本文選題：卵巢癌 + 長(zhǎng)鏈非編碼RNA　； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年博士論文

【摘要】：研究背景 卵巢癌是病死率最高的婦科惡性腫瘤,而早期診斷技術(shù)以及長(zhǎng)期有效的治療方案的缺乏是卵巢癌病死率居高不下的原因。因此,尋找新的腫瘤標(biāo)記物和治療靶標(biāo)一直以來(lái)都是卵巢癌研究領(lǐng)域的熱點(diǎn)。 長(zhǎng)鏈非編碼RNA (long non-coding RNA, lncRNA)是一類長(zhǎng)度大于200nt、不具備蛋白編碼功能的RNA。與niRNA等小分子非編碼RNA相比,lncRNA近幾年才開始受到關(guān)注。然而,已有越來(lái)越多的研究顯示1ncRNA能夠在染色質(zhì)修飾、轉(zhuǎn)錄或轉(zhuǎn)錄后等水平調(diào)控下游基因的表達(dá),進(jìn)而參與細(xì)胞增殖、凋亡及侵襲等多種生物學(xué)過(guò)程并與腫瘤等疾病的發(fā)生發(fā)展相關(guān)。近年來(lái),基因芯片和高通量測(cè)序技術(shù)在lncRNA的研究中發(fā)揮了重要作用。 Matastasis-associated lung adenocarcinoma transcript1(MALATl)是一個(gè)長(zhǎng)約8,000nt的非編碼RNA,在正常人體組織中普遍表達(dá)。2003年,Ji等首次報(bào)道MALAT1在非小細(xì)胞肺癌中表達(dá)上調(diào),并與患者的預(yù)后相關(guān)。此后,MALAT1又被證實(shí)與肝癌、宮頸癌、膀胱癌及膽囊癌等腫瘤的進(jìn)展相關(guān)。然而,其在卵巢癌中的作用尚無(wú)研究涉及。 本研究分為兩個(gè)部分。在第一部分中,我們利用基因芯片比較了具有不同侵襲潛能的卵巢癌細(xì)胞系的lncRNA表達(dá)譜,證實(shí)了lncRNA在具有不同侵襲潛能的卵巢癌細(xì)胞系中存在差異表達(dá)。在第二部分中,我們檢測(cè)了MALAT1表達(dá)下調(diào)對(duì)卵巢癌細(xì)胞生物學(xué)行為的影響,發(fā)現(xiàn)MALAT1表達(dá)下調(diào)能夠明顯抑制卵巢癌細(xì)胞的增殖和轉(zhuǎn)移,且MALAT1表達(dá)下調(diào)可導(dǎo)致多個(gè)與細(xì)胞增殖、轉(zhuǎn)移和/或凋亡等生物學(xué)過(guò)程相關(guān)的基因的差異表達(dá)。 第一部分長(zhǎng)鏈非編碼RNA在具有不同侵襲潛能的卵巢癌細(xì)胞系中表達(dá)譜的變化 目的 比較具有不同侵襲潛能的卵巢癌細(xì)胞系的lncRNA表達(dá)譜,篩選可能與卵巢癌轉(zhuǎn)移相關(guān)的lncRNA,為后續(xù)研究奠定基礎(chǔ)。方法 1.Transwell侵襲實(shí)驗(yàn)驗(yàn)證人卵巢癌細(xì)胞系SKOV3及其亞系SKOV3.ip1的體外侵襲能力。 2.基因芯片檢測(cè)兩個(gè)細(xì)胞系lncRNA表達(dá)譜的差異。 3.選取9個(gè)差異表達(dá)的lncRNA進(jìn)行qRT-PCR驗(yàn)證。 結(jié)果 1.與其母系細(xì)胞相比,SKOV3.ip1細(xì)胞的體外侵襲能力明顯增強(qiáng)。 2.芯片共檢出4,956個(gè)lncRNA,其中上調(diào)及下調(diào)2倍及以上的lncRNA分別有583個(gè)及578個(gè)。 3.7個(gè)lncRNA的qRT-PCR結(jié)果與芯片結(jié)果相符。 結(jié)論 lncRNA在具有不同侵襲潛能的卵巢癌細(xì)胞系中存在差異表達(dá),這一結(jié)果提示某些lncRNA可能在卵巢癌轉(zhuǎn)移中發(fā)揮一定的作用,但其具體功能尚需進(jìn)一步的研究證實(shí)。 第二部分下調(diào)長(zhǎng)鏈非編碼RNA MALAT1的表達(dá)抑制卵巢癌細(xì)胞增殖和轉(zhuǎn)移 目的 檢測(cè)長(zhǎng)鏈非編碼RNA MALAT1在卵巢癌細(xì)胞中的表達(dá)情況,并進(jìn)一步探索MALAT1在卵巢癌細(xì)胞增殖及轉(zhuǎn)移中發(fā)揮的作用. 方法 1.用qRT-PCR檢測(cè)人卵巢癌細(xì)胞株SKOV3和人正常卵巢上皮細(xì)胞HOSE中MALAT1的表達(dá)情況。 2.構(gòu)建穩(wěn)定低表達(dá)MALAT1的細(xì)胞株SKOV3-MALA-T1-KD及其陰性對(duì)照SKOV3-NC。 3.細(xì)胞增殖實(shí)驗(yàn)和平板克隆形成實(shí)驗(yàn)檢測(cè)MALAT1表達(dá)下調(diào)對(duì)卵巢癌細(xì)胞體外增殖能力的影響；細(xì)胞遷移和侵襲實(shí)驗(yàn)檢測(cè)MALAT1表達(dá)下調(diào)對(duì)卵巢癌細(xì)胞體外遷移和侵襲能力的影響；流式細(xì)胞術(shù)檢測(cè)MALAT1表達(dá)下調(diào)對(duì)卵巢癌細(xì)胞凋亡水平的影響。 