發(fā)布時間：2018-05-18 04:33

  本文選題：Ⅰ型子宮內膜腺癌 + miRNA-mRNA網絡��； 參考：《南方醫(yī)科大學》2016年博士論文

【摘要】：研究背景：子宮內膜癌(endometrial carcinoma, EC)是子宮內膜上皮細胞來源的一種常見的女性生殖系統(tǒng)惡性腫瘤,是婦科三大惡性腫瘤之一,發(fā)病率僅次于宮頸癌,位于第二位,占婦科腫瘤癌癥的30%左右。雖然相對于其它女性生殖系統(tǒng)惡性腫瘤患者,子宮內膜癌患者大多數五年的生存率不低,預后程度也較好,但在我國有逐年上升趨勢。嚴重危害女性健康。作為一種病因尚不明確的疾病,子宮內膜癌中有85%-90%為Ⅰ型子宮內膜癌；目前腫瘤疾病相關的研究依舊不能很好的解釋子宮內膜癌的發(fā)病過程。子宮內膜癌的高發(fā)人群主要是絕經后婦女,年齡多為50-60歲,約占總發(fā)病人數的75%左右。近年來,在國內外的相關研究報道中,子宮內膜癌的發(fā)病率和死亡率在全世界范圍內呈明顯年輕化和迅速上升的趨勢。美國癌癥協(xié)會的評估報告顯示,2005年美國新發(fā)現的子宮內膜癌40880例,其中7310例患者死亡,2010年,有新增病例43470例,死亡7950例,而最新的流行病學調查資料則顯示,在2015年美國女性所有新發(fā)的癌癥中,子宮內膜癌發(fā)病率明顯上升,僅排在乳腺癌、肺癌和結腸癌之后位居第4位,并且預計因子宮內膜癌死亡的人數將達到10170之多。在我國,目前還沒有大規(guī)模完全的子宮內膜癌統(tǒng)計學資料報道,但據不完全的調查統(tǒng)計結果顯示,我國子宮內膜癌的發(fā)病率逐年上升的趨勢已非常明顯。根據腫瘤病理形態(tài)特征不同,子宮內膜癌分為兩種類型：即Ⅰ型雌激素依賴和Ⅱ型非雌激素依賴,兩者的發(fā)生發(fā)展的分子機制、形態(tài)學特征以及預后等存在明顯的差別。Ⅰ型與雌激素過度刺激相關,主要為子宮內膜過度生長的基礎上發(fā)展形成的子宮內膜樣腺癌,占子宮內膜癌的80-90%；Ⅱ型病理類型主要為透明細胞癌,漿液性乳頭狀癌,粘液腺癌以及腺鱗癌等,臨床以雌激素依賴的Ⅰ型為主[9],因此本研究主要針對Ⅰ型的子宮內膜樣腺癌進行研究,后面提到的子宮內膜癌均指代Ⅰ型子宮內膜樣腺癌。子宮內膜癌臨床早期表現為陰道不規(guī)則流血癥狀,可有助于早期診斷,并且80%子宮內膜癌患者的病灶會局限在子宮體內,因此,相對于其它的女性生殖系統(tǒng)惡性腫瘤患者,子宮內膜癌患者大多數五年的生存率不低,預后程度也較好,有研究報道,早期子宮內膜癌患者的5年無病存活率可達98%,5年總生存率可達93%。然而,仍然有部分子宮內膜癌患者的病理分化程度低,侵襲轉移率高,預后效果差,通常會因為腫瘤的轉移和浸潤生長,導致病情的深度惡化而死亡。目前,對于子宮內膜癌的發(fā)病機理尚未完全清楚,對于病理分期高、發(fā)生復發(fā)性轉移的患者目前也沒有確切有效的治療措施,因此,深入研究子宮內膜癌的生物學特點,搜尋子宮內膜癌相關標記物并分析其與子宮內膜癌的分化、轉移和侵襲存在的不同差異及其分子機制,對提高子宮內膜癌病程的判斷預測、臨床治療的指導及患者預后的改善具有重要的意義。微小RNA (micro RNAs, miRNA)是一種由22-25個核苷酸組成的非編碼單鏈RNAs,目前認為在哺乳動物體內,miRNA與靶基因作用,使靶基因的mRNA在轉錄后的翻譯過程中被抑制或直接降解,導致靶基因的蛋白表達水平降低。通過這種方式,miRNA參與到包括生長發(fā)育、造血、器官形成、細胞增殖、凋亡乃至腫瘤發(fā)生等多種生命活動中。據研究表明,每個miRNA可以調控200個靶基因,同樣一個靶基因可以被多個miRNA調控。生物信息學則是利用miRNA與靶基因mRNA可以完全或部分互補的原則,通過各自的堿基序列預測出可能與特定miRNA(或mRNA)作用的所有mRNA(或niRNA),以縮小研究范圍,進一步通過實驗驗證二者的確切關系。miRNA-mRNA調控網絡定義為在相似生物過程中的一組miRNAs和一組mRNAs。一個調控模塊中包含的miRNAs和靶基因mRNAs都具有高度的關聯(lián)性,他們被認為具有相似的生物功能。目前,較為廣泛應用的是MRMs,這種方法就是利用多種異構數據源miRNA-mRNA堿基互補配對信息、miRNAs和mRNAs表達信息來構建miRNA-mRNA調控網絡,他們他們所發(fā)現的miRNA-mRNA對具有較高的置信度并且miRNAs與mRNAs的表達模式高度相關。因此,通過挖掘miRNA-mRNA調控模塊可以在分子層次上了解疾病的生物過程；其次,可以了解包括癌癥或腫瘤在內的疾病生物機理；另外,還可以為基因診斷和治療提供參考。胞質型多聚腺苷酸化原件結合蛋白(cytoplasmic polyadenylation element binding protein, CPEBs)是一組高度保守的RNA結合蛋白家族。在其與腫瘤關系的研究中,以CPEB1和CPEB4研究較為廣泛。但結合前期工作基礎,子宮內膜癌高通量測序提示CPEBs家族中的CPEB1與子宮內膜癌的發(fā)生更為密切。已有文獻研究,CPEBs人類乳頭瘤病毒(human papilloma virus, HPV)的感染有關[14]。HPV持久的感染和蛋白質E5、E6和E7的表達是宮頸癌發(fā)生的先決條件,HPVE5、E6、E7 mRNA含有3'不翻譯區(qū)域(3'UTR)特定序列(富含U的胞質型聚腺苷酸化原件,CPE區(qū)),它們是CPEB1作用的特異性靶點,其多聚腺苷酸化、翻譯受到CPEB1的調控。CPEB1在HPV陽性腫瘤發(fā)展中可能具有重要的調節(jié)功能,將CPEB mRNA作為生殖器官癌癥的標記物應該非常有用,因此探究CPEB1在子宮內膜癌的發(fā)生中的作用有重要意義。研究目標：本研究旨在通過采用網絡生物信息學理論,從子宮內膜癌相關miRNA文獻中挖掘Traits associated miRNA,結合已知基因功能和miRNA靶基因預測數據庫,構建miRNA和靶基因的綜合調控關系網絡,通過與前期研究工作想結合并初步驗證,篩選出新的與子宮內膜癌高度相關的靶基因CPEB1及以靶基因CPEB1為中心的關系調控網絡；在此基礎上再以獲得性與缺失性功能試驗明確所篩選靶基因在子宮內膜癌細胞中的生物學功能,并初步探求CPEB1在子宮內膜癌發(fā)生發(fā)展中可能的分子機制。方法：使用自由檢索詞,以FACTA工具和Pubmed數據庫進行文獻挖掘子宮內膜癌相關miRNAs;4種不同的預測方法(TargetScan、miRanda、miRDB和Starbase)預測所挖掘出來每個miRNA的作用靶基因獲得miRNA-mRNA對；從miRNA-mRNA對中選取至少5個以上miRNA共同靶向的mRNA為子宮內膜癌相關基因,構建子宮內膜癌的miRNA-mRNA網絡；利用QRT-PCR法驗證調控網絡中綜合排名靠前基因mRNA表達情況,篩選出特異性差異表達的基因CPEB1為目的基因進行深入研究。