本文選題：子宮肌瘤 + 子宮肌層��； 參考：《鄭州大學(xué)》2016年博士論文

【摘要】：子宮平滑肌瘤(uterine leiomyomas)是育齡期女性生殖系統(tǒng)最常見(jiàn)的良性腫瘤,育齡期婦女平均發(fā)病率約為77%,而45歲女性的發(fā)病率則高達(dá)60%,且發(fā)病率呈逐年上升的趨勢(shì)。子宮肌瘤典型的臨床表現(xiàn)包括:經(jīng)量過(guò)多、經(jīng)期紊亂及以頭暈、血色素降低為表現(xiàn)的繼發(fā)性貧血癥狀;因瘤體腫大造成的盆腔壓迫癥狀,如尿頻、尿急、腹痛等;嚴(yán)重的子宮肌瘤會(huì)導(dǎo)致女性不孕和習(xí)慣性流產(chǎn)等生育力低下的癥狀,是婦科住院及全子宮切除的首要原因,浪費(fèi)大量衛(wèi)生資源,嚴(yán)重威脅婦女的身心健康。而子宮肌瘤的發(fā)病機(jī)制至今不清,是國(guó)內(nèi)外研究的熱點(diǎn)之一。微小核糖核酸(micro ribonucleic acid,miRNAs)是一種廣泛存在于真核生物細(xì)胞中,大小約為21-23個(gè)堿基的非編碼單鏈小分子核糖核酸(ribonucleic acid,RNA),在生物體內(nèi)發(fā)揮重要作用,如細(xì)胞增殖,凋亡,應(yīng)激反應(yīng),甚至腫瘤發(fā)病等。降解靶基因的信使核糖核酸(message RNA,m RNA)或者抑制靶基因的翻譯最終沉默靶基因表達(dá),是細(xì)胞內(nèi)普遍存在的一種精細(xì)調(diào)節(jié)蛋白表達(dá)的轉(zhuǎn)錄后調(diào)控機(jī)制。Mi RNA參與多種腫瘤的發(fā)病過(guò)程,如細(xì)胞增殖、凋亡、炎癥反應(yīng)、血管生成、組織更新和抑癌致癌基因修飾,與腫瘤預(yù)后密切相關(guān),是腫瘤的早期診斷及其預(yù)后判斷的良好的生物標(biāo)記物。Mi RNA參與子宮肌瘤發(fā)病的作用機(jī)制的研究尚處于初始階段。多篇報(bào)道顯示,子宮肌瘤和子宮肌層中存在差異表達(dá)顯著的miRNA。檢測(cè)子宮肌瘤和子宮肌層miRNA的差異表達(dá),進(jìn)而深入探討差異miRNA對(duì)肌瘤細(xì)胞的生物學(xué)功能和調(diào)控,為揭示miRNA參與子宮肌瘤的發(fā)病機(jī)制奠定良好基礎(chǔ)。目前,miRNA的研究方法主要有熒光實(shí)時(shí)定量PCR(Real time-PCR)、miRNA芯片及二代測(cè)序技術(shù)。而miRNA芯片是篩選子宮肌瘤和子宮肌層差異表達(dá)的miRNA的主要方法和經(jīng)典手段。第一部分:子宮肌瘤組織差異表達(dá)micro RNA的篩選研究目的本研究通過(guò)miRNA芯片篩選子宮肌瘤和配對(duì)的子宮肌層樣本中差異表達(dá)的miRNA,芯片聯(lián)合生物信息學(xué)分析,預(yù)測(cè)差異表達(dá)顯著的miRNA的靶基因及其生物學(xué)功能。方法收集2012年11月至2013年1月在鄭州大學(xué)第三附屬醫(yī)院婦產(chǎn)科因子宮肌瘤行子宮全切術(shù)的10例育齡期子宮肌瘤患者的肌瘤組織和配對(duì)的肌層組織為研究對(duì)象。采用Agilent Human miRNA(8*60K)V19.0芯片篩選3例子宮肌瘤和配對(duì)的肌層組織中差異表達(dá)顯著的miRNA,芯片結(jié)果用Agilent配套軟件Genespring進(jìn)行數(shù)據(jù)預(yù)處理和差異分析,采用聚類軟件MEV進(jìn)行聚類分析。應(yīng)用Real time-PCR在10例子宮肌瘤和配對(duì)的肌層組織中驗(yàn)證hsa-miR-15b-5p、hsa-miR-21-5p、hsa-miR-34a-3p、hsa-miR-34a-5p的差異表達(dá)。利用Mi RDB、Tar Base、Target Scan、RNA22、Target Miner數(shù)據(jù)庫(kù)預(yù)測(cè)上述4個(gè)miRNA的靶基因,采用基因本體論(Gene Ontology,GO)和KEGG信號(hào)通路分析(Kyoto Encyclopedia of Genes and Genomes,KEGG Pathway)探尋靶基因可能參與的生物學(xué)過(guò)程和相關(guān)信號(hào)通路。結(jié)果1、發(fā)現(xiàn)人子宮肌瘤和子宮肌層組織中45個(gè)差異表達(dá)的miRNA,其中19個(gè)miRNA在子宮肌瘤中表達(dá)升高,26個(gè)miRNA在子宮肌瘤中表達(dá)下降。2、驗(yàn)證miR-15b-5p、miR-34a-5p、miR-34a-3p、miR-21-5p在子宮肌瘤組織表達(dá)顯著升高,與芯片結(jié)果基本一致,P均0.0001。3、子宮肌瘤和肌層差異表達(dá)的miRNA的靶基因主要參與形態(tài)發(fā)育、細(xì)胞生長(zhǎng)發(fā)育等30個(gè)生物學(xué)過(guò)程。4、子宮肌瘤和肌層差異表達(dá)的miRNA的靶基因主要參與癌癥、絲裂原活化蛋白激酶(Mitogen-activated protein kinase,MAPK)、內(nèi)噬作用等25個(gè)信號(hào)通路。結(jié)論子宮肌瘤和正常子宮肌層組織中存在差異表達(dá)顯著的miRNA。第二部分:miR-15b-5p過(guò)表達(dá)和低表達(dá)對(duì)子宮肌瘤細(xì)胞生物學(xué)特征的影響目的根據(jù)第一部分研究結(jié)果,選擇子宮肌瘤組織中表達(dá)顯著升高的miR-15b-5p,通過(guò)基因轉(zhuǎn)染技術(shù),使miR-15b-5p在各型肌瘤細(xì)胞和肌層細(xì)胞中過(guò)表達(dá)和低表達(dá),并觀察miR-15b-5p低表達(dá)對(duì)子宮肌瘤細(xì)胞增殖的影響,為后續(xù)全面研究miR-15b-5p的生物學(xué)功能及遠(yuǎn)期探尋其下游靶基因提供鋪墊。方法采集于2013年8月-2014年2月在美國(guó)麻省總院(Massachusetts General Hospital MGH)婦產(chǎn)科生殖內(nèi)分泌中心因子宮肌瘤行子宮全切術(shù)的育齡期患者的肌瘤和配對(duì)的肌層組織共20例,部分消化和原代細(xì)胞分離培養(yǎng)為子宮肌瘤細(xì)胞(p LYO cells)和子宮肌層細(xì)胞(p MYO cells)。