本文關(guān)鍵詞： HOTAIR 上皮性卵巢癌 q PCR SKOV3 A2780 增殖 侵襲 轉(zhuǎn)移 HOTAIR PIK3R3 機(jī)制 免疫組化　出處：《重慶醫(yī)科大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：卵巢癌是繼宮頸癌和子宮內(nèi)膜癌的三大惡性腫瘤之一,其病死率高居?jì)D科惡性腫瘤之首,由于起病隱匿、早期缺乏特異性癥狀與體征及有效的醫(yī)學(xué)篩查手段,約70%卵巢癌患者就診時(shí)已發(fā)生局部或遠(yuǎn)處轉(zhuǎn)移,失去了手術(shù)的最佳時(shí)期,結(jié)果導(dǎo)致5年的總體生存率欠佳。早期卵巢癌(Ⅰ期和Ⅱ期)的遠(yuǎn)期生存率可達(dá)到80%~95%,相比之下,晚期卵巢癌(Ⅲ期和Ⅳ期)的遠(yuǎn)期生存率只有10%~30%。因此卵巢惡性腫瘤存在“兩個(gè)70%”:超過(guò)70%的患者確診時(shí)已屬晚期;約70%的患者在兩年內(nèi)復(fù)發(fā)。故由此可見(jiàn),尋找早期診斷及有效的治療方法對(duì)于卵巢癌患者的生存率至關(guān)重要。近幾年,學(xué)者們一直在尋找具有特異性的方法,以提高卵巢癌的生存率,保證患者的有效預(yù)后。另外一種學(xué)說(shuō)“二元論模型”認(rèn)為,卵巢癌分為高級(jí)別和低級(jí)別兩類。高級(jí)別卵巢上皮性癌占卵巢癌發(fā)病的75%,占卵巢癌病死率的90%,其發(fā)病迅速,侵襲性極強(qiáng),常伴發(fā)廣泛的盆腹腔轉(zhuǎn)移和種植,預(yù)后極差。而低級(jí)別卵巢上皮性癌發(fā)病緩慢,多經(jīng)歷良性、交界性和低度惡性的發(fā)展過(guò)程,多為早期,預(yù)后較好。因此高級(jí)別卵巢上皮性癌由于極易發(fā)生侵襲和轉(zhuǎn)移,是威脅婦女健康的惡性腫瘤。然而其發(fā)生侵襲和轉(zhuǎn)移的機(jī)制不明。近來(lái),繼mi RNA的大量研究之后,被稱為長(zhǎng)鏈非編碼RNA(long non-coding RNA,lnc RNA)的一類分子量大于200nt的非編碼RNA被發(fā)現(xiàn)并逐漸受到越來(lái)越多的研究。因其對(duì)靶基因表達(dá)的調(diào)控作用,lnc RNA參與了許多癌癥發(fā)生、發(fā)展的過(guò)程。近年來(lái)的研究表明lnc RNA參與了轉(zhuǎn)錄激活、染色質(zhì)修飾、轉(zhuǎn)錄干擾和核內(nèi)運(yùn)輸多種重要的調(diào)控。圖1 Lnc RNA的調(diào)控我們的前期研究,對(duì)44例卵巢癌組織及14例正常卵巢組織樣本采用實(shí)時(shí)熒光定量PCR(RT-PCR)的方法檢測(cè)長(zhǎng)鏈非編碼RNA HOTAIR m RNA的表達(dá)。結(jié)果卵巢癌組織中HOTAIR m RNA表達(dá)高于正常卵巢組織[(1.26士0.27 vs.(0.14士0.09)],差異有統(tǒng)計(jì)學(xué)意義(P㩳0.05),病理類型為低度分化及未分化的卵巢癌組織中HOTAIR m RNA表達(dá)高于中-低、中一高及高度分化組織⺌(1.65士0.4 1)vs(0.39士0.l4)⺗,差異有統(tǒng)計(jì)學(xué)意義(P㩳0.05)。結(jié)論卵巢癌組織中HOTA IR的表達(dá)增高,且癌組織分化越低,HOTA IR表達(dá)越高。提示HOTA IR有可能作為發(fā)現(xiàn)卵巢癌,并判斷其惡性程度的一個(gè)分子標(biāo)志,可能在卵巢癌的發(fā)生、發(fā)展中扮演重要的角色。但機(jī)制不清。因此本研究擬在前期基礎(chǔ)上進(jìn)一步研究Hotair在卵巢癌中的作用及其機(jī)制。為Hotair在卵巢癌中的作用以及精準(zhǔn)治療提供理論依據(jù)和基礎(chǔ)。第一部分HOTAIR促進(jìn)卵巢上皮性癌惡性生物學(xué)行為及其機(jī)制的研究目的研究沉默HOTAIR后對(duì)上皮性卵巢癌惡性生物學(xué)行為的影響。方法(1)q PCR檢測(cè)在HOTAIR在卵巢癌細(xì)胞株SKOV3,OVCAR3和A2780的表達(dá)情況。(2)沉默HOTAIR后,劃痕實(shí)驗(yàn)檢測(cè)卵巢癌細(xì)胞轉(zhuǎn)移能力,transwell檢測(cè)卵巢癌細(xì)胞侵襲能力,Ed U檢測(cè)卵巢癌細(xì)胞增殖能力。結(jié)果(1)HOTAIR在SKOV3和OVCAR3細(xì)胞中表達(dá)高于A2780細(xì)胞;(2)沉默HOTAIR后,卵巢癌SKOV3細(xì)胞轉(zhuǎn)移、侵襲和增殖能力降低;結(jié)論沉默HOTAIR可以抑制卵巢癌SKOV3細(xì)胞惡性生物學(xué)行為。第二部分HOTAIR通過(guò)mi R-214和mi R-217調(diào)控PIK3R3參與卵巢癌惡性生物學(xué)行為目的探索HOTAIR影響卵巢癌惡性生物學(xué)行為的分子機(jī)制。方法(1)生物信息學(xué)預(yù)測(cè)HOTAIR可能調(diào)控的ce RNA;(2)q PCR檢測(cè)沉默HOTAIR后,PIK3R3的表達(dá)情況;同時(shí)檢測(cè)沉默PIK3R3后HOTAIR的表達(dá)情況;(3)q PCR檢測(cè)沉默HOTAIR或PIK3R3后,mi R-214和mi R-217表達(dá)情況;(4)q PCR檢測(cè)mi R-214和mi R-217以及mi R-214和mi R-217inhibitor對(duì)HOTAIR和PIK3R3的影響;(5)雙熒光素酶報(bào)告基因檢測(cè)HOTAIR或PIK3R3是否是mi R-214和mi R-217的直接靶點(diǎn)。(6)免疫組化檢測(cè)PIK3R3在卵巢癌組織的表達(dá)情況;(7)沉默PIK3R3后,檢測(cè)卵巢癌細(xì)胞的增殖、轉(zhuǎn)移和侵襲能力。