本文選題：良性前列腺增生癥 + 微小RNA�。� 參考：《第三軍醫(yī)大學(xué)》2016年博士論文

【摘要】：研究背景:良性前列腺增生癥(benign prostatic hyperplasia,BPH)是一種常見(jiàn)于老年男性的由前列腺移行區(qū)上皮和基質(zhì)良性增生造成膀胱出口梗阻,從而引起患者一系列下尿路癥狀的良性疾病,其發(fā)病率與年齡呈正相關(guān)。目前我國(guó)即將進(jìn)入老齡化社會(huì),由BPH帶來(lái)的衛(wèi)生經(jīng)濟(jì)學(xué)壓力更加嚴(yán)峻。目前認(rèn)為BPH是一種由多因素參與的具有復(fù)雜發(fā)病機(jī)制的疾病,到目前為止其確切發(fā)病機(jī)制及病因仍不清楚。于是明確BPH的確切發(fā)病機(jī)制將有可能發(fā)現(xiàn)更加有效的預(yù)防及治療方案,對(duì)提高老年男性的生活質(zhì)量、減少社會(huì)醫(yī)療保障負(fù)擔(dān)具有重要的意義。研究目的:本研究針對(duì)性激素受體包括雄激素受體(AR)、雌激素受體α(ERα)、雌激素受體β(ERβ)和孕激素受體(PGR)在BPH中的可能機(jī)制做一探索性研究,期望能找到一個(gè)突破口。鑒于BPH的可能發(fā)病機(jī)制的多因素性,在明確上述性激素受體在BPH組織中的確切表達(dá)變化后,擬從可能參與性激素受體m RNA調(diào)控的micro RNAs、可能受性激素受體調(diào)控且與細(xì)胞增殖或凋亡相關(guān)的細(xì)胞因子和生長(zhǎng)因子、代謝綜合征與性激素受體的相關(guān)性等多方面進(jìn)行探索,在研究過(guò)程中根據(jù)實(shí)驗(yàn)發(fā)現(xiàn)結(jié)果及時(shí)調(diào)整方案,為進(jìn)一步深入研究并揭示性激素受體在BPH中的確切發(fā)病機(jī)制提供一定的思路。研究方法:1.收集2015年2月~2015年6月在第三軍醫(yī)大學(xué)第一附屬醫(yī)院泌尿外科住院并行手術(shù)治療且病例資料完整的BPH病例40例,同時(shí)收集器官捐獻(xiàn)者以及其他手術(shù)切除前列腺并通過(guò)病理診斷明確為正常前列腺的病例5例。2.通過(guò)聯(lián)合丙酸睪酮和苯甲酸雌二醇誘導(dǎo)去勢(shì)SD雄性大鼠建立大鼠BPH模型。3.聯(lián)合使用IHC、qRT-PCR和WB的方法確定性激素受體包括AR、ERα、ERβ和PGR在BPH組織中較正常前列腺組織的表達(dá)差異,然后采用同樣方法檢測(cè)大鼠BPH模型組織中這些受體的表達(dá)差異變化。4.通過(guò)芯片檢測(cè)初步了解及篩查BPH組織中mi RNAs是否存在異常表達(dá),然后通過(guò)qRT-PCR的方法對(duì)mi RNAs表達(dá)芯片提示可能具有異常表達(dá)的mi RNAs的確切表達(dá)進(jìn)行驗(yàn)證。5.采用qRT-PCR的方法檢測(cè)BPH組織中可能受性激素受體調(diào)控且有可能與BPH發(fā)病相關(guān)的細(xì)胞因子、生長(zhǎng)因子在轉(zhuǎn)錄水平的表達(dá)差異情況。6.根據(jù)MetS的診斷標(biāo)準(zhǔn)對(duì)納入研究的BPH病例進(jìn)行分組,分為BPH伴MetS組和BPH不伴MetS組,并對(duì)比分析兩組間臨床資料差異性明確MetS與BPH的相關(guān)性,然后使用qRT-PCR及WB的研究方法明確兩組各性激素受體的表達(dá)差異情況。研究結(jié)果:1.在人BPH組織中AR和PGR表達(dá)顯著升高,ERα的表達(dá)顯著下降;大鼠BPH模型實(shí)驗(yàn)組中PGR的表達(dá)顯著上調(diào),AR和ERα的表達(dá)顯著下調(diào);ERβ的表達(dá)未見(jiàn)顯著性差異;IHC、qRT-PCR、WB在檢測(cè)上述性激素受體表達(dá)的結(jié)果一致。2.mi RNAs芯片檢測(cè)結(jié)果發(fā)現(xiàn)發(fā)現(xiàn)mi R-126-3p和mi R-4672在BPH組織中表達(dá)下調(diào)具有統(tǒng)計(jì)學(xué)意義,但是qRT-PCR的驗(yàn)證結(jié)果未見(jiàn)mi R-126-3p、mi R-4672、mi R-143-3p和mi R-145-3p在BPH組織中和正常前列腺組織中的表達(dá)具有顯著性差異。3.采用qRT-PCR方法檢測(cè)發(fā)現(xiàn)ETV1、TLR1基因轉(zhuǎn)錄水平的表達(dá)在BPH組織中顯著性上調(diào),而TGFβ1-SMAD2/3、IL6R-JAK2-STAT3、KRAS-ERK、TLR2基因的轉(zhuǎn)錄水平表達(dá)在BPH組織和正常前列腺組織中的差異無(wú)統(tǒng)計(jì)學(xué)意義。4.BPH不伴MetS組與BPH伴MetS組的臨床資料分析:兩組之間年齡相仿;在代謝綜合征相關(guān)各診斷因素上,如BMI、空腹血糖、甘油三酯、高密度脂蛋白、血壓,兩組間具有顯著性差異(P0.05);在BPH相關(guān)的檢查檢驗(yàn)結(jié)果方面,國(guó)際前列腺癥狀評(píng)分以及最大尿流率在兩組間的差異并無(wú)統(tǒng)計(jì)學(xué)意義(P0.05),但總前列腺特異性抗原和前列腺體積在BPH伴MetS組顯著性升高(P0.05);組織炎癥情況對(duì)比方面,BPH不伴MetS組內(nèi)的患者前列腺組織炎癥檢出率為46.7%(7/15),而BPH伴MetS組的患者前列腺組織炎癥檢出率為76.2%(16/21),但該差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05);采用qRT-PCR和WB法的檢測(cè)發(fā)現(xiàn)在伴有MetS的BPH患者的前列腺組織中AR、ERα和PGR在轉(zhuǎn)錄水平和蛋白水平的表達(dá)均顯著性升高(P0.05),而ERβ的表達(dá)在兩組間未見(jiàn)顯著性差異(P0.05)。研究結(jié)論:1.證實(shí)了BPH組織中AR和PGR的表達(dá)上調(diào)以及ERα的表達(dá)下調(diào)。推測(cè)在BPH中AR和PGR具有誘導(dǎo)疾病起病、促進(jìn)疾病進(jìn)展的作用,而ERα則具有抑制作用。激素誘導(dǎo)大鼠BPH模型與人BPH中雄激素/AR通路的活化機(jī)制具有差異性。2.就目前該研究的數(shù)據(jù)來(lái)看,尚不能認(rèn)為mi RNAs與BPH組織中性激素受體的異常表達(dá)具有相關(guān)性,也不能認(rèn)為mi RNAs在BPH發(fā)病機(jī)制中具有顯著的作用。在篩查BPH組織中mi RNAs差異表達(dá)方面需要靈敏度和特異度更高的實(shí)驗(yàn)方法,同時(shí)需要擴(kuò)大正常前列腺樣本量繼續(xù)驗(yàn)證以排除樣本偏倚的影響。3.通過(guò)目前所得到的實(shí)驗(yàn)數(shù)據(jù),發(fā)現(xiàn)BPH組織中ETV1、TLR1基因在轉(zhuǎn)錄水平的表達(dá)較正常前列腺組織顯著性上調(diào),而其余所檢測(cè)的因子在轉(zhuǎn)錄水平表達(dá)則無(wú)統(tǒng)計(jì)學(xué)意義。但是尚不能就此實(shí)驗(yàn)結(jié)果予以下結(jié)論,還需要進(jìn)一步研究明確這些因子蛋白水平及蛋白磷酸化水平的變化。初步推測(cè)AR-ETV1通路可能與BPH的發(fā)病具有相關(guān)性,也是我們深入研究的可能方向。4.證實(shí)了MetS和BPH的相關(guān)性,伴有MetS的BPH的患者前列腺總體積更大、血清PSA水平更高、組織炎癥更顯著,但目前尚不能認(rèn)為MetS對(duì)BPH的相關(guān)癥狀有顯著性的影響。發(fā)現(xiàn)伴MetS的BPH患者前列腺組織內(nèi)AR、ERα和PGR表達(dá)顯著性上調(diào)。推測(cè)MetS可誘導(dǎo)前列腺組織AR、ERα和PGR表達(dá)上調(diào),促進(jìn)BPH的發(fā)生及疾病進(jìn)展。
