本文選題：微小RNA + 癌基因微小RNA��； 參考：《廣西醫(yī)科大學(xué)》2010年博士論文

【摘要】： 背景與目的 鼻咽癌是中國(guó)南方和東南亞地區(qū)最常見(jiàn)的惡性腫瘤之一,具有明顯的區(qū)域分布特征、與EB病毒的密切關(guān)系。LMP1是EBVⅡ型潛伏感染的鼻咽癌細(xì)胞表達(dá)的一個(gè)病毒癌基因,他能促進(jìn)上皮細(xì)胞轉(zhuǎn)化,能通過(guò)NF-κB、p38、JNK等信號(hào)通路激活下游基因的轉(zhuǎn)錄,影響細(xì)胞的生長(zhǎng)與增殖、凋亡以及侵蝕和轉(zhuǎn)移能力。同時(shí),它在EBVⅢ型潛伏感染的淋巴瘤細(xì)胞中能調(diào)節(jié)miRNAs的表達(dá),并通過(guò)miRNAs的靶基因調(diào)控作用保持病毒的潛伏感染狀態(tài)、影響腫瘤的生物學(xué)行為等等。 miRNAs一種新型的、內(nèi)源性的、非蛋白編碼小RNA分子,長(zhǎng)約22個(gè)核苷酸,發(fā)揮轉(zhuǎn)錄后基因表達(dá)調(diào)控作用。miRNAs通過(guò)miRISC抑制靶mRNA的翻譯或促使其降解,從而調(diào)節(jié)細(xì)胞的發(fā)育、分化、增殖、凋亡、代謝等生命活動(dòng)。其中部分miRNAs具有癌基因和腫瘤抑制基因的功能,稱為癌基因miRNAs (oncomiRs),對(duì)腫瘤的生物學(xué)行為起重要作用。 通過(guò)miRNA芯片進(jìn)行高通量篩選,找出差異表達(dá)的miRNAs分子,特別是oncomiRs分子,能全面了解腫瘤發(fā)生和發(fā)展的分子機(jī)制、更為精確地對(duì)腫瘤的進(jìn)行分型和預(yù)后。找出差異表達(dá)：miRNA分子后,可以通過(guò)多個(gè)靶基因預(yù)測(cè)軟件對(duì)靶基因進(jìn)行預(yù)測(cè),對(duì)于了解其生物學(xué)功能具有重要意義。最近有學(xué)者通過(guò)對(duì)鼻咽癌組織與癌旁正常組織的差異表達(dá)miRNA的靶基因參與的信號(hào)通路進(jìn)行計(jì)算機(jī)預(yù)測(cè),來(lái)了解差異表達(dá)miRNA的生物學(xué)功能,并發(fā)現(xiàn)它們能通過(guò)靶基因干預(yù)多條與腫瘤生物學(xué)行為相關(guān)的信號(hào)通路,對(duì)腫瘤的生長(zhǎng)與增殖、凋亡、轉(zhuǎn)移及血管生成產(chǎn)生重要作用。 miRNA的功能研究及生物信息學(xué)預(yù)測(cè)結(jié)果可以通過(guò)轉(zhuǎn)染miRNA mimics、antagomiRs或miRNA抑制劑,正向或反向誘導(dǎo)miRNA的功能,來(lái)研究或驗(yàn)證細(xì)胞中該miRNA分子的功能。該轉(zhuǎn)染的有效性可以通過(guò)靶基因的表達(dá)水平的改變獲得證實(shí)。同時(shí)可以通過(guò)檢測(cè)相關(guān)靶基因的表達(dá)來(lái)探討其功能發(fā)生的具體機(jī)制。 本實(shí)驗(yàn)旨在探討LMP1對(duì)鼻咽癌細(xì)胞miRNA表達(dá)的調(diào)控作用,并探討其對(duì)鼻咽癌生物學(xué)行為的影響。通過(guò)比較鼻咽癌細(xì)胞系CNE1與其EB病毒的潛伏膜蛋白1(latent membrane protein 1, LMP1)穩(wěn)定轉(zhuǎn)染細(xì)胞系CNE1-LMP1的癌基因微小RNA (oncogenic microRNAs, oncomiRs)表達(dá)譜的差異,探討LMP1對(duì)EBVⅡ型潛伏感染的鼻咽癌細(xì)胞系CNE1oncomiRs表達(dá)的影響。并通過(guò)生物信息學(xué)分析,從中找出對(duì)細(xì)胞生物學(xué)功能影響較關(guān)鍵的分子；通過(guò)antagomiRs阻斷后探討其對(duì)鼻咽癌細(xì)胞生物學(xué)行為的影響,并在鼻咽癌組織中檢測(cè)其表達(dá)及與LMP1的相關(guān)性及與臨床病理特征的關(guān)系,探討其在鼻咽癌組織中表達(dá)的意義。 方法 1.采用包含有132個(gè)oncomiRs分子的膜基microRNA芯片,檢測(cè)鼻咽癌細(xì)胞系CNE1及其EBV LMP1的穩(wěn)定轉(zhuǎn)染細(xì)胞系oncomiRs的表達(dá)譜及差異表達(dá)譜。采用實(shí)時(shí)定量PCR檢測(cè)驗(yàn)證表達(dá)差異較大的(達(dá)2倍)miRNAs分子,并對(duì)兩者結(jié)果進(jìn)行相關(guān)分析,驗(yàn)證芯片檢測(cè)結(jié)果的可靠性。 