利用QRT-PCR法檢測CPEB1在子宮內膜癌組織和細胞中的表達情況；構建CPEB1過表達載體,通過體外轉染CPEB1過表達載體過表達CPEB1,以MTT、克隆形成、流式細胞術、劃痕實驗、transwell小室等實驗方式體外檢測CPEB1對子宮內膜癌細胞株生物學行為的影響；構建穩(wěn)定過表達CPEB1的子宮內膜癌細胞株,以裸鼠成瘤實驗體內分析CPEB1的生物學功能；通過轉染CPEB1過表達載體,觀察細胞形態(tài)變化,應用western blot分析細胞凋亡相關蛋白以及EMT標記關鍵蛋白分子的表達,初步探討CPEB1參與子宮內膜癌細胞生物學行為調控的分子機制。結果：1.通過多步分析,結合現有近五年來41篇相關文獻,初步篩選出208個子宮內膜癌相關miRNA及其靶基因；經過4個不同數據庫比對分析,篩選同時存在于兩個或兩個以上數據庫,并至少有兩篇研究報道的miRNA為目標miRNA,最終獲得35個子宮內膜癌相關miRNA。2.通過4種預測方法對35個子宮內膜癌相關miRNA進行靶基因預測,獲得110995個miRNA-mRNA對,去除出現次數少于3的miRNA-mRNA對,最終獲得由27個miRNAs和3082個基因組成的7919個miRNA-mRNA對,其中至少5個miRNA同時靶向的基因457個。3.分析457個候選基因的蛋白間的相互作用,有61個基因至少存在5個互作蛋白,14個基因至少有10個互作蛋白。信號通路分析這61個候選基因富集的調控網絡,大部分通路為癌相關通路。4.從61個候選基因中挑選互作蛋白數量靠前的10個基因進行QRT-PCR實驗驗證,有3個基因表達失調,其中CDC25A和IGF1R在子宮內膜癌中表達上調,CPEB1表達下調,CDC25A和IGF1R已有文獻報道與子宮內膜癌密切相關,篩選CPEB1為目標基因進行功能驗證。5.分別檢測CPEB1在20對子宮內膜癌組織及配對癌旁組織、3株子宮內膜癌細胞和1株正常子宮內膜上皮細胞的表達水平,結果顯示CPEB1在子宮內膜癌組織和子宮內膜癌細胞株中表達顯著下調,提示CPEB1可能作為子宮內膜癌發(fā)生的分子標記。6. CPEB1體外功能研究結果顯示：MTT、克隆形成實驗證實CPEB1能顯著抑制子宮內膜癌細胞的體外增殖能力；流式細胞凋亡檢測發(fā)現CPEB1能促進子宮內膜癌細胞的凋亡；劃痕實驗證實CPEB1過表達抑制子宮內膜癌細胞的遷移；transwell實驗證實CPEB1能顯著抑制子宮內膜癌細胞的侵襲能力；小鼠體表皮下成瘤實驗及HE、IHC檢測證實,CPEB1能顯著抑制腫瘤在體內的形成。7. CPEB1在ISK細胞株中極低表達,CPEB1-siRNA實驗未能成功構建CPEB1低表達干擾載體用于后續(xù)實驗。8.通過生物信息學分析及數據庫的預測,提示CPEB1可能通過細胞凋亡通路及EMT相關通路參與腫瘤疾病的發(fā)生；凋亡相關分子檢測結果顯示,過表達CPEB1后,子宮內膜癌細胞ISK中細胞凋亡相關分子P53、Bax、Caspase-3表達上調,Bcl-2表達下調；提示CPEB1可能參與P53介導子宮內膜癌細胞凋亡調控。9.EMT相關分子檢測結果顯示,過表達CPEB1后,細胞發(fā)生上皮化的形態(tài)學改變。子宮內膜癌細胞ISK中上皮-間質轉化特征標志物和相關轉錄因子E-cadherin、β-catenin的表達明顯上調,Vimentin、SMA、Snail的表達顯著下調,Twist不發(fā)生明顯變化,由此證實,CPEB1高表達促進細胞發(fā)生間質-上皮化改變(MET)。結論1.成功構建子宮內膜癌特異miRNA-mRNA調控網絡,篩選CPEB1為子宮內膜癌密切相關基因。2.證實CPEB1在子宮內膜癌組織及細胞中特異性低表達,CPEB1低表達可能是子宮內膜癌發(fā)生及惡性轉移的分子標記。3. CPEB1作為抑癌因子,具有抑制子宮內膜癌細胞的生長和增殖、促進子宮內膜癌細胞的凋亡、抑制侵襲和轉移,抑制小鼠皮下成瘤腫瘤形成的生物學功能。4. CPEB1影響子宮內膜癌細胞中細胞凋亡相關蛋白P53、Bax、Bcl-2. caspase-3的表達,推測CPEB1可能通過P53介導的信號通路參與子宮內膜癌細胞凋亡的調控,參與子宮內膜癌的發(fā)生。5. CPEB1影響子宮內膜癌細胞中EMT特異標記物E-cadherin、Vimentin、 SMA、β-catenin及促EMT轉錄因子Snail的表達,推測CPEB1可能通過下調子宮內膜癌細胞EMT轉錄因子的表達,促進腫瘤發(fā)生MET,抑制腫瘤細胞的侵襲。
[Abstract]:Background: endometrial carcinoma (EC) is a common malignant tumor of female reproductive system from endometrium epithelial cells. It is one of the three most malignant gynecologic malignancies. The incidence is second only to cervical cancer, which is located in the second place, accounting for about 30% of the cancer of gynecologic cancer. The five year survival rate of the patients with endometrial cancer is not low and the prognosis is good, but it is increasing year by year in our country. It is serious harm to women's health. As a disease that is not clear, 85%-90% is type I endometrium cancer in endometrial cancer, and the research of tumor related diseases is still not very good. The high incidence of endometrial carcinoma is mainly the postmenopausal women, the age of which is 50-60 years old and about 75% of the total incidence of endometrium. In recent years, the incidence and mortality of endometrial cancer are becoming more and more young and rapidly rising in the world. In 2005, 40880 newly discovered endometrial cancer cases were found in the United States, of which 7310 patients died. In 2010, there were 43470 new