miR-106a、miR-21在肾细胞癌中的表达及临床意义研究

发布时间：2018-05-25 06:36

本文选题：肾细胞癌 + 血清　；参考：《新疆医科大学》2017年博士论文

【摘要】：目的:通过回顾性分析我中心近10年收治的1005例肾细胞癌患者临床资料,了解新疆地区肾细胞癌患者临床特点、病理类型、种族特征等流行病学特点。检测肾细胞癌患者血清中miR-106a与miR-21的表达水平,分析其与健康人群中的表达差异,评价其能否用于肾细胞癌的早期诊断;同时检测miR-106a、mi R-21在手术前、后的表达水平变化,并研究其与临床病理特征间的相互关系及临床应用价值。方法:回顾性分析2006年1月至2015年12月就诊于我院且行手术治疗的1005例新发肾细胞癌患者的临床和病理学特点,分别对性别构成、发病年龄、城乡分布、民族构成、危险因素、治疗方式、病理特征进行分析。并以2013年2月至2015年2月期间在我中心收集的30例新诊断为肾细胞癌患者的术前血清样本作为实验组,另外收集30例健康体检者的血清样本作为对照组,采用实时荧光定量PCR技术检测各组血清样本中miR-106a、miR-21表达水平,分析其在肾细胞癌及健康人群中的表达是否存在差异。对上述30例实验组患者再对应的收集其术后1个月、6个月血清样本作为本研究的术后组,分别检测各血清样本中术后1个月、6个月miR-106a、mi R-21表达水平,分析其表达水平与术前组间的差异以及与病理特征的相关性。结果:1055例肾细胞癌患者中男性患者占672例(66.9%),女性患者333例(33.1%),男女比例为2.02:1.00;发病年龄12岁~88岁,平均年龄54.2岁,高发年龄为40岁~60岁;城市地区患者人数为806例,农村地区患者人数为199例,城市地区发病率为农村地区的4.1倍;2006年就诊41例(4.1%),2007年就诊55例(5.5%),2008年就诊81例(8.1%),2009年就诊107例(10.6%),2010年就诊115例(11.4%),2011年就诊125例(12.4%),2012年就诊94例(9.4%),2013年就诊111例(11.0%),2014年就诊137例(13.6%),2015年就诊139例(13.8%),按患者就诊年份排序,可见就诊人数逐年升高;民族构成中汉族605例(60.1%),少数民族400例(39.8%),汉族构成比例较少数民族高。不同人口特征肾细胞癌患者的病理类型进行比较,结果显示随着年龄的增长,肾细胞癌患者中透明细胞癌的比例呈上升趋势(p0.05);汉族患者中透明细胞癌所占比例显著高于少数民族患者(p0.05);男性和女性肾细胞癌患者病理类型的差异无统计学意义(p0.05)。城市和乡镇肾细胞癌患者病理类型的差异无统计学意义(p0.05)。城市和乡镇肾细胞癌患者的临床分期和病理分级进行比较,结果显示相对于城市患者,乡镇患者的临床分期较晚,病理分级较高,其差异有统计学意义(p0.05)。肾细胞癌患者根据是否吸烟、是否有高血压和是否有糖尿病等情况分组,比较不同组患者的临床分期和病理分级,结果显示其差异无统计学意义(p0.05),即吸烟、高血压和糖尿病等特征对肾细胞癌患者的临床分期和病理分级无影响。手术方式随年变化趋势可见开放手术比例逐年下降,而腔镜手术比例逐年上升;手术种类随年变化趋势可见根治术比例逐年下降,而保留肾单位手术比例逐年上升;患者住院天数也在随年逐渐下降。肾细胞癌与健康对照组外周血mir-106a、mir-21测定结果显示,肾细胞癌组血清中mir-106a的相对表达量为8.87(2.71~12.68),健康对照组外周血清mir-106a的相对表达量为0.87(0.31~2.13),与对照组相比较,肾细胞癌组血清mir-106a的相对表达量呈明显高表达,两组相对表达量差异具有统计学意义(z=-4.728,p=0.0001);在肾细胞癌组中,mirna-106a表达下调者有4例(13.3%),而表达量上调有26例(86.7%)。肾细胞癌组血清中mir-21的相对表达量为8.49(3.92~16.68),健康对照组中血清mirna-21的相对表达量为0.79(0.69~3.60),肾细胞癌组中mir-21相对表达量与对照组相比,其表达水平明显增高,其相对表达量差异具有统计学意义(z=-4.727,p=0.0001);根据mir-106a的表达量差异来绘制roc曲线,结果显示其曲线下面积(auc)为0.801(95%ci:0.710~0.963,p=0.0001),灵敏度为0.750,特异度为0.814,约登指数为0.564。根据mir-21的表达量差异来绘制roc曲线,结果显示其曲线下面积(auc)为0.854(95%ci:0.786~0.947,p=0.0001),灵敏度为0.795,特异度为0.907,约登指数为0.702,采用mir-106a与mir-106a进行联合检测,其结果显示系列实验中灵敏度下降为0.596,特异度为上升为0.983,约登指数为0.579;平行实验中灵敏度提高为0.949,特异度下降为0.738,约登指数为0.687。进一步检测肾细胞癌患者对应术后1个月、6个月的外周血mir-106a、mir-21表达水平,术后1月组中mir-106a相对表达量为1.12(0.38~2.57),mir-21相对表达量为0.61(0.42~1.07),与健康对照组比较,术后1月组中mir-106a(z=-0.214,p=0.708)及mir-21(z=-1.301,p=0.272)表达水平差异没有统计学意义;与术前组相比,术后1月组mir-106a(z=-4.218,p=0.0001)及mir-21(z=-3.119,p=0.002)表达水平明显下降,其差异具有统计学意义;术后6个月组中mir-106a相对表达量为1.01(0.23~2.44),mir-21相对表达量为0.71(0.39~1.27),与健康对照组比较,术后6月组中miR-106a(Z=-0.232,P=0.874)及miR-21(Z=-1.221,P=0.291)表达水平差异无统计学意义。miR-106a、mi R-21在肾细胞癌患者外周血清的表达与肿瘤的组织病理学分级、临床分期无关(P0.05)。结论:肾细胞癌患者血清中miR-106a和miR-21的表达水平明显上调,ROC曲线分析提示其已经达到临床应用价值,是肾细胞癌可选的分子标志物。血清miR-106a和mi R-21的表达水平在切除肿瘤病灶后均明显下降,并在术后表达水平稳定,提示其有望用于术后随访监测。
[Abstract]:Objective: through a retrospective analysis of the clinical data of 1005 cases of renal cell carcinoma in our center in recent 10 years, the clinical characteristics, pathological types and racial characteristics of renal cell carcinoma in Xinjiang were analyzed, and the expression of miR-106a and miR-21 in the serum of renal cell carcinoma patients was detected and the difference of expression in the healthy population was analyzed. To evaluate whether it can be used in the early diagnosis of renal cell carcinoma, and to detect the changes in the expression level of miR-106a, MI R-21 before and after operation, and to study the relationship between the clinicopathological features and the clinical application value. Methods: a retrospective analysis of 1005 cases of new renal cell carcinoma in our hospital from January 2006 to December 2015 and the operation treatment of renal cell carcinoma