同時(shí)體外培養(yǎng)子宮肌瘤細(xì)胞系(cp LYO cells)和子宮肌層細(xì)胞系(cp MYO cells)。Real time-PCR檢測(cè)不同細(xì)胞miR-15b-5p的本底表達(dá)水平。脂質(zhì)體在各型細(xì)胞瞬時(shí)轉(zhuǎn)染miR-15b-5p的模擬物(mimic)、抑制物(inhibitor)及其陽(yáng)性、陰性對(duì)照,應(yīng)用Real time-PCR驗(yàn)證miR-15b-5p在各組表達(dá)情況,建立miR-15b-5p高表達(dá)或低表達(dá)的模式。采用噻唑藍(lán)實(shí)驗(yàn)(methylthiazolyldiphenyl-tetrazolium,MTT)檢測(cè)miR-15b-5p對(duì)原代子宮肌瘤細(xì)胞增殖能力的影響。結(jié)果1、miR-15b-5p在各型細(xì)胞中本底表達(dá)情況:原代子宮肌瘤細(xì)胞中miR-15b-5p的表達(dá)水平顯著高于原代子宮肌層細(xì)胞;子宮肌瘤細(xì)胞系中miR-15b-5p的表達(dá)水平顯著高于子宮肌層細(xì)胞系(配對(duì)t檢驗(yàn),P0.001)。2、miR-15b-5p mimic轉(zhuǎn)染各型細(xì)胞24和48h,各型細(xì)胞中miR-15b-5p的表達(dá)顯著升高(配對(duì)t檢驗(yàn),P0.001)。3、miR-15b-5p inhibitor轉(zhuǎn)染各型細(xì)胞24和48h,各型細(xì)胞中miR-15b-5p表達(dá)顯著降低(配對(duì)t檢驗(yàn),P0.001)。4、原代子宮肌瘤細(xì)胞和子宮肌瘤細(xì)胞系中,不同濃度轉(zhuǎn)染miR-15b-5p inhibitor組與轉(zhuǎn)染其陰性對(duì)照組相比,細(xì)胞增殖率顯著降低(配對(duì)t檢驗(yàn),P0.05)。結(jié)論miR-15b-5p可促進(jìn)子宮肌瘤細(xì)胞的增殖能力。第三部分:miR-15b-5p調(diào)控子宮肌瘤細(xì)胞生物學(xué)特征的下游靶蛋白研究目的預(yù)測(cè)并驗(yàn)證miR-15b-5p在子宮肌瘤細(xì)胞的下游靶基因/靶蛋白,檢測(cè)miR-15b-5p的下游靶蛋白在子宮肌瘤組織和子宮肌層中的表達(dá)差異,進(jìn)一步揭示miR-15b-5p參與子宮肌瘤發(fā)病的分子機(jī)制。方法利用生物信息學(xué)數(shù)據(jù)庫(kù)Mi RDB、Tar Base、Target Scan、RNA22、Target Miner聯(lián)合預(yù)測(cè)miR-15b-5p的靶基因。轉(zhuǎn)染miR-15b-5p的mimic,Real time-PCR驗(yàn)證預(yù)測(cè)的miR-15b-5p的靶基因RECK(Reversion-inducing cysteine-rich protein with Kazal motifs)在各型細(xì)胞的m RNA的表達(dá)水平;轉(zhuǎn)染miR-15b-5p的mimic和inhibitor及各自陰性對(duì)照,免疫印跡實(shí)驗(yàn)(Western Blot)驗(yàn)證RECK蛋白在各型細(xì)胞的表達(dá)水平;轉(zhuǎn)染miR15b-5p inhibitor及其陰性對(duì)照,細(xì)胞免疫熒光(Immunoflunence,IF)檢測(cè)原代肌瘤及肌層細(xì)胞RECK蛋白的表達(dá)變化。繼而采用Western Blot和免疫組織化學(xué)染色法(Immunohistochemical staining,IHC)檢測(cè)RECK在肌瘤和肌層組織的表達(dá)差異及RECK蛋白的細(xì)胞定位。結(jié)果1、miR-15b-5p mimic轉(zhuǎn)染各型細(xì)胞24小時(shí),與空白對(duì)照組相比,肌瘤細(xì)胞系和肌層細(xì)胞系RECK m RNA表達(dá)下降(配對(duì)t檢驗(yàn),P0.05,P0.001)。miR-15b-5p mimic轉(zhuǎn)染各型細(xì)胞48小時(shí),與空白對(duì)照組相比,子宮肌瘤細(xì)胞系、子宮肌層細(xì)胞系及原代子宮肌瘤細(xì)胞RECK m RNA表達(dá)下降(配對(duì)t檢驗(yàn),P0.01,P0.001,P0.001)。2、使用10n M的miR-15b-5p mimic和inhibitor及各自陰性對(duì)照轉(zhuǎn)染各型細(xì)胞48h。子宮肌瘤細(xì)胞系和原代子宮肌瘤細(xì)胞系轉(zhuǎn)染miR-15b-5p mimic組與其陰性對(duì)照組相比,RECK蛋白表達(dá)顯著下降;轉(zhuǎn)染miR-15b-5p inhibitor組RECK蛋白表達(dá)顯著升高,差異具有統(tǒng)計(jì)學(xué)意義(配對(duì)t檢驗(yàn),P均0.001)。子宮肌層細(xì)胞系轉(zhuǎn)染miR-15b-5p mimic組與其陰性對(duì)照組相比,RECK蛋白表達(dá)顯著下降(配對(duì)t檢驗(yàn),P0.001);轉(zhuǎn)染inhibitor組RECK蛋白表達(dá)顯著升高,差異具有統(tǒng)計(jì)學(xué)意(配對(duì)t檢驗(yàn),P0.01)。原代子宮肌層細(xì)胞轉(zhuǎn)染mimic RECK蛋白表達(dá)顯著下降;轉(zhuǎn)染inhibitor組RECK蛋白表達(dá)顯著升高,差異具有統(tǒng)計(jì)學(xué)意義(配對(duì)t檢驗(yàn),P0.05)。3、使用40n M的miR-15b-5p inhibitor和其陰性對(duì)照分別轉(zhuǎn)染原代子宮肌瘤細(xì)胞和原代肌層細(xì)胞,轉(zhuǎn)染inhibitor組轉(zhuǎn)綠色熒光標(biāo)記的RECK蛋白表達(dá)增多。4、RECK蛋白在子宮肌層組織表達(dá)顯著高于配對(duì)的子宮肌瘤組織(配對(duì)t檢驗(yàn),P0.001)。RECK蛋白在子宮肌層細(xì)胞表達(dá)顯著高于配對(duì)的子宮肌瘤細(xì)胞(配對(duì)t檢驗(yàn),P0.05)。5、RECK蛋白表達(dá)位于子宮肌纖維細(xì)胞的胞漿,配對(duì)的子宮肌層組織較子宮肌瘤組織中RECK蛋白表達(dá)顯著升高(非配對(duì)t檢驗(yàn),P0.05)。結(jié)論miR-15b-5p通過(guò)調(diào)控RECK參與子宮肌瘤發(fā)病。