cases and 7950 deaths. The latest epidemiological data showed that in all new American women's cancers, the incidence of endometrial cancer was significantly increased in 2015, only in line with the incidence of endometrial cancer. The number of breast cancer, lung cancer and colon cancer is the fourth place, and the number of deaths due to endometrial cancer is expected to reach more than 10170. In China, there are no statistical reports on large scale endometrial cancer in China. However, according to the incomplete survey statistics, the trend of the incidence of endometrial cancer in China has been increasing year by year. According to the pathological features of the tumor, endometrial carcinoma is divided into two types: type I estrogen dependence and type II non estrogen dependence. There are obvious differences in the molecular mechanism, morphological characteristics and prognosis of the two. Type I is associated with over stimulation of estrogen, mainly the overgrowth of endometrium. Endometrioid adenocarcinoma, which is based on the development of endometrioid adenocarcinoma, accounts for 80-90% of endometrial carcinoma. Type II pathological types are mainly transparent cell carcinoma, serous papillary carcinoma, mucous adenocarcinoma, and adenosscale carcinoma. The main clinical type of estrogen dependent type I is [9]. Therefore, this study mainly focuses on type I endometrioid adenocarcinoma. Endometrial carcinoma of the endometrium refers to type I endometrioid adenocarcinoma. The early clinical manifestations of endometrial carcinoma are irregular vaginal bleeding, which can help early diagnosis, and 80% of the endometrium cancer patients are localized in the uterus. Therefore, most of the patients with endometrial cancer are compared to other women with reproductive system cancer. The survival rate of the five years is not low and the prognosis is good. The 5 year disease free survival rate of the patients with early endometrial cancer can reach 98%, the total survival rate of 5 years can reach 93%., however, there are still some endometrium cancer patients with low degree of pathological differentiation, high invasion and metastasis rate and poor prognosis, usually because of tumor metastasis and infiltration. At present, the pathogenesis of endometrial cancer is not completely clear. There is no effective and effective treatment for patients with high pathological stages and recurrent metastasis. Therefore, the biological characteristics of endometrial cancer are studied, and the related markers of endometrial cancer are searched and analyzed. The differentiation, metastasis and invasion of endometrial carcinoma have different differences and their molecular mechanisms. It is of great significance to predict the course of endometrial cancer, guide the clinical treatment and improve the prognosis of the patients. RNA (micro RNAs, miRNA) is a non coding single chain RNAs consisting of 22-25 nucleotides, which is currently considered to be feeding. In milk moving objects, miRNA and