was reviewed. The clinical and pathological features of the patients were analyzed in terms of gender composition, age of onset, urban and rural distribution, ethnic composition, risk factors, treatment and pathological features, and 30 newly diagnosed patients with renal cell carcinoma were collected in our center from February 2013 to February 2015 as experimental group, and 30 cases of health were collected. The serum samples of the examiners were used as the control group. The expression of miR-106a and miR-21 in the serum samples of each group was detected by real time fluorescence quantitative PCR. The difference in the expression of the serum samples in the renal cell carcinoma and the healthy population was analyzed. The serum samples of the 30 patients in the experimental group were collected for 1 months after the operation, and the serum samples were taken as this study for 6 months. After operation, the expression level of miR-106a and MI R-21 was detected in 1 months, 6 months after operation, and the correlation between the expression level and the preoperative group and the pathological features were analyzed. Results: 1055 cases of renal cell carcinoma were male 672 cases (66.9%), women 333 cases (33.1%), male and female ratio 2.02:1.00; age 12. ~88 years old, the average age of 54.2 years and the age of 40 years old at the age of 40 years, 806 cases in urban areas, 199 in rural areas, 4.1 times in the urban area, 41 in 2006 (4.1%), 55 in 2007 (5.5%), 81 in 2008 (8.1%), 2009 for 107 cases (10.6%) and 2010 visits in 2010. In 2011, there were 125 cases (12.4%), 94 cases (9.4%) in 2012, 111 cases in 2013 (11%), 137 in 2014 (13.6%), 139 in 2015 (13.8%). According to the year of the patients, the number of patients was increased year by year, 605 (60.1%) in the ethnic group and minority 400 cases (39.8%), and the proportion of Han nationality was higher than that of minority nationalities. The pathological types of the patients with human renal cell carcinoma were compared. The results showed that the proportion of clear cell carcinoma in the patients with renal cell carcinoma increased with age (P0.05), and the proportion of clear cell carcinoma in Han patients was significantly higher than that of ethnic minority patients (P0.05), and the pathological types of renal cell carcinoma in male and female were different. Statistical significance (P0.05). The pathological types of renal cell carcinoma patients in cities and towns were not statistically significant (P0.05). The clinical stages and pathological grades of renal cell carcinoma patients in cities and towns were compared. The results showed that compared with urban patients, the clinical stages of township patients were late, and the pathological grades were higher, and the difference was statistically significant (P0.05 Patients with renal cell carcinoma were divided into groups according to whether they were smoking, whether there were hypertension or whether there was diabetes. The clinical stages and pathological grades of different groups were compared. The results showed that the difference was not statistically significant (P0.05), that is, smoking, hypertension and diabetes had no effect on the clinical staging and pathological classification of patients with renal cell carcinoma. The rate of open operation decreased year by year, and the proportion of endoscopic surgery increased year by year, and the trend of radical operation decreased year by year, while the proportion of kidney preserving operation increased year by year, and the number of hospitalization days decreased gradually. The peripheral blood of renal cell carcinoma and healthy control