[Abstract]:Uterine leiomyoma (uterine leiomyomas) is the most common benign tumor of reproductive system in women of childbearing age. The average incidence of women in childbearing age is about 77%, while the incidence of 45 year old women is up to 60%, and the incidence is increasing year by year. The typical clinical manifestations of uterine myoma include: excessive menstruation, menstrual disorder and dizziness and hemoglobin. The symptoms of secondary anemia low, such as the pelvic cavity pressure caused by tumor enlargement, such as frequency of urination, urgency of urine and abdominal pain, and severe uterine fibroids can lead to low fertility symptoms such as female infertility and habitual abortion. It is the primary cause of gynecologic inpatient and total hysterectomy, wasting a large amount of health resources and seriously threatening the physical and mental health of women. The pathogenesis of uterine myoma is not clear, it is one of the hot spots at home and abroad. Micro ribonucleic acid (miRNAs) is a kind of non coding single strand small molecule ribonucleic acid (ribonucleic acid, RNA), which is widely used in eukaryotic cells and is about 21-23 bases in size, and plays an important role in the organism. Such as cell proliferation, apoptosis, stress response, and even tumor disease. Message RNA (m RNA) degrading target gene or the translation of target gene in the final silence target gene expression is a post transcriptional regulation mechanism of fine regulation protein expression,.Mi RNA involved in the pathogenesis of various tumors. Cell proliferation, apoptosis, inflammatory reaction, angiogenesis, tissue regeneration and tumor suppressor gene modification are closely related to the prognosis of tumor. It is a good biomarker for the early diagnosis and prognosis of tumor and the study of the mechanism of.Mi RNA in the pathogenesis of uterine myoma is still in the initial stage. The differential expression of differential expression of miRNA. in myoma and myometrium miRNA in myoma was found in the myometrium, and further explored the biological function and regulation of differential miRNA on myoma cells, which lay a good foundation for revealing the mechanism of miRNA to participate in the pathogenesis of uterine myoma. At present, the research methods of miRNA are mainly real-time quantitative quantitative PCR (Real Ti). Me-PCR), miRNA chip and two generation sequencing technology. MiRNA chip is the main method and classical means to screen the differential expression of uterine myoma and uterine myometrium. Part 1: the screening of differential expression of micro RNA in uterine myoma tissue, the purpose of this study was to screen the differences of uterine myoma and paired uterine myometrium