Zhang Xinchen, Guo Gordon, Wang Guang, Zhao Jinyao, Wang Bo, Yu Xiaotang, Ding Yanfang
Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
Department of Radiation Oncology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
Mol Med Rep. 2015 Dec;12(6):8021-31. doi: 10.3892/mmr.2015.4485. Epub 2015 Oct 26.
Improved insight into the molecular and genetic profile of different types of epithelial ovarian cancer (EOC) is required for understanding the carcinogenesis of EOC and may potentially be exploited by future targeted therapies. The aim of the present study was to identify a unique microRNA (miRNA) patterns and key miRNAs, which may assist in predicting progression and prognosis in high‑grade serous carcinoma (HGSC) and clear cell carcinoma (CCC). To identify unique miRNA patterns associated with HGSC and CCC, a miRNA microarray was performed using Chinese tumor bank specimens of patients with HGSC or CCC in a retrospective analysis. The expression levels of four deregulated miRNAs were further validated using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) in an external cohort of 42 cases of HGSC and 36 cases of CCC. Kaplan‑Meier analysis was performed to analyze the correlation between the expression levels of the four miRNAs and patient prognosis. Among these validated miRNAs, miR‑510 was further examined in another cohort of normal ovarian tissues, as well as the HGSC, low‑grade serous carcinoma (LGSC) and CCC specimens using RT‑qPCR and in situ hybridization. The results revealed that, of the 768 miRNAs analyzed in the microarray, 33 and 50 miRNAs were significantly upregulated and downregulated, respectively, with at least a 2‑fold difference in HGSC, compared with CCC. The quantitative analysis demonstrated that miR‑510 and miR‑129‑3p were significantly downregulated, and that miR‑483‑5p and miR‑miR‑449a were significantly upregulated in CCC, compared with HGSC (P<0.05), which was consistent with the microarray results. Kaplan‑Meier analysis revealed low expression levels of miR‑510 and low expression levels of miR‑129‑3p, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymphatic metastasis and that HGSC was significantly associated with the poorer overall survival rates (P<0.05). The expression of miR‑510 was significantly higher in the LGSC and CCC tissues, compared with the HGSC and normal ovarian tissues. The results of the present study suggested that different subtypes of EOC have specific miRNA signatures, and that miR‑510 may be involved differently in HGSC and CCC. Thus, miR‑510 and miR‑129‑3p may be considered as potential novel candidate clinical biomarkers for predicting the outcome of EOC.
为了深入了解不同类型上皮性卵巢癌（EOC）的分子和基因特征，以理解EOC的致癌机制，并可能为未来的靶向治疗提供依据。本研究的目的是确定独特的微小RNA（miRNA）模式和关键miRNA，这可能有助于预测高级别浆液性癌（HGSC）和透明细胞癌（CCC）的进展和预后。为了确定与HGSC和CCC相关的独特miRNA模式，我们对中国肿瘤库中HGSC或CCC患者的标本进行了miRNA微阵列回顾性分析。在42例HGSC和36例CCC的外部队列中，使用逆转录定量聚合酶链反应（RT-qPCR）进一步验证了4种失调miRNA的表达水平。采用Kaplan-Meier分析来分析这4种miRNA的表达水平与患者预后之间的相关性。在这些经过验证的miRNA中，使用RT-qPCR和原位杂交技术在另一组正常卵巢组织以及HGSC、低级别浆液性癌（LGSC）和CCC标本中进一步检测了miR-510。结果显示，在微阵列分析的768种miRNA中，与CCC相比，HGSC中有33种miRNA显著上调，50种miRNA显著下调，差异至少为2倍。定量分析表明，与HGSC相比，CCC中miR-510和miR-129-3p显著下调，miR-483-5p和miR-449a显著上调（P<0.05），这与微阵列结果一致。Kaplan-Meier分析显示，miR-510低表达、miR-129-3p低表达、国际妇产科联盟（FIGO）分期较晚、有淋巴转移以及HGSC与较差的总生存率显著相关（P<0.05）。与HGSC和正常卵巢组织相比，LGSC和CCC组织中miR-510的表达显著更高。本研究结果表明，EOC的不同亚型具有特定的miRNA特征，并且miR-510在HGSC和CCC中的作用可能不同。因此，miR-510和miR-129-3p可被视为预测EOC预后的潜在新型候选临床生物标志物。