4.將穩(wěn)轉(zhuǎn)細(xì)胞株SKOV3-MALAT1-KD及其陰性對(duì)照分別做裸鼠移植瘤模型,檢測(cè)MALAT1表達(dá)下調(diào)對(duì)卵巢癌細(xì)胞體內(nèi)成瘤能力的影響。 5.分別從SKOV3-MALAT1-KD和SKOV3-NC細(xì)胞中提取RNA用于基因表達(dá)譜芯片研究,比較兩組細(xì)胞基因表達(dá)差異并從中選取20個(gè)差異表達(dá)的、與細(xì)胞增殖、轉(zhuǎn)移和/或凋亡等生物學(xué)過(guò)程相關(guān)的基因進(jìn)行qRT-PCR驗(yàn)證。 結(jié)果 1. qRT-PCR結(jié)果顯示MALAT1在人卵巢癌細(xì)胞株中表達(dá)水平明顯上調(diào)。 2.成功構(gòu)建穩(wěn)轉(zhuǎn)細(xì)胞株SKOV3-MALAT1-KD和SKOV3-NC,干擾效果達(dá)77%。 3.細(xì)胞增殖實(shí)驗(yàn)和克隆形成實(shí)驗(yàn)證實(shí)MALAT1表達(dá)下調(diào)可顯著地抑制卵巢癌細(xì)胞的體外增殖能力(P0.01)；遷移和侵襲實(shí)驗(yàn)證實(shí)MALAT1表達(dá)下調(diào)可顯著地抑制卵巢癌細(xì)胞的體外遷移和侵襲能力(P0.01)；與其陰性對(duì)照相比,MALAT1表達(dá)下調(diào)的細(xì)胞凋亡水平顯著升高(P0.01)。 4.體內(nèi)實(shí)驗(yàn)結(jié)果顯示SKOV3-MALAT1-KD組移植瘤的體積明顯小于陰性對(duì)照組的體積,差異具有統(tǒng)計(jì)學(xué)意義(P0.01)。 5.芯片結(jié)果顯示MALAT1表達(dá)下調(diào)所導(dǎo)致的2倍以上差異表達(dá)的基因有921個(gè)；qRT-PCR結(jié)果顯示其中19個(gè)基因確實(shí)存在差異表達(dá)。 結(jié)論 MALAT1表達(dá)下調(diào)能夠在體外抑制卵巢癌細(xì)胞的增殖和轉(zhuǎn)移。此外,MALAT1表達(dá)下調(diào)還能夠抑制卵巢癌細(xì)胞的體內(nèi)成瘤能力。MALAT1表達(dá)下調(diào)可導(dǎo)致多個(gè)與細(xì)胞增殖、轉(zhuǎn)移及凋亡等生物學(xué)過(guò)程相關(guān)的基因的差異表達(dá)。我們的研究結(jié)果顯示MALAT1對(duì)卵巢癌有促進(jìn)作用,或許能夠成為新的卵巢癌治療靶點(diǎn)。
[Abstract]:Research background
Ovarian cancer is the most fatal gynecologic malignant tumor, and the early diagnosis technology and the lack of long-term effective treatment are the reasons for the high mortality of ovarian cancer. Therefore, looking for new tumor markers and therapeutic targets has always been a hot spot in the field of ovarian cancer research.
Long chain non coding RNA (long non-coding RNA, lncRNA) is a class of non coded RNA, such as RNA. and niRNA, which has a length larger than 200nt and does not have the function of protein coding. LncRNA has attracted much attention in recent years. However, more and more studies have shown that 1ncRNA can be controlled by the level of chromatin modification, transcription or post transcription. A variety of biological processes, such as cell proliferation, apoptosis and invasion, are associated with the development of cancer and other diseases. In recent years, gene chip and high throughput sequencing technology have played an important role in the research of lncRNA.