[Abstract]:Background: benign prostatic hyperplasia (BPH) is a kind of benign disease common in elderly men, which is caused by epithelial and benign hyperplasia of the prostatic migrating area, causing a series of benign diseases of lower urinary tract symptoms. The incidence of the disease is positively related to age. The pressure of health economics brought by BPH is more severe. BPH is now considered to be a complex disease with multiple factors, and the exact pathogenesis and cause of the disease are still unclear so far. Therefore, it is clear that the exact pathogenesis of BPH will be possible to find more effective prevention and treatment programs and to improve the old. The quality of life of men is of great significance in reducing the burden of social health care. Objective: This study aims to explore the mechanism of the ability of sex hormone receptors, including androgen receptor (AR), estrogen receptor alpha (ER alpha), estrogen receptor beta (ER beta) and progestin receptor (PGR) in BPH, to find a breakthrough. The multiple factors of the possible pathogenesis of BPH, after identifying the exact changes in the expression of the sex hormone receptor in the BPH tissue, are intended to be regulated by the micro RNAs, which may be regulated by the sex hormone receptor m RNA, and may be regulated by the hormone receptor and the cytokines and growth factors associated with cell proliferation or apoptosis, metabolic syndrome and sex hormone receptor In order to further study and reveal the exact pathogenesis of sex hormone receptor in BPH, the research method: 1. collected in the Department of Urology, the First Affiliated Hospital of Third Military Medical University, February 2015, and in the Department of Urology of the First Affiliated Hospital of Third Military Medical University. 40 cases of BPH cases with complete surgical treatment and case data were collected and 5 cases of.2. were combined with testosterone propionate and estradiol benzoate to establish rat BPH model.3. combined with IHC, qRT-PCR and WB using IHC, qRT-PCR and WB. Methods deterministic hormone receptors, including AR, ER a, ER beta and PGR, were different in the expression of normal prostate tissue in BPH tissues. Then the same method was used to detect the differences in the expression of these receptors in the rat BPH model tissue..4. was detected by chip detection and screened for the existence of abnormal expression of MI RNAs in BPH tissues and then through qRT-P. CR's approach to the MI RNAs expression chip suggesting the exact expression of MI RNAs that may have abnormal expression..5. uses qRT-PCR to detect cytokines in BPH tissues that may be regulated by the sex hormone receptor and may be associated with the pathogenesis of BPH. The difference of the growth factor at the transcriptional level of.6. is based on MetS diagnostic criteria The BPH cases included in the study were divided into groups of BPH with MetS and BPH without MetS, and the correlation between MetS and BPH was clearly defined in the two groups. Then the expression difference between the two groups of sex hormone receptors was determined by qRT-PCR and WB. The results were as follows: 1. the AR and PGR expressions were significantly increased in the human BPH tissue. The expression of ER alpha was significantly decreased, and the expression of PGR in the experimental group of BPH was significantly up-regulated, and the expression of AR and ER alpha was significantly down, and there was no significant difference in the expression of ER beta. IHC, qRT-PCR, and WB detected the expression of the above sex hormone receptors by.2.mi RNAs chips. The down regulation