本文選題：子宮肌瘤 + 子宮肌層　； 參考：《鄭州大學》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60%,且發(fā)病率呈逐年上升的趨勢。子宮肌瘤典型的臨床表現(xiàn)包括:經(jīng)量過多、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;嚴重的子宮肌瘤會導致女性不孕和習慣性流產(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,浪費大量衛(wèi)生資源,嚴重威脅婦女的身心健康。而子宮肌瘤的發(fā)病機制至今不清,是國內(nèi)外研究的熱點之一。微小核糖核酸(micro ribonucleic acid,miRNAs)是一種廣泛存在于真核生物細胞中,大小約為21-23個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,如細胞增殖,凋亡,應激反應,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,是細胞內(nèi)普遍存在的一種精細調(diào)節(jié)蛋白表達的轉(zhuǎn)錄后調(diào)控機制。Mi RNA參與多種腫瘤的發(fā)病過程,如細胞增殖、凋亡、炎癥反應、血管生成、組織更新和抑癌致癌基因修飾,與腫瘤預后密切相關,是腫瘤的早期診斷及其預后判斷的良好的生物標記物。Mi RNA參與子宮肌瘤發(fā)病的作用機制的研究尚處于初始階段。多篇報道顯示,子宮肌瘤和子宮肌層中存在差異表達顯著的miRNA。檢測子宮肌瘤和子宮肌層miRNA的差異表達,進而深入探討差異miRNA對肌瘤細胞的生物學功能和調(diào)控,為揭示miRNA參與子宮肌瘤的發(fā)病機制奠定良好基礎。目前,miRNA的研究方法主要有熒光實時定量PCR(Real time-PCR)、miRNA芯片及二代測序技術。而miRNA芯片是篩選子宮肌瘤和子宮肌層差異表達的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micro RNA的篩選研究目的本研究通過miRNA芯片篩選子宮肌瘤和配對的子宮肌層樣本中差異表達的miRNA,芯片聯(lián)合生物信息學分析,預測差異表達顯著的miRNA的靶基因及其生物學功能。方法收集2012年11月至2013年1月在鄭州大學第三附屬醫(yī)院婦產(chǎn)科因子宮肌瘤行子宮全切術的10例育齡期子宮肌瘤患者的肌瘤組織和配對的肌層組織為研究對象。采用Agilent Human miRNA(8*60K)V19.0芯片篩選3例子宮肌瘤和配對的肌層組織中差異表達顯著的miRNA,芯片結果用Agilent配套軟件Genespring進行數(shù)據(jù)預處理和差異分析,采用聚類軟件MEV進行聚類分析。應用Real time-PCR在10例子宮肌瘤和配對的肌層組織中驗證hsa-miR-15b-5p、hsa-miR-21-5p、hsa-miR-34a-3p、hsa-miR-34a-5p的差異表達。利用Mi RDB、Tar Base、Target Scan、RNA22、Target Miner數(shù)據(jù)庫預測上述4個miRNA的靶基因,采用基因本體論(Gene Ontology,GO)和KEGG信號通路分析(Kyoto Encyclopedia of Genes and Genomes,KEGG Pathway)探尋靶基因可能參與的生物學過程和相關信號通路。結果1、發(fā)現(xiàn)人子宮肌瘤和子宮肌層組織中45個差異表達的miRNA,其中19個miRNA在子宮肌瘤中表達升高,26個miRNA在子宮肌瘤中表達下降。2、驗證miR-15b-5p、miR-34a-5p、miR-34a-3p、miR-21-5p在子宮肌瘤組織表達顯著升高,與芯片結果基本一致,P均0.0001。3、子宮肌瘤和肌層差異表達的miRNA的靶基因主要參與形態(tài)發(fā)育、細胞生長發(fā)育等30個生物學過程。4、子宮肌瘤和肌層差異表達的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個信號通路。結論子宮肌瘤和正常子宮肌層組織中存在差異表達顯著的miRNA。第二部分:miR-15b-5p過表達和低表達對子宮肌瘤細胞生物學特征的影響目的根據(jù)第一部分研究結果,選擇子宮肌瘤組織中表達顯著升高的miR-15b-5p,通過基因轉(zhuǎn)染技術,使miR-15b-5p在各型肌瘤細胞和肌層細胞中過表達和低表達,并觀察miR-15b-5p低表達對子宮肌瘤細胞增殖的影響,為后續(xù)全面研究miR-15b-5p的生物學功能及遠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的育齡期患者的肌瘤和配對的肌層組織共20例,部分消化和原代細胞分離培養(yǎng)為子宮肌瘤細胞(p LYO cells)和子宮肌層細胞(p MYO cells)。同時體外培養(yǎng)子宮肌瘤細胞系(cp LYO cells)和子宮肌層細胞系(cp MYO cells)。Real time-PCR檢測不同細胞miR-15b-5p的本底表達水平。