miRNA-17~92基因簇、线粒体融合蛋白2在子宫内膜癌组织中的表达及其临床意义

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目的:探讨miRNA-17~92(miR-17~92)基因簇及线粒体融合蛋白2(MFN2)蛋白在子宫内膜癌(EC)中的表达及其临床意义。方法:收集2008年1月至2014年12月山东第一医科大学第二附属医院72例EC、36例子宫内膜非典型增生患者子宫内膜病变组织及22例因子宫颈上皮内瘤变Ⅲ级行全子宫切除术的正常子宫内膜组织;同时收集所有患者蜡块组织。采用实时荧光定量聚合酶链反应检测各组织中miR-17~92表达水平,免疫组织化学SP法检测各蜡块组织中MFN2蛋白定位及表达水平。分析miR-17~92、MFN2蛋白与EC患者临床病理特征的关系;采用Kaplan-Meier法绘制miR-17~92、MFN2不同水平患者生存曲线,并行log-rank检验;应用Cox比例风险回归模型进行多因素生存分析。结果:miR-17~92在EC、非典型增生及正常子宫内膜组织中相对表达量分别为1.49±0.46、1.01±0.30、0.69±0.20;EC组织中miR-17~92的表达水平高于其他子宫内膜组织,差异均有统计学意义(均n P<0.01)。MFN2蛋白在EC、非典型增生、正常子宫内膜组织中的高表达率分别为20.8%(15/72)、39.4%(13/33)、85.0%(17/20);EC组织中MFN2蛋白高表达率低于其他子宫内膜组织,差异均有统计学意义(均n P<0.012 5)。EC患者中,组织学类型Ⅱ型患者miR-17~92相对表达量高于Ⅰ型患者(n P<0.05),肌层浸润深度≥1/2患者miR-17~92相对表达量高于浸润深度<1/2患者(n P<0.05);组织学类型Ⅰ型患者MFN2蛋白高表达率高于Ⅱ型患者(n P<0.05),国际妇产科联盟(FIGO)分级Ⅰ级患者MFN2蛋白高表达率高于Ⅱ、Ⅲ级患者(n P<0.05)。Kaplan-Meier生存分析显示,按EC患者miR-17~92中位相对表达量(1.421)分组时,低表达组(36例)中位总生存(OS)时间未达到,高表达组(36例)为36个月(95%n CI 32~42个月),两组间OS差异有统计学意义(n P=0.049);MFN2蛋白高表达组(15例)中位OS时间未达到,低表达组(57例)为38个月(95% n CI 33~41个月),两组间OS差异有统计学意义(n P=0.046)。多因素Cox回归分析显示,miR-17~92、MFN2表达水平为EC患者生存的独立影响因素(n HR=3.10,95% n CI 1.36~7.07,n P=0.007;n HR=0.30,95% n CI 0.09~0.99,n P=0.048)。n 结论:EC组织中miR-17~92高表达、MFN2蛋白低表达,二者可能参与了EC的发生、发展,可作为判断EC患者预后的指标。“,”Objective:To explore the expressions of miRNA-17-92 (miR-17-92) cluster and mitofusin 2 (MFN2) protein in endometrial cancer (EC) and their clinical significances.Methods:A total of 72 EC tissues, 36 endometrial lesions of patients with endometrial atypical hyperplasia, and 22 normal endometrial tissues from total hysterectomy for grade Ⅲ cervical intraepithelial neoplasia in the Second Affiliated Hospital of Shandong First Medical University from January 2008 to December 2014 were collected; at the same time, all patients' paraffin-embedded tissues were collected. Real-time quantitative polymerase chain reaction was used to detect the expression level of miR-17-92 in each tissue. Immunohistochemical SP method was used to detect the localization and expression level of MFN2 protein in each paraffin-embedded tissue. The correlation of miR-17-92 and MFN2 protein with clinicopathological features of EC patients was analyzed. Kaplan-Meier method was used to draw survival curve of patients with different miR-17-92 and MFN2 levels, and log-rank test was made; Cox proportional hazard regression model was used for multivariate survival analysis.Results:The relative expression of miR-17-92 in EC, atypical hyperplasia and normal endometrial tissues were 1.49±0.46, 1.01±0.30 and 0.69±0.20, respectively. The expression of miR-17-92 in EC tissues was higher than that in the other endometrial tissues, and the differences were statistically significant (both n P < 0.01). The high-expression rates of MFN2 protein in EC, atypical hyperplasia and normal endometrial tissues were 20.8% (15/72), 39.4% (13/33) and 85.0% (17/20); the high-expression rate of MFN2 protein in EC tissue was lower than that in the other endometrial tissues, and the differences were statistically significant (both n P < 0.012 5). In EC patients, the relative expression of miR-17-92 in patients with histological type Ⅱ was higher than that in patients with histological type Ⅰ ( n P < 0.05); the relative expression of miR-17-92 in patients with myometrial invasion depth ≥1/2 were higher than that in patients with myometrial invasion depth <1/2 ( n P < 0.05). The high-expression rate of MFN2 protein in patients with histological type Ⅰ was higher than that in patients with histological type Ⅱ ( n P < 0.05); the high-expression rate of MFN2 protein in patients with International Federation of Gynecology and Obstetrics (FIGO) grade Ⅰ was higher than that in patients with FIGO grade Ⅱ and Ⅲ ( n P < 0.05). When the EC patients were grouped according to the median relative expression of miR-17-92 (1.421), Kaplan-Meier survival analysis showed that the median overall survival (OS) time of the miR-17-92 low-expression group (36 cases) was not reached, and the high-expression group (36 cases) was 36 months (95% n CI 32-42 months), and the difference in OS between the two groups was statistically significant (n P = 0.049); the median OS time of the MFN2 high-expression group (15 cases) was not reached, and the low-expression group (57 cases) was 38 months (95% n CI 33-41 months), and the difference in OS between the two groups was statistically significant (n P = 0.046). Multivariate Cox regression analysis showed that the expression levels of miR-17-92 and MFN2 were independent influencing factors for the survival of EC patients (n HR = 3.10, 95% n CI 1.36-7.07, n P = 0.007; n HR = 0.30, 95% n CI 0.09-0.99, n P = 0.048).n Conclusion:The high-expression of miR-17-92 and low-expression of MFN2 protein in EC tissues may be involved in the occurrence and development of EC, and they can be used as indicators for judging the prognosis of EC patients.
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