samples by miRNA chip. The expression of miRNA, chip combined bioinformatics analysis, prediction of differentially expressed miRNA target genes and their biological functions. Methods from November 2012 to January 2013, the myoma and paired myoma group of 10 patients with uterine myoma at the Third Affiliated Hospital of Zhengzhou University with hysteromyoma underwent hysteromyoma The Agilent Human miRNA (8*60K) V19.0 chip was used to screen 3 cases of uterine myoma and the distinct miRNA in the paired myometrium. The chip results were pretreated with Agilent supporting software Genespring for data preprocessing and difference analysis. Cluster software MEV was used to cluster analysis. Real time-PCR was used in 10 cases of uterine myoma. The differential expression of hsa-miR-15b-5p, hsa-miR-21-5p, hsa-miR-34a-3p, and hsa-miR-34a-5p was demonstrated in the paired muscle tissue. Mi RDB, Tar Base, Target Scan, RNA22, Target databases were used to predict the above 4 target genes. Genomes, KEGG Pathway) explored the biological processes and related signaling pathways that the target gene might participate in. Results 1, 45 differentially expressed miRNA in human uterine myoma and myometrium were found, of which 19 miRNA were expressed in the uterine myoma, and 26 miRNA in the uterine fibroids decreased.2, verifying miR-15b-5p, miR-34a-5p, miR-34a-3p, miR. The expression of -21-5p in the uterine myoma tissue was significantly increased, which was basically consistent with the results of the chip, P was 0.0001.3. The target genes for the differential expression of miRNA in uterine myoma and myoma were mainly involved in 30 biological processes, such as morphological development, cell growth and development,.4. The target genes of miRNA in the differential expression of myoma and myometrium were mainly involved in cancer and mitogen activated eggs. 25 signaling pathways such as Mitogen-activated protein kinase (MAPK) and internal phagocytosis. Conclusion there is a significant difference in the expression of miRNA. second in uterine myoma and normal uterine myometrium. The effect of miR-15b-5p overexpression and low expression on the biological characteristics of uterine myoma cells is based on the results of the first part of the study and the selection of the selector The expression of miR-15b-5p in the uterine myoma tissue is significantly elevated. Through gene transfection, the expression and low expression of miR-15b-5p in various myoma cells and myometrium cells are made, and the effect of miR-15b-5p low expression on the proliferation of myoma cells is observed. The biological function of miR-15b-5p and the target gene of downstream target are explored for the future. Methods a total of 20 cases of myoma and paired myoma in the reproductive endocrine center of the gynecology and obstetrics and Gynecology of the