結(jié)果:(1)生物信息學(xué)預(yù)測(cè)HOTAIR和PIK3R3互為ce RNA,HOTAIR和PIK3R3是mi R-214和mi R-217的潛在靶點(diǎn);(2)沉默HOTAIR后,PIK3R3表達(dá)降低;沉默PIK3R3后,HOTAIR表達(dá)下調(diào)(P0.05);(3)沉默HOTAIR或PIK3R3后,mi R-214和mi R-217表達(dá)上調(diào)(P0.05);(4)轉(zhuǎn)染mi R-214和mi R-217 mimics后,HOTAIR或PIK3R3表達(dá)降低;轉(zhuǎn)染mi R-214和mi R-217 inhibitor后,HOTAIR或PIK3R3表達(dá)增加;(5)和對(duì)照組比較,共轉(zhuǎn)染mi R-214 mimics和p MIR-HOTAIR3’UTR后,熒光素酶活性明顯下降(P0.05);和對(duì)照組比較,共轉(zhuǎn)染mi R-214 mimics和MIR-HOTAIR 3’UTRm后,熒光素酶活性無(wú)明顯改變(P0.05);共轉(zhuǎn)染mi R-217 mimics和p MIR-HOTAIR3’UTR后,熒光素酶活性明顯下降(P0.05);和對(duì)照組比較,共轉(zhuǎn)染mi R-217 mimics和MIR-HOTAIR 3’UTRm后,熒光素酶活性無(wú)明顯改變(P0.05);(6)免疫組化結(jié)果顯示,PIK3R3在卵巢漿液性癌和粘液性癌中表達(dá)高于正常卵巢組織;(7)沉默PIK3R3后,SKOV3細(xì)胞增殖能力、轉(zhuǎn)移能力和侵襲能力均受到抑制。結(jié)論:卵巢癌SKOV3細(xì)胞株沉默HOTAIR基因表達(dá)后,細(xì)胞增殖、轉(zhuǎn)移和侵襲能力降低;HOTAIR通過(guò)mi R-214和mi R-217靶向PIK3R3調(diào)控卵巢癌SKOV3細(xì)胞的惡性生物學(xué)行為。第三部分沉默HOTAIR影響SKOV3體內(nèi)成瘤能力目的探究HOTAIR在體內(nèi)對(duì)卵巢癌SKOV3細(xì)胞生長(zhǎng)的影響方法(1)慢病毒載體構(gòu)建HOTAIR沉默的穩(wěn)定細(xì)胞株,然后移植到裸鼠左側(cè)腋窩,觀察移植瘤生長(zhǎng)情況;(2)采用免疫組織化學(xué)檢測(cè)沉默HOTAIR基因后,裸鼠移植瘤中PIK3R3的表達(dá)情況。結(jié)果(1)和對(duì)照組比較,沉默HOTAIR后,移植瘤生長(zhǎng)緩慢,體積和重量降低(P0.05)(2)免疫組化結(jié)果顯示,卵巢癌SKOV3細(xì)胞株感染慢病毒攜帶的HOTAIR基因sh RNA后,沉默組和對(duì)照組比較,PIK3R3的表達(dá)降低(P0.05)。結(jié)論沉默HOTAIR后,卵巢癌致瘤能力降低。
[Abstract]:Ovarian cancer is one of the three malignant tumors of the cervical cancer and endometrial cancer, the mortality rate in gynecologic cancers, because of insidious onset, the lack of specific symptoms and signs and effective screening early, about 70% of patients with ovarian cancer have local or distant metastases, lost the best time for operation as a result, the overall 5 year survival rate is poor. Early ovarian cancer (stages I and II) the survival rate can reach 80%~95%, compared with advanced ovarian cancer (stage III and IV) the long-term survival rate of ovarian malignant tumor is only 10%~30%. so there is a "two 70%": more than 70% patients are diagnosed at advanced stage; approximately 70% of patients within two years. Therefore, thus, for early diagnosis and effective treatment for patients with ovarian cancer survival rate is very important. In recent years, scholars have been looking for a specific The method to improve the survival rate of ovarian cancer, ensure effective prognosis. Another theory of "dualism model" that ovarian cancer is divided into high grade and low grade two. High grade ovarian cancer ovarian cancer accounted for 75%, accounting for 90% of the death rate of ovarian cancer, the disease rapidly that is highly invasive, often accompanied by extensive abdominal metastasis and poor prognosis. The cultivation of epithelial ovarian cancer has low level of slow, benign, and malignant tumor at the junction of the development process, for the early, the prognosis is good. So the high level of epithelial ovarian cancer as prone to invasion and metastasis that is a healthy women. However, the threat of malignant tumor invasion and metastasis mechanism is unknown. Recently, after extensive research of MI RNA, called the long chain of non RNA (long non-coding RNA encoding, LNC encoding RNA RNA) non a molecular weight greater than 200nt was found And they have attracted more and more research. Because of the effect of regulation on the expression