target genes act to inhibit or directly degrade the target gene mRNA in the post transcriptional translation process, resulting in a decrease in the protein expression level of the target gene. By this way, miRNA participates in a variety of life activities including growth, hematopoiesis, organogenesis, cell proliferation, apoptosis and even tumorigenesis. The study shows that 200 target genes can be regulated by each miRNA, and the same target gene can be regulated by multiple miRNA. Bioinformatics uses the principle that miRNA and target gene mRNA can be fully or partially complementary, and all the mRNA (or niRNA) that may interact with a specific miRNA (or mRNA) can be predicted by their respective base sequences to reduce the scope of the study. Further experiments verify that the exact relationship between the two.MiRNA-mRNA regulatory networks is defined as a high correlation between a group of miRNAs in similar biological processes and the miRNAs and target gene mRNAs contained in a set of mRNAs. regulatory modules, and they are considered to have similar biological functions. At present, MRMs is widely used. The method is to use a variety of heterogeneous data sources miRNA-mRNA base complementary pairing information, miRNAs and mRNAs to construct the miRNA-mRNA regulatory network, they found that the miRNA-mRNA pairs have high confidence and the miRNAs and mRNAs expression patterns are highly correlated. Therefore, the miRNA-mRNA regulation module can be divided by mining the miRNA-mRNA regulation module. The biological processes of disease are understood at the sub level; secondly, we can understand the biological mechanisms of diseases including cancer or tumor; in addition, it can provide reference for genetic diagnosis and treatment. The cytoplasmic polyadenosine acidified original binding protein (cytoplasmic polyadenylation element binding protein, CPEBs) is a highly conserved RNA CPEB1 and CPEB4 are more widely used in the study of the association with the tumor. But combined with the early work basis, high throughput sequencing of endometrial cancer suggests that CPEB1 in the CPEBs family is more closely related to endometrial cancer. The infection of the CPEBs human mammary head tumor virus (human papilloma virus, HPV) has been studied. [14].HPV persistent infection and the expression of protein E5, E6 and E7 are the prerequisites for cervical cancer. HPVE5, E6, and E7 mRNA contain 3'untranslated region (3'UTR) specific sequence (rich in U cytoplasmic polyadenosine acidification original, CPE region). They are the specific targets of the action. The role of CPEB mRNA as a marker of reproductive organ cancer should be very useful in the development of positive tumor. Therefore, it is important to explore the role of CPEB1 in the occurrence of endometrial cancer. Traits associated miRNA was excavated, combined with the known gene function and the miRNA target gene prediction database, the comprehensive regulatory network of miRNA and target genes was constructed. Through the