group was mir-106a, Mir The relative expression of mir-106a in the serum of renal cell carcinoma group was 8.87 (2.71~12.68), and the relative expression of serum mir-106a in the healthy control group was 0.87 (0.31~2.13). Compared with the control group, the relative expression of serum mir-106a in the renal cell carcinoma group was significantly higher than that of the control group. The difference of the relative expression of the two groups was statistically significant, and the difference of the relative expression of the two groups was statistically significant. Z=-4.728 (p=0.0001); in the renal cell carcinoma group, the expression of mirna-106a expression was 4 (13.3%), and the expression was up to 26 (86.7%). The relative expression of miR-21 in the serum of the renal cell carcinoma group was 8.49 (3.92~16.68), the relative expression of miRNA-21 in the healthy control group was 0.79 (0.69~3.60), and the relative expression of miR-21 in the renal cell carcinoma group and the relative expression of miR-21 in the renal cell carcinoma group. The expression level of the control group was significantly higher than that in the control group (z=-4.727, p=0.0001), and the ROC curve was drawn according to the difference of mir-106a expression. The results showed that the area under the curve (AUC) was 0.801 (95%ci:0.710~0.963, p=0.0001), the sensitivity was 0.750, the specificity was 0.814, and the Jordan index was 0.564. based mir-. 21 of the difference in expression to draw the ROC curve, the results show that the area under the curve (AUC) is 0.854 (95%ci:0.786~0.947, p=0.0001), the sensitivity is 0.795, the specificity is 0.907, and the Jordan index is 0.702. The combined detection of mir-106a and mir-106a shows that the sensitivity of the series is 0.596, the specificity rises to 0.983, about 0.983. The index was 0.579, the sensitivity of the parallel experiment was 0.949, the specificity decreased to 0.738, and the mir-106a index was 0.687., and the expression level of mir-106a and miR-21 in the peripheral blood was 1.12 (0.38~2.57) in the January group, and the relative expression of miR-21 was 0.61 (0.42~1.07) in the January group. Compared with the healthy control group, there was no significant difference in the expression level of mir-106a (z=-0.214, p=0.708) and miR-21 (z=-1.301, p=0.272) in the January group. Compared with the pre operation group, the level of mir-106a (z=-4.218, p=0.0001) and miR-21 (z=-3.119, p=0.002) in the January group decreased significantly, and the difference was statistically significant; 6 months after the operation, the difference was statistically significant. The relative expression of 106A was 1.01 (0.23~2.44), and the relative expression of miR-21 was 0.71 (0.39~1.27). Compared with the healthy control group, there was no significant difference in the expression level of miR-106a (Z=-0.232, P=0.874) and miR-21 (Z=-1.221, P=0.291) in the June group, and the expression of the peripheral blood serum and the histopathology of the tumor in the patients with renal cell carcinoma. P0.05. Conclusion: the expression level of miR-106a and miR-21 in the serum of renal cell carcinoma patients is obviously up-regulated. The ROC curve analysis suggests that it has reached clinical application value. It is an optional molecular marker of renal cell carcinoma. The expression level of serum miR-106a and MI R-21 decreased significantly after the tumor resection, and in the postoperative table. The level is stable, suggesting that it is expected to be used for postoperative follow-up monitoring.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.11

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