 细胞（I 型 EC）中 miR-21 的上调。酸中毒触发 AN3-CA 细胞（II 型 EC）中肿瘤促进 miR-125b 的上调，而 Ishikawa 细胞（I 型 EC）中具有肿瘤抑制功能的 miRNA 则以不同的方向改变，miR-22 被上调，而 let-7a 被下调。我们目前的研究结果强调了分泌 miRNA 在 EC 细胞对外源性应激情况（如典型的肿瘤现象缺氧和酸中毒）的即时反应中的功能重要性。关注分泌的，因此循环的 miRNA 分子的特定潜力，表达水平的改变不仅影响细胞内基因表达和信号级联，而且还将（肿瘤）生物学细胞变化的诱导传递到相邻细胞。