combination of previous research work and preliminary verification, the new target based on endometrial carcinoma was screened by CPEB1 and the target gene CPEB1 as the center. On this basis, the biological function of the screened target gene in endometrial cancer cells is identified by the acquired and missing function test, and the possible molecular mechanism of CPEB1 in the development of endometrial cancer is preliminarily explored. Methods: using free retrieval words, using FACTA tool and Pubmed database to carry out the literature mining in the uterus. Membrane cancer related miRNAs; 4 different prediction methods (TargetScan, miRanda, miRDB and Starbase) predicted that each miRNA target gene was excavated to obtain miRNA-mRNA pairs; at least 5 more miRNA common targets were selected from miRNA-mRNA pairs for endometrial cancer related basis, and the miRNA-mRNA network of endometrial cancer was constructed; Q was used for Q. The RT-PCR method was used to verify the expression of mRNA in the regulatory network, and the specific gene CPEB1 was screened out for the target gene. QRT-PCR was used to detect the expression of CPEB1 in endometrial carcinoma tissues and cells; to construct CPEB1 overexpressed carrier and transfect CPEB1 overexpression vector in vitro The effect of CPEB1 on the biological behavior of endometrial carcinoma cell lines was detected by MTT, cloned formation, flow cytometry, scratching experiment, and Transwell chamber. The biological function of the endometrial carcinoma cell line that stably overexpressed CPEB1 was constructed, and the biological function of CPEB1 in nude mice was analyzed in vivo of the tumor in nude mice; through transfection of CPEB1 over the table of CPEB1 The molecular mechanism of CPEB1 involvement in the regulation of biological behavior of endometrial cancer cells was preliminarily investigated by Western blot analysis of cell morphological changes. The molecular mechanism of CPEB1 involvement in the regulation of biological behavior of endometrial cancer cells was preliminarily discussed. Results: 1. through multistep analysis, 41 related documents have been screened in recent five years, and a preliminary screening was made. Endometrial carcinoma associated miRNA and its target genes were screened by 4 different database comparisons and at least two or more databases were screened at the same time, and at least two reported miRNA were targeted miRNA, and 35 endometrial cancer related miRNA.2. was finally obtained by 4 pretests for 35 endometrial cancer related miRNA. Target gene prediction, obtained 110995 miRNA-mRNA pairs, the removal of less than 3 of the miRNA-mRNA pair, and finally got 7919 miRNA-mRNA pairs of 27 miRNAs and 3082 genes, of which at least 5 miRNA targeted gene 457.3. analysis of the protein interaction between 457 candidate genes, 61 genes at least 5 interacts. Protein, 14 genes have at least 10 interacting proteins. The signaling pathway analyses the regulatory network of the 61 candidate genes, and most of the pathways are the