of target genes, LNC RNA is involved in many cancers, the process of development. Recent studies have shown that LNC RNA is involved in transcriptional activation, chromatin modification, transcriptional interference and nuclear transport several important regulation. Early regulation of figure 1 Lnc RNA the US, in 44 cases of ovarian carcinoma and 14 cases of normal ovarian tissue samples by real-time fluorescent quantitative PCR (RT-PCR) method to detect the expression of RNA encoding HOTAIR m long chain non RNA. The expression of HOTAIR in ovarian cancer m RNA higher than that of normal ovarian tissues [(1.26 + 0.27 vs. (0.14 + 0.09)], the difference was statistically significant (P? 0.05), the pathological types were poorly differentiated and undifferentiated ovarian carcinoma HOTAIR m RNA was higher than that in low and high, in a highly differentiated tissue? (1.65 + 0.41) vs (0.39 + 0.l4)?, the difference was statistically significant (P 0.? 05). Conclusions the increased expression of HOTA in ovarian cancer IR, and the differentiation of the carcinoma is lower, the higher the expression of IR HOTA suggest that HOTA IR may be found in ovarian cancer, and to judge the malignant degree of a molecular marker, in ovarian cancer, plays an important role in the development of it. The mechanism is not clear. Therefore the study effect and mechanism in the early stage on the basis of further study of Hotair in ovarian cancer. The role of Hotair in ovarian cancer and accurate treatment and provide a theoretical basis and foundation. Influence on the biological behavior of malignant epithelial ovarian cancer the first part of the research on HOTAIR to aim to study the silencing of HOTAIR in epithelial ovarian cancer for the malignant biological behavior and its mechanism. Methods (1) Q PCR in the detection of HOTAIR in ovarian cancer cell line SKOV3, the expression of OVCAR3 and A2780. (2) after silencing HOTAIR, metastasis detection of ovarian cancer cell scratch test, t The invasion ability of ovarian cancer cell ranswell detection, Ed detection of U ovarian cancer cell proliferation. Results (1) the expression of HOTAIR in SKOV3 and OVCAR3 cells than A2780 cells; (2) after silencing HOTAIR, SKOV3 ovarian cancer cell metastasis, reduce proliferation and invasion; conclusion silencing of HOTAIR can inhibit the malignant biological behavior of ovarian cancer cell line SKOV3 the second part of the HOTAIR. Through the MI R-214 and MI R-217 PIK3R3 is involved in the regulation of malignant biological behavior of ovarian cancer objective to explore the molecular mechanism of HOTAIR affecting the malignant biological behavior of ovarian cancer. Methods (1) bioinformatics prediction CE HOTAIR may regulate the RNA; (2) HOTAIR Q PCR after the detection of silence, the expression of PIK3R3 and expression; HOTAIR silencing of PIK3R3; (3) Q PCR detection of silencing HOTAIR or PIK3R3, MI R-214 and MI R-217 expression; (4) Q PCR and MI R-214 