Survivin在前列腺癌的表达及临床意义的Meta分析

发布时间：2018-06-15 04:14

本文选题：存活素 + 前列腺　；参考：《南方医科大学》2012年硕士论文

【摘要】：研究背景前列腺癌(PCa)是一种严重影响老年男性生活质量及预期寿命的疾病。随着人们生活水平的不断提高,前列腺癌的发病率亦日益增高。在欧洲和北美,其发病率及病死率分别位居男性恶性肿瘤的第2位及第6位。在我国,随着人口老龄化、生活质量的提高,生活方式改变诸多因素,前列腺癌的发病增长率已居泌尿生殖系恶性肿瘤之首。前列腺癌具有潜伏性,发病率高的特点,我国70岁以上男性人群中,高达25%的人患有前列腺癌,但发展到临床癌者仅占极小部分。前列腺癌的主要检测手段是前列腺特异性抗原(PSA),但血清PSA测定有局限性,诊断的敏感性与特异性欠理想,尤其对于检测结果的灰区(4～10ng/ml,),常不易确诊；在前列腺癌的治疗方面,虽然方法较多,但均具有一定的局限性,化疗药物难以进入前列腺癌组织,前列腺癌出现临床症状时多已发生了转移,手术治疗效果差,内分泌治疗虽可改善患者症状,减轻病人痛苦,但对延长生存时间有限。前列腺癌临床治疗的最大难题在于对雄激素非依赖性前列腺癌缺乏有效的治疗方案。分子生物学研究发现去势治疗、放疗及某些化疗药物都是通过诱导前列腺癌细胞凋亡发挥作用。研究表明随着细胞向恶性转变,细胞的凋亡水平呈下降趋势。目前对前列腺癌由雄激素依赖转为雄激素非依赖(AIPC)的形成提出了两种观点：一是雄激素受体(AR)信号的增加促使雄激素受体增加,使AR对低水平雄激素或雌激素敏感增强甚至对雄激素阻断剂敏感。另一种观点认为AIPC的形成是一种与AR无关的信号克服了凋亡,由此认为凋亡信号的阻断是肿瘤继续生存的原因。前列腺癌的生长取决于细胞的增生率和死亡率之间的平衡,凋亡抑制蛋白在前列腺癌的发生中起着重要的作用。Survivin是新近发现的凋亡抑制蛋白(IAP)家族的成员。在众多人类恶性肿瘤中上调表达,并与肿瘤的凋亡、增殖、血管生成及其预后有密切关系,而在成人正常分化组织中不表达。Survivin很可能成为肿瘤诊断和治疗的新靶点。目前,Survivin在前列腺癌中的表达及其意义的相关研究国内外已有文献报道,但结果不尽相同。因此,我们通过查阅大量国内外文献,参考国内外应用免疫组织化学方法(S-P法)检测Survivin在前列腺癌、正常前列腺及前列腺增生组织中表达的研究成果,进一步系统评价Survivin与前列腺癌生物学行为之间的关系,期待为前列腺癌早期诊断提供一种新方法,为判断前列腺癌的生物学行为提供新的手段,为前列腺癌的治疗开辟一种新的途径。目的收集国内外有关应用免疫组织化学方法检测Survivin在前列腺癌、正常前列腺及良性前列腺增生组织中表达的文献,通过Meta分析的方法比较Survivin在正常前列腺(NP)、良性前列腺增生(BPH)和前列腺癌(PCa)组织中的表达,以及Survivin表达强度与前列腺癌(PCa)的临床分期、病理分化、伴随转移是否存在临床意义,旨在系统评价Survivin与前列腺癌的发生、发展等生物学行为的关系,为前列腺癌早期诊断提供一种新方法,为判断前列腺癌的生物学行为提供新的手段,为前列腺癌的治疗开辟一种新的途径。方法 1按系统评价要求制定相应的详细的纳入与排除标准,包括研究对象的特征、干预措施以及结局指标的测量等。 2根据拟定的标准制定出系统、全面的检索策略。计算机检索MEDLINE、 Cochrane Library、CBM、CNKI数字图书馆、万方数据库、维普于(1997.1～2011.6)公开发表的原始文献、会议论文集、毕业论文。采用主题词与自由词相结合的方式,所有检索策略通过多次预检索后确定。用Google等搜索引擎查找互联网上的相关文献,辅以人工检索并进行文献追溯。 3文献的质量评价及数据信息提取：由两位评价者根据QUADAS (quality assessment of diagnostic accuracy studies)条目对纳入研究质量进行独立评价,如遇分歧通过讨论或由第三位研究者协助解决。资料提取内容包括①试验的基本情况、两组标本的基线情况；②试验设计、检查方法、结局测量指标、反应研究质量的指标。 4资料的统计学处理：Revman5.1软件进行数据处理和分析。对提取所有计数资料效应量均用比值比(Odds ratio,OR)及其95%可信区间(Confidence interval,CI)表示。研究间统计学异质性检验采用卡方检验,以α=0.1为检验水准,以判断多个研究结果的总体效应是否一致。若多个研究结果的效应一致,则采用固定效应模型；反之,则用随机效应模型。对可能影响合并效应的不同人种因素采用敏感性分析,从而判断结果的稳定性和强度。结果 1资料概括本研究共纳入18项研究。18篇诊断对照研究经文献质量评价均为高质量文献。共1387例前列腺标本,正常前列腺(NP)标本133例、前列腺增生(BPH)标本402例、前列腺癌(PCa)标本852例。其中9篇文献行前列腺癌与正常前列腺组织比较；16篇文献行前列腺癌与良性前列腺增生比较；14篇涉及不同分化程度Survivin表达的比较；11篇涉及不同临床分期的比较；6篇行伴随转移与否情况下前列腺癌组织Survivin表达阳性的比较。 2Meta分析结果2.1对前列腺癌与正常前列腺Survivin表达阳性比较：9项研究进行Meta分析,异质性检验(χ2=4.48,P=0.810,12=0%)采用固定效应模型,结果显示,前列腺癌阳性率66.20%(296/454),正常前列腺阳性率3.0%(4/133),OR值47.23,95%CI(20.00,111.56),两组阳性率差别有统计学意义(P0.001)提示Survivin在前列腺癌的表达显著强于正常前列腺组织。 2.2前列腺癌与良性前列腺增生Survivin表达阳性比较：16项研究进行Meta分析,异质性检验,(χ2=44.99,P0.001,12=67%),采用随机效应模型,结果显示,前列腺癌阳性率67.67%(519/767),良性前列腺增生阳性率11.44%(46/402),OR值21.25,95%CI(10.32,43.75),两组阳性表达率差异有统计学意义(P0.001),提示Survivin在前列腺癌表达较良性前列腺增生显著增强。 2.3前列腺高分化癌组织与低分化癌组织Survivin表达阳性比较：14项研究进行Meta分析,异质性检验,(χ2=17.13,P=0.190,I2=24%),采用固定效应模型,结果显示,前列腺高分化癌阳性率52.66%(99/188),低分化癌阳性率89.66%(182/203),OR值0.11,95%CI(0.06,0.20),两组阳性表达率差异有统计学意义(P0.001),提示Survivin在前列腺高分化癌组织表达较低分化癌组织的表达显著降低。 2.4Survivin在临床A+B期与C+D期前列腺癌组织表达的阳性比较：11项研究进行Meta分析,异质性检验,(χ2=6.40,P=0.780,12=0%),采用固定效应模型,结果显示,临床A+B期前列腺癌阳性率65.43%(159/243),C+D期癌组织的表达阳性率91.77%(223/243),OR值0.14,95%CI(0.08,0.26),两组阳性表达率比较有统计学意义(P0.001),提示Survivin蛋白在前列腺癌临床A+B期与C+D期癌组织的表达阳性率有显著差异。 