cancer related pathway.4. from 61 candidate genes to select 10 genes from the 61 candidate genes to perform the QRT-PCR test, and 3 genes are dysfunctional, of which CDC25A and IGF1R are in endometrial cancer. The expression of CPEB1, CDC25A and IGF1R were closely related to endometrial cancer, and CPEB1 was selected as the target gene for functional verification..5. was used to detect CPEB1 in 20 endometrial and paracancerous tissues, 3 endometrial cancer cells and 1 normal endometrium epithelial cells. The expression of CPEB1 in endometrial carcinoma and endometrial carcinoma cell lines showed a significant downregulation, suggesting that CPEB1 may be a molecular marker of endometrial carcinoma in vitro. The results of the function of.6. CPEB1 in vitro showed: MTT, the clone formation experiment confirmed that CPEB1 could significantly inhibit the proliferation ability of endometrial carcinoma cells in vitro; flow cytometry It was found that CPEB1 could promote the apoptosis of endometrial cancer cells, and the scratch test confirmed that CPEB1 overexpression inhibited the migration of endometrial cancer cells, and the Transwell experiment confirmed that CPEB1 could significantly inhibit the invasion ability of endometrial cancer cells, the tumor formation experiment under the epidermis of the mice and the HE, IHC test evidence, CPEB1 could significantly inhibit the form of the tumor in the body. The expression of.7. CPEB1 was very low in ISK cell lines, and the CPEB1-siRNA experiment failed to construct CPEB1 low expression interference carrier for the follow-up experiment.8. through bioinformatics analysis and the prediction of database, suggesting that CPEB1 may participate in the occurrence of tumor disease through the apoptosis pathway and EMT related pathway; apoptosis related molecular detection results show that After overexpression of CPEB1, the apoptosis related molecules P53, Bax, Caspase-3, and Bcl-2 expression are up regulated in endometrial carcinoma cells, suggesting that CPEB1 may participate in the regulation of P53 mediated apoptosis of endometrial carcinoma cells and the results of.9.EMT related molecular detection show that after overexpression of CPEB1, the morphological changes of epithelial cells occur. Endometrial carcinoma is fine. The expression of epithelial mesenchymal transition in cell ISK and related transcription factor E-cadherin, the expression of beta -catenin was obviously up-regulated, the expression of Vimentin, SMA, Snail decreased significantly, and Twist did not change obviously. Thus, the high expression of CPEB1 promoted the change of cytoplasm epithelialization of cells (MET). Conclusion 1. successfully constructed the specific miRNA-mRNA of endometrial carcinoma. Regulatory network, screening CPEB1 for endometrial cancer closely related gene.2. confirmed that CPEB1 in endometrial cancer tissues and cells of low expression, CPE
【學位授予單位】：南方醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R737.33

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