detection of MI R-217 and MI R-214 and MI R-217inhibitor The effects on HOTAIR and PIK3R3; (5) dual luciferase reporter gene assay of HOTAIR or PIK3R3 is a direct target of MI R-214 and MI R-217. (6) the expression of immunohistochemical detection of PIK3R3 in ovarian cancer tissues; (7) after silencing PIK3R3, detection of ovarian cancer cell proliferation and invasion, metastasis results: (1) forecasting of biological information HOTAIR and PIK3R3 are CE, RNA, HOTAIR and PIK3R3 is a potential target for MI R-214 and MI R-217; (2) after HOTAIR was silenced, the decreased expression of PIK3R3; PIK3R3 silencing, downregulation of HOTAIR (P0.05); (3) the silencing of HOTAIR or PIK3R3, up regulation the expression of MI R-214 and MI R-217 (P0.05); (4) mi R-214 and MI R-217 transfected with mimics, HOTAIR or PIK3R3 decreased expression of R-214 and MI R-217; transfection of MI inhibitor, HOTAIR or PIK3R3 expression increased; (5) and the control group, mimics and P were transfected into mi R-214 MIR-HOTAIR3 'UTR, luciferase activity obviously Drop (P0.05); and the control group, mimics and MIR-HOTAIR were transfected into mi R-214 3 'UTRm, luciferase activity had no significant change (P0.05); MI R-217 and P mimics were transfected into MIR-HOTAIR3 UTR, luciferase activity was significantly decreased (P0.05); and the control group, mimics and R-217 were transfected into mi MIR-HOTAIR 3 "UTRm, luciferase activity had no significant change (P0.05); (6) immunohistochemistry showed that the expression of PIK3R3 in ovarian serous carcinoma and mucinous carcinoma was higher than that in normal ovarian tissues; (7) after PIK3R3 was silenced, SKOV3 cell proliferation, metastasis and invasion ability was inhibited. Conclusion: the expression of silence HOTAIR gene, cell proliferation of ovarian cancer cell line SKOV3, reduce the metastasis and invasion ability; the malignant biological behavior of HOTAIR PIK3R3 by Mi R-214 to control MI and R-217 target of ovarian cancer SKOV3 cells. The third part effects of SKOV3 silencing HOTAIR in vivo tumorigenicity Objective to explore the effects of HOTAIR on the ability of in vivo on growth of ovarian cancer cell line SKOV3 (1) to construct a lentiviral vector of HOTAIR silencing stable cell lines, and then transplanted into nude mice to observe the tumor growth of the left armpit; (2) immunohistochemical detection of HOTAIR gene silencing by PIK3R3, expression of tumor in nude mice. Results (1) compared with the control group, after HOTAIR was silenced, tumor growth is slow, the volume and weight reduction (P0.05) (2) immunohistochemistry results showed that SKOV3 of ovarian cancer cell lines infected with lentivirus HOTAIR sh RNA, the silent group and the control group, decreased the expression of PIK3R3 (P0.05) conclusion silencing of HOTAIR after ovarian cancer tumorigenicity decreased.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R737.31

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