2.5伴转移与非转移前列腺癌组织Survivin阳性表达率比较：对6项研究进行Meta分析,异质性检验(χ2=5.73,P=0.330,12=13%),采用固定效应模型,结果显示,伴随转移前列腺癌阳性率90.48%(95/105),非转移前列腺癌阳性率62.50%(120/192),OR值5.76,95%CI(2.81,11.84),两组阳性表达率比较有统计学意义(P0.001),提示Survivin蛋白在伴有淋巴结或全身他处转移较非转移的前列腺癌组织的表达阳性率显著增强。结论前列腺癌Survivin表达明显高于正常前列腺及良性前列腺增生；且Survivin在前列腺癌组织的表达与肿瘤病理分化,临床分期,是否伴随转移明显相关,提示Survivin表达阳性越高,前列腺癌发生的机率越高,越具有侵袭性,肿瘤的预后越差。因此Survivn检测可作为前列腺癌早期诊断提供一种新方法,为判断前列腺癌的生物学行为提供新的手段,为前列腺癌的基因治疗开辟一种新的途径。
[Abstract]:Research background
Prostate cancer (PCa) is a disease that seriously affects the life quality and life expectancy of old men. With the continuous improvement of people's living standards, the incidence of prostate cancer is also increasing. In Europe and North America, the incidence and mortality rate are the second and 6 in male malignant tumors. In our country, with the aging of the population, life is in China. The increase of quality and lifestyle changes many factors, the incidence of prostate cancer has been the first of the malignant tumor of the genitourinary system. Prostate cancer is latent and the incidence is high. In the male population over 70 years old, up to 25% of the people have prostate cancer, but only a small part of the cancer is developed to the clinical cancer. The detection method is prostate specific antigen (PSA), but the determination of serum PSA is limited, the sensitivity and specificity of diagnosis are not ideal, especially in the grey area (4 ~ 10ng/ml) of the test results, it is often difficult to diagnose. Although there are many methods in the treatment of prostate cancer, they are all limited, and the chemotherapeutic drugs are difficult to enter the prostate cancer. The most difficult problem in the clinical treatment of prostate cancer is the lack of effective treatment for androgen independent prostate cancer. The study found that castration, radiotherapy and some chemotherapeutic agents play a role in inducing apoptosis in prostate cancer cells. The study showed that the apoptosis level of the cells decreased as the cell turned to malignant transformation. Two views on the formation of prostate cancer from androgen dependence to androgens (AIPC) were proposed: first, male irritable. An increase in the hormone receptor (AR) signal causes an increase in androgen receptor, which makes AR sensitive to low androgen or estrogen sensitivity and is sensitive to androgen blockade. Another view is that the formation of AIPC is a AR independent signal that overcomes apoptosis, thus suggesting that the blocking of apoptotic signals is the cause of the tumor's continued survival. Prostate cancer Growth depends on the balance between the proliferation rate and death rate of the cells. The apoptosis inhibitory protein plays an important role in the development of prostate cancer..Survivin is a member of the newly discovered family of apoptosis suppressor (IAP). It is up-regulated in a large number of human malignant tumors and is closely related to the