Massachusetts General Hospital MGH, United States, in February -2014 August 2013, were collected in the reproductive endocrinology center of the gynecology and obstetrics and Gynecology of the United States, and the uterine myoma cells (P LYO cell) were isolated and cultured in partial and primary cells. S) and uterine myometrium (P MYO cells). At the same time, in vitro culture of the uterine myoma cell line (CP LYO cells) and the uterine myometrium cell line (CP MYO cells).Real time-PCR to detect the underlying expression level of different cells. In contrast, Real time-PCR was used to verify the expression of miR-15b-5p in each group and to establish a pattern of high expression or low expression of miR-15b-5p. The effect of miR-15b-5p on the proliferation of primary myoma cells was detected by methylthiazolyldiphenyl-tetrazolium (methylthiazolyldiphenyl-tetrazolium, MTT). Results 1, the expression of miR-15b-5p in various types of cells: original generation The expression level of miR-15b-5p in uterine myoma cells was significantly higher than that of the primary myometrium. The expression level of miR-15b-5p in the uterine myoma cell lines was significantly higher than that of the uterine myometrium (paired t test, P0.001).2, miR-15b-5p mimic transfected to 24 and 48h, and the expression of miR-15b-5p in each cell was significantly increased (paired t test, P0.00 1).3, miR-15b-5p inhibitor transfected cells 24 and 48h, miR-15b-5p expression in all types of cells decreased significantly (paired t test, P0.001).4, primary uterine myoma cells and uterine myoma cell lines, the proliferation rate of different concentration transfected miR-15b-5p inhibitor group was significantly lower than that of the negative control group (paired t test, P0.05). MiR-15b-5p can promote the proliferation of uterine myoma cells. Third part: the target protein of miR-15b-5p regulating the biological characteristics of uterine leiomyoma to predict and verify the downstream target gene / target protein of miR-15b-5p in the uterine myoma cells, and to detect the downstream target protein of miR-15b-5p in the uterine myoma tissue and the myometrium of the uterus. To further reveal the molecular mechanism of miR-15b-5p participation in the pathogenesis of uterine myoma. Methods using the bioinformatics database Mi RDB, Tar Base, Target Scan, RNA22, and Target Miner combined to predict the miR-15b-5p target gene. Ine-rich protein with Kazal motifs) expression level of M RNA in all types of cells; mimic and inhibitor and their negative controls for transfection of miR-15b-5p; immunoblotting experiments (Western Blot) verified the expression level of the protein in various cells; transfection and negative control, cell immunofluorescence detection The expression of RECK protein in primary myoma and myometrium cells. Then Western Blot and immunohistochemical