Nymoen Dag Andre, Slipicevic Ana, Holth Arild, Emilsen Elisabeth, Hetland Falkenthal Thea E, Tropé Claes G, Reich Reuven, Flørenes Vivi Ann, Davidson Ben
Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
Hum Pathol. 2016 Aug;54:74-81. doi: 10.1016/j.humpath.2016.03.010. Epub 2016 Apr 8.
The objective of this study was to analyze the clinical role of 9 microRNAs (miRs) previously found to be overexpressed in ovarian carcinoma effusions compared with primary ovarian carcinomas. High-grade serous carcinoma effusions (n=148) were analyzed for expression of miR-29a, miR-31, miR-99b, miR-182, miR-210, miR-221, miR-222, miR-224, and miR-342 using quantitative polymerase chain reaction. Expression levels were analyzed for association with clinicopathological parameters and survival. miR-29a and miR-31 levels were further assessed for association with protein expression of their targets Stathmin and DNA methyltransferase-3A (DNMT3A) by immunohistochemistry and Western blotting, respectively. miRNA levels were unrelated to clinicopathological parameters. However, higher miR-29a levels were significantly related to longer overall survival in univariate (P=.007) and Cox multivariate survival analysis (P=.045). miR-29a levels were inversely related to those of its target DNMT3A (P=.048), and higher DNMT3A expression was significantly related to poor overall survival in univariate (P=.03) and Cox multivariate (P=.016) survival analysis. In contrast, miR-31 levels were directly related to cytoplasmic phospho-Stathmin expression (P=.029) and unrelated to Stathmin and nuclear phospho-Stathmin, and both Stathmin and phospho-Stathmin expressions were unrelated to survival. miR-29a and its target DNMT3A are novel candidate biomarkers of longer and shorter survival, respectively, in metastatic high-grade serous carcinoma.
本研究的目的是分析9种微小RNA（miR）的临床作用，这些miR先前被发现与原发性卵巢癌相比，在卵巢癌腹水中过表达。使用定量聚合酶链反应分析了148例高级别浆液性癌腹水样本中miR-29a、miR-31、miR-99b、miR-182、miR-210、miR-221、miR-222、miR-224和miR-342的表达情况。分析了表达水平与临床病理参数及生存率的相关性。分别通过免疫组织化学和蛋白质印迹法进一步评估miR-29a和miR-31水平与其靶标Stathmin和DNA甲基转移酶-3A（DNMT3A）蛋白表达的相关性。miRNA水平与临床病理参数无关。然而，在单因素分析（P = 0.007）和Cox多因素生存分析（P = 0.045）中，较高的miR-29a水平与较长的总生存期显著相关。miR-29a水平与其靶标DNMT3A水平呈负相关（P = 0.048），在单因素分析（P = 0.03）和Cox多因素生存分析（P = 0.016）中，较高的DNMT3A表达与较差的总生存期显著相关。相比之下，miR-31水平与细胞质磷酸化Stathmin表达直接相关（P = 0.029），与Stathmin和细胞核磷酸化Stathmin无关，且Stathmin和磷酸化Stathmin的表达均与生存率无关。在转移性高级别浆液性癌中，miR-29a及其靶标DNMT3A分别是生存期较长和较短的新型候选生物标志物。