脂質(zhì)體在各型細胞瞬時轉(zhuǎn)染miR-15b-5p的模擬物(mimic)、抑制物(inhibitor)及其陽性、陰性對照,應用Real time-PCR驗證miR-15b-5p在各組表達情況,建立miR-15b-5p高表達或低表達的模式。采用噻唑藍實驗(methylthiazolyldiphenyl-tetrazolium,MTT)檢測miR-15b-5p對原代子宮肌瘤細胞增殖能力的影響。結果1、miR-15b-5p在各型細胞中本底表達情況:原代子宮肌瘤細胞中miR-15b-5p的表達水平顯著高于原代子宮肌層細胞;子宮肌瘤細胞系中miR-15b-5p的表達水平顯著高于子宮肌層細胞系(配對t檢驗,P0.001)。2、miR-15b-5p mimic轉(zhuǎn)染各型細胞24和48h,各型細胞中miR-15b-5p的表達顯著升高(配對t檢驗,P0.001)。3、miR-15b-5p inhibitor轉(zhuǎn)染各型細胞24和48h,各型細胞中miR-15b-5p表達顯著降低(配對t檢驗,P0.001)。4、原代子宮肌瘤細胞和子宮肌瘤細胞系中,不同濃度轉(zhuǎn)染miR-15b-5p inhibitor組與轉(zhuǎn)染其陰性對照組相比,細胞增殖率顯著降低(配對t檢驗,P0.05)。結論miR-15b-5p可促進子宮肌瘤細胞的增殖能力。第三部分:miR-15b-5p調(diào)控子宮肌瘤細胞生物學特征的下游靶蛋白研究目的預測并驗證miR-15b-5p在子宮肌瘤細胞的下游靶基因/靶蛋白,檢測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差異,進一步揭示miR-15b-5p參與子宮肌瘤發(fā)病的分子機制。方法利用生物信息學數(shù)據(jù)庫Mi RDB、Tar Base、Target Scan、RNA22、Target Miner聯(lián)合預測miR-15b-5p的靶基因。轉(zhuǎn)染miR-15b-5p的mimic,Real time-PCR驗證預測的miR-15b-5p的靶基因RECK(Reversion-inducing cysteine-rich protein with Kazal motifs)在各型細胞的m RNA的表達水平;轉(zhuǎn)染miR-15b-5p的mimic和inhibitor及各自陰性對照,免疫印跡實驗(Western Blot)驗證RECK蛋白在各型細胞的表達水平;轉(zhuǎn)染miR15b-5p inhibitor及其陰性對照,細胞免疫熒光(Immunoflunence,IF)檢測原代肌瘤及肌層細胞RECK蛋白的表達變化。繼而采用Western Blot和免疫組織化學染色法(Immunohistochemical staining,IHC)檢測RECK在肌瘤和肌層組織的表達差異及RECK蛋白的細胞定位。結果1、miR-15b-5p mimic轉(zhuǎn)染各型細胞24小時,與空白對照組相比,肌瘤細胞系和肌層細胞系RECK m RNA表達下降(配對t檢驗,P0.05,P0.001)。miR-15b-5p mimic轉(zhuǎn)染各型細胞48小時,與空白對照組相比,子宮肌瘤細胞系、子宮肌層細胞系及原代子宮肌瘤細胞RECK m RNA表達下降(配對t檢驗,P0.01,P0.001,P0.001)。2、使用10n M的miR-15b-5p mimic和inhibitor及各自陰性對照轉(zhuǎn)染各型細胞48h。子宮肌瘤細胞系和原代子宮肌瘤細胞系轉(zhuǎn)染miR-15b-5p mimic組與其陰性對照組相比,RECK蛋白表達顯著下降;轉(zhuǎn)染miR-15b-5p inhibitor組RECK蛋白表達顯著升高,差異具有統(tǒng)計學意義(配對t檢驗,P均0.001)。子宮肌層細胞系轉(zhuǎn)染miR-15b-5p mimic組與其陰性對照組相比,RECK蛋白表達顯著下降(配對t檢驗,P0.001);轉(zhuǎn)染inhibitor組RECK蛋白表達顯著升高,差異具有統(tǒng)計學意(配對t檢驗,P0.01)。原代子宮肌層細胞轉(zhuǎn)染mimic RECK蛋白表達顯著下降;轉(zhuǎn)染inhibitor組RECK蛋白表達顯著升高,差異具有統(tǒng)計學意義(配對t檢驗,P0.05)。3、使用40n M的miR-15b-5p inhibitor和其陰性對照分別轉(zhuǎn)染原代子宮肌瘤細胞和原代肌層細胞,轉(zhuǎn)染inhibitor組轉(zhuǎn)綠色熒光標記的RECK蛋白表達增多。4、RECK蛋白在子宮肌層組織表達顯著高于配對的子宮肌瘤組織(配對t檢驗,P0.001)。RECK蛋白在子宮肌層細胞表達顯著高于配對的子宮肌瘤細胞(配對t檢驗,P0.05)。5、RECK蛋白表達位于子宮肌纖維細胞的胞漿,配對的子宮肌層組織較子宮肌瘤組織中RECK蛋白表達顯著升高(非配對t檢驗,P0.05)。結論miR-15b-5p通過調(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.

【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R737.33

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