was statistically significant, but the results of qRT-PCR's verification were not mi R-126-3p, MI R-4672, MI R-143-3p and MI R-145-3p in the BPH tissues and normal prostate tissues. The transcriptional levels of IL6R-JAK2-STAT3, KRAS-ERK, and TLR2 genes were expressed in BPH tissues and normal prostate tissues with no statistical significance,.4.BPH was not associated with the clinical data of the MetS group and the BPH with the MetS group: the age of the two groups was similar; in the metabolic syndrome related diagnostic factors, such as BMI, fasting blood glucose, triglycerides, and high-density lipoprotein There was a significant difference between the two groups (P0.05). In the BPH related examination results, the International Prostatic Symptom Score and the maximum urinary flow rate were not statistically significant between the two groups (P0.05), but the total prostatic specific antigen and the prostate volume were significantly higher in the BPH group (P0.05), and the tissue inflammation was compared. The positive rate of prostatic tissue inflammation in the patients with BPH without MetS was 46.7% (7/15), while the rate of prostatic tissue inflammation in the BPH and MetS group was 76.2% (16/21), but the difference was not statistically significant (P0.05). The detection of the prostate tissue with qRT-PCR and WB was found in the prostate tissue of BPH patients with MetS and at the transcriptional level and at the transcriptional level. The expression of protein level was significantly increased (P0.05), but the expression of ER beta was not significantly different between the two groups (P0.05). 1. confirmed the up regulation of AR and PGR expression in BPH tissue and the downregulation of ER a. It is suggested that AR and PGR have the effect of inducing disease onset and promoting disease progression in BPH, while ER alpha has inhibitory effect. The activation mechanism of the BPH model in rats and the androgen /AR pathway in human BPH is different from that of the human BPH. In the present study, it is not yet believed that the MI RNAs has a correlation with the abnormal expression of the neutrosteroid receptor in the BPH tissue, nor is it that MI RNAs has a significant role in the pathogenesis of BPH. The difference expression requires a higher sensitivity and specificity, and it is necessary to expand the sample size of the normal prostate to exclude the effect of the sample bias to exclude the effect of the bias of the sample.3. through the present experimental data, it is found that the expression of ETV1 in the BPH tissue is significantly up-regulated at the transcriptional level compared with the normal prostate tissue. There is no statistical significance in the expression of the transcription factors at the transcriptional level. However, the results of this experiment are not yet given, and further studies are needed to clarify the changes in the level of these proteins and the levels of protein phosphorylation. It is preliminarily presumed that the AR-ETV1 pathway may be related to the pathogenesis of BPH and is the possible direction of our in-depth study. .4. confirmed the correlation between MetS and BPH. The total volume of the prostate was larger in patients with BPH with MetS, the level of serum PSA was higher, and the tissue inflammation was more significant. However, it is still not considered that MetS has a significant effect on the related symptoms of BPH. The expression of AR, ER, and PGR in prostate tissue is upregulated, which promotes BPH and disease progression.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R697.3

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