Matastasis-associated lung adenocarcinoma transcript1 (MALATl) is a non coding RNA with a long approximately 8000nt, which is generally expressed in normal human tissues. Ji is reported for the first time that MALAT1 is up-regulated in non-small cell lung cancer and is associated with the prognosis of the patients. Thereafter, MALAT1 was confirmed with liver cancer, cervical, bladder and gallbladder cancer. It is related to tumor progression. However, its role in ovarian cancer has not been studied.
This study is divided into two parts. In the first part, we use gene chip to compare the lncRNA expression profiles of ovarian cancer cell lines with different invasive potential and confirm that lncRNA has differential expression in ovarian cancer cell lines with different invasive potential. In the second part, we detected the downregulation of MALAT1 expression to ovarian cancer cells. The effect of biological behavior shows that down regulation of MALAT1 expression can obviously inhibit the proliferation and metastasis of ovarian cancer cells, and the downregulation of MALAT1 can lead to the differential expression of many genes related to biological processes such as cell proliferation, metastasis and / or apoptosis.
Part 1 the expression profile of long chain non coding RNA in ovarian cancer cell lines with different invasive potential.
objective
LncRNA expression profiles of ovarian cancer cell lines with different invasive potential were compared, and lncRNA, which might be related to metastasis of ovarian cancer, was screened.
1.Transwell invasion test confirmed the invasion ability of human ovarian cancer cell line SKOV3 and its subunit SKOV3.ip1 in vitro.
2. gene chip was used to detect the difference of lncRNA expression profiles between two cell lines.
3. select 9 differentially expressed lncRNA for qRT-PCR verification.
Result
1. compared with its maternal cells, the invasion ability of SKOV3.ip1 cells increased significantly in vitro.
A total of 4956 lncRNA were detected in 2. chips, of which 583 and 578 were up and down 2 times and above lncRNA respectively.
The qRT-PCR results of the 3.7 lncRNA coincide with the results of the chip.
conclusion
The differential expression of lncRNA in ovarian cancer cell lines with different invasive potential suggests that some lncRNA may play a role in ovarian cancer metastasis, but its specific function needs further research.
The second part down regulated the expression of long non coding RNA MALAT1 to inhibit the proliferation and metastasis of ovarian cancer cells.
objective
To detect the expression of long chain non coding RNA MALAT1 in ovarian cancer cells, and further explore the role of MALAT1 in the proliferation and metastasis of ovarian cancer cells.
Method
1. detect the expression of MALAT1 in human ovarian cancer cell line SKOV3 and human normal ovarian epithelial cell HOSE by qRT-PCR.
2. construction of stable cell line SKOV3-MALA-T1-KD with low expression of MALAT1 and its negative control SKOV3-NC.
The effect of down regulation of MALAT1 expression on the proliferation of ovarian cancer cells in vitro was detected by 3. cell proliferation experiments and flat clones. Cell migration and invasion tests were used to detect the effect of down regulation of MALAT1 expression on the migration and invasion ability of ovarian cancer cells in vitro; flow cytometry was used to detect the down regulation of MALAT1 expression on the apoptosis level of ovarian cancer cells Influence.
4. SKOV3-MALAT1-KD and its negative control were used as the transplanted tumor model in nude mice respectively, and the effect of down regulation of MALAT1 expression on the tumorigenicity of ovarian cancer cells in vivo was detected.
5. RNA was extracted from SKOV3-MALAT1-KD and SKOV3-NC cells to study the gene expression spectrum chip, and compared the difference of gene expression in the two groups and selected 20 differentially expressed genes. The genes related to biological processes such as cell proliferation, metastasis and / or apoptosis were verified by qRT-PCR.
Result
1. qRT-PCR results showed that MALAT1 expression was significantly up-regulated in human ovarian cancer cell lines.
2. successfully constructed stable cell lines SKOV3-MALAT1-KD and SKOV3-NC, and the interference effect reached 77%.
3. cell proliferation and cloning experiments confirmed that down regulation of MALAT1 could significantly inhibit the proliferation ability of ovarian cancer cells in vitro (P0.01). Migration and invasion experiments confirmed that down regulation of MALAT1 expression significantly inhibited the migration and invasion ability of ovarian cancer cells in vitro (P0.01); compared with negative to photography, the expression of MALAT1 was down regulated. The level of apoptosis was significantly increased (P0.01).
4. in vivo experiments showed that the volume of transplanted tumor in group SKOV3-MALAT1-KD was significantly smaller than that in negative control group (P0.01).
The 5. chip results showed that there were 921 genes of 2 times more differential expression resulting from the downregulation of MALAT1, and the results of qRT-PCR showed that there were 19 differentially expressed genes.
conclusion
The down regulation of MALAT1 expression can inhibit the proliferation and metastasis of ovarian cancer cells in vitro. In addition, the down regulation of MALAT1 expression can also inhibit the down regulation of.MALAT1 expression in ovarian cancer cells, which can lead to the differential expression of many genes related to biological processes such as cell proliferation, metastasis and apoptosis. Our results show MALAT1 pairs Ovarian cancer may be a new target for ovarian cancer therapy.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R737.31

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