apoptosis, proliferation, angiogenesis and prognosis of the tumor. The non expression of.Survivin in normal adult tissues is likely to be a new target for the diagnosis and treatment of cancer. At present, the related research on the expression and significance of Survivin in prostate cancer has been reported at home and abroad, but the results are not the same. Therefore, we refer to a large number of domestic and foreign literature and refer to the exemption from domestic and foreign applications. The research results of the expression of Survivin in prostate cancer, normal prostate and prostatic hyperplasia tissue were detected by S-P method. The relationship between Survivin and biological behavior of prostate cancer was evaluated systematically, and a new method for the early diagnosis of prostate cancer was expected to provide a new method to judge the biological behavior of prostate cancer. New means of opening up a new way for the treatment of prostate cancer.
The literature on the expression of Survivin in prostate cancer, normal prostate and benign prostatic hyperplasia tissue was collected at home and abroad, and the expression of Survivin in normal prostate (NP), benign prostatic hyperplasia (BPH) and anterior adenocarcinoma (PCa) tissue was compared by Meta analysis, and the expression intensity of Survivin was compared. The clinical staging of prostate cancer (PCa), pathological differentiation and the clinical significance of metastasis are designed to systematically evaluate the relationship between Survivin and the occurrence and development of prostate cancer, to provide a new method for the early diagnosis of prostate cancer, and to provide a new method for judging the biological behavior of prostate cancer and the treatment of prostate cancer. The treatment opens up a new way.
Method
1 according to the requirements of systematic review, the detailed inclusion and exclusion criteria should be worked out, including the characteristics of subjects, intervention measures and the measurement of outcome indicators.
2 according to the proposed standards, a system, a comprehensive retrieval strategy. Computer retrieval of MEDLINE, Cochrane Library, CBM, CNKI digital library, Wanfang database, VP in the (1997.1 to 2011.6) published original documents, conference papers, graduation thesis. After the pre examination, it will be identified. Search engines on the Internet will be searched by Google and other search engines, supplemented by manual retrieval and literature review.
3 literature quality evaluation and data information extraction: two evaluators based on the QUADAS (quality assessment of diagnostic accuracy studies) entry for the independent evaluation of the quality of the study, such as in the case of disagreement through discussion or by the assistance of third researchers. The content of data extraction includes the basic conditions of the test and the two groups of specimens Baseline conditions; 2. Test design, examination methods, outcome measures, and indicators of response research quality.