staining (Immunohistochemical staining, IHC) were used to detect the difference of expression of RECK in myoma and myometrium and the cell location of RECK protein. Results 1, miR-15b-5p mimic was transferred to each type of cells for 24 hours, compared with the blank control group, the muscle was compared with the blank control group. The expression of RECK m RNA in the tumor cell line and the myometrium cell line decreased (paired t test, P0.05, P0.001).MiR-15b-5p mimic transfected for 48 hours. Compared with the blank control group, the uterine myoma cell line, the myometrium cell line and the original uterine myoma cells decreased the RECK m RNA expression. The expression of RECK protein in the 48h. uterine myoma cell lines and the primary uterine myoma cells transfected by b-5p mimic and inhibitor and their negative control cells transfected to miR-15b-5p mimic group was significantly lower than that of the negative control group. The expression of RECK protein in the miR-15b-5p inhibitor group was significantly higher than that of the miR-15b-5p inhibitor group (paired t test, P). The expression of RECK protein in the miR-15b-5p mimic group was significantly decreased (paired t test, P0.001), and the expression of RECK protein in the transfected inhibitor group was significantly higher than that of the negative control group. The difference was statistically significant (paired t test, P0.01). The expression of mimic RECK protein transfected in the primary myometrium cells decreased significantly; the expression of mimic RECK protein was significantly decreased; the transfection of the primary myometrium cells transfected to the inhibitor group was significantly decreased. The expression of RECK protein in group inhibitor was significantly higher, and the difference was statistically significant (paired t test, P0.05).3. 40n M miR-15b-5p inhibitor and its negative control were used to transfect the primary myoma cells and primary myometrium cells respectively. The RECK protein expressed in the inhibitor group was increased to the RECK protein, and the protein was in the myometrium of the uterus. The expression of the fabric was significantly higher than that of the paired uterine myoma (paired t test, P0.001), the expression of.RECK protein in the uterine myoma cells was significantly higher than that of the paired uterine myoma cells (paired t test, P0.05).5, the RECK protein expression was located in the cytoplasm of the fibroblast cells of the uterus, and the paired uterine myometrium was significantly more expressed than the RECK protein in the uterine myoma tissue. Elevated (unpaired t test, P0.05). Conclusion miR-15b-5p participates in the pathogenesis of uterine fibroids by regulating RECK.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R737.33

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