4 data processing: Revman5.1 software for data processing and analysis. The ratio Ratio ratio (Odds ratio, OR) and its 95% confidence interval (Confidence interval, CI) were used to extract all the count data. Statistical heterogeneity test was used in Chi square test and alpha =0.1 as the test level to judge the general results of multiple research. If the effect of the body effect is consistent. If the effects of the results are the same, the fixed effect model is used. On the contrary, the random effect model is used to analyze the different human factors that may affect the combination effect, so as to determine the stability and intensity of the results.
Result
1 a total of 18 studies were included in the study. The quality evaluation of the.18 diagnosis was high quality literature. There were 1387 cases of prostate specimens, 133 normal prostate (NP) specimens, 402 cases of benign prostatic hyperplasia (BPH), and 852 cases of prostate cancer (PCa). 9 literature compared the prostate cancer to the normal prostate tissue; 16 articles were compared with the normal prostate tissue. The literature was compared with benign prostatic hyperplasia in the literature; 14 articles were compared with the Survivin expression of different degrees of differentiation; 11 were compared to different clinical stages, and the positive of Survivin in the prostate cancer tissue was compared in the 6 cases.
2Meta analysis results 2.1 positive prostate cancer and normal prostate Survivin expression positive: 9 studies performed Meta analysis, heterogeneity test (chi 2=4.48, P=0.810,12=0%) using the fixed effect model, the results showed that the positive rate of prostate cancer was 66.20% (296/454), normal prostaglandin gland positive rate 3% (4/133), OR value 47.23,95%CI (20.00111.56), two groups of Yang. The difference in sex ratio was statistically significant (P0.001), suggesting that the expression of Survivin in prostate cancer was significantly stronger than that in normal prostate tissue.
2.2 positive comparison of Survivin expression in prostate cancer and benign prostatic hyperplasia: 16 studies performed Meta analysis, heterogeneity test, (x 2=44.99, P0.001,12=67%), using random effect model. The results showed that the positive rate of prostate cancer was 67.67% (519/767), benign prostatic growth positive rate 11.44% (46/402), OR value 21.25,95%CI (10.32,43.75), two groups of Yang. The difference of sex expression rate was statistically significant (P0.001), suggesting that Survivin expression in prostate cancer was significantly higher than that in benign prostatic hyperplasia.
2.3 the positive comparison of Survivin expression in highly differentiated prostate cancer tissue and low differentiated carcinoma tissue: 14 studies performed Meta analysis, heterogeneity test, (x 2=17.13, P=0.190, I2=24%), using the fixed effect model. The results showed that the positive rate of high differentiated prostate cancer was 52.66% (99/188), the positive rate of low differentiated carcinoma (182/203), OR value 0.11,95%CI (0.06,0.20), The positive expression rate of the two groups was statistically significant (P0.001), indicating that Survivin expression was significantly reduced in poorly differentiated cancer tissues.
The positive comparison of the expression of 2.4Survivin in phase A+B and C+D stage prostate cancer tissue: 11 studies performed Meta analysis, heterogeneity test, (x 2=6.40, P=0.780,12=0%), using the fixed effect model. The results showed that the positive rate of prostate cancer in A+B phase was 65.43% (159/243), the positive rate of C+D stage carcinoma tissue was 91.77% (223/243), OR 0.14,95%CI (0) .08,0.26), the positive expression rate of the two groups was statistically significant (P0.001), suggesting that the positive rate of Survivin protein in the A+B and C+D stage of prostate cancer was significantly different.
The positive rate of positive expression of Survivin in 2.5 and non metastatic prostate cancer tissues: 6 studies were analyzed by Meta, heterogeneity test (x 2=5.73, P=0.330,12=13%), using the fixed effect model. The results showed that the positive rate of the adjoint metastatic prostate cancer was 90.48% (95/105), the positive rate of non metastatic prostate cancer was 62.50% (120/192), and OR value 5.76,95%CI (2.81,1). 1.84) the positive rate of the two groups was statistically significant (P0.001), suggesting that the positive rate of Survivin protein expression was significantly enhanced in the metastatic prostate cancer tissue with lymph node or whole body metastasis.
conclusion
The expression of Survivin in prostate cancer is significantly higher than that of normal prostate and benign prostatic hyperplasia; and the expression of Survivin in the prostate cancer tissue is associated with the pathological differentiation of the tumor, and the clinical stages are associated with the metastasis. The higher the expression of Survivin is, the higher the probability of the prostate cancer, the more invasive, the worse the prognosis of the tumor. This Survivn detection can provide a new method for the early diagnosis of prostate cancer. It provides a new way to judge the biological behavior of prostate cancer and opens a new way for the gene therapy of prostate cancer.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R737.25

【参考文献】