2.采用miRNA分子功能預(yù)測(cè)在線工具DIANA-mirPath,分析差異表達(dá)miRNA參與的已知信號(hào)通路——京都基因及基因組百科全書(shū)(KEGG)信號(hào)通路,來(lái)闡明它們參與的生物學(xué)功能。 3.通過(guò)hsa-miR-19b knockdown探針阻斷鼻咽癌細(xì)胞CNE1-LMP1中的hsa-miR-19b,然后分析其對(duì)細(xì)胞周期、增殖、凋亡和細(xì)胞遷移、侵襲的影響；及其對(duì)靶基因蛋白SOCS1及STAT3 (Signal transducer and activator of transcription 3)信號(hào)通路的影響,以初步探討鼻咽癌細(xì)胞中hsa-miR-19b的功能和作用機(jī)制。 4.選擇芯片篩選及qRT-PCR驗(yàn)證獲得的表達(dá)差異較為明顯的hsa-miR-19b分子,采用實(shí)時(shí)定量PCR檢測(cè)46例鼻咽癌組織中差異表達(dá)最大的miRNA分子hsa-miR-19b表達(dá),并采用免疫組化技術(shù)原位檢測(cè)46例鼻咽癌組織中LMP1表達(dá),并探討其與LMP1表達(dá)的相關(guān)性。并探討兩者表達(dá)與臨床病理特征之間的關(guān)系,探討其表達(dá)作為診斷分子標(biāo)記的意義。 結(jié)果 1.CNE1的oncomiRs表達(dá)譜 在芯片包含的132個(gè)oncomiRs中,CNE1中檢出oncomiRs分子21個(gè)；其中高表達(dá)的(表達(dá)量與內(nèi)參RUN48比大于1)有4個(gè),低表達(dá)(表達(dá)量與內(nèi)參RUN48比小于1)的有17個(gè)。 2. CNE1-LMP1的oncomiRs表達(dá)譜 在芯片包含的132個(gè)oncomiRs中,NE1-LMP1中檢出30個(gè)；其中高表達(dá)的(表達(dá)量與內(nèi)參RUN48比大于1)有7個(gè),低表達(dá)(表達(dá)量與內(nèi)參RUN48比小于1)的有23個(gè)。 3.CNE1和CNE1-LMP1的oncomiRs差異表達(dá)譜 通過(guò)比較較鼻咽癌細(xì)胞系CNE1與其LMP1穩(wěn)定轉(zhuǎn)染細(xì)胞系CNE1-LMP1的腫瘤相關(guān)miRNAs (oncomiRs)表達(dá)譜的差異,其中CNE1檢出oncomiRs分子21個(gè),而CNE1-LMP1中檢出30個(gè),顯示LMP1能調(diào)節(jié)miRNAs的表達(dá)。與CNE1比較,CNE1-LMP1中miRNAs分子表達(dá)總量增加,有9個(gè)在CNE1-LMP1中特異性表達(dá)。分析共同表達(dá)的21個(gè)miRNA分子發(fā)現(xiàn),CNE1-LMP1中有8個(gè)輕度降低,13個(gè)表達(dá)升高,其中表達(dá)升高達(dá)兩倍以上的miRNA分子有7個(gè):hsa-miR-19b、hsa-miR-17-3p、hsa-miR-22、hsa-miR-149、hsa-miR-150、hsa-miR-188和hsa-miR-205。9個(gè)在CNE1-LMP1中特異性表達(dá)的miRNA中,hsa-miR-122a呈高水平表達(dá),其表達(dá)量相對(duì)值大于1。綜上所述,CNE1-LMP1中miRNA表達(dá)的總體水平升高。 4. qRT-PCR驗(yàn)證兩細(xì)胞系中差異表達(dá)較大的miRNA分子 通過(guò)熒光定量RT-RCR檢測(cè),對(duì)芯片檢測(cè)發(fā)現(xiàn)的7個(gè)(hsa-miR-19b、hsa-miR-17-3p、hsa-miR-22、hsa-miR-149、hsa-miR-150、hsa-miR-188和hsa-miR-205)表達(dá)差異較大的miRNA進(jìn)行驗(yàn)證,芯片檢測(cè)發(fā)現(xiàn)結(jié)果差異與qRT-RCR檢測(cè)發(fā)現(xiàn)的結(jié)果差異相關(guān)(r=0.970,P=0.000)。兩種方法檢測(cè)結(jié)果一致。 5. DIANA-mirPath對(duì)差異表達(dá)miRNA參與的信號(hào)通路及功能預(yù)測(cè) 通過(guò)軟件預(yù)測(cè)到與細(xì)胞信號(hào)通路相關(guān)的靶基因數(shù)目總共有95個(gè)；在差異表達(dá)的8個(gè)miRNA分子中,miR-17有預(yù)測(cè)參與信號(hào)通路靶基因44個(gè),miR-19b有53個(gè),其余6個(gè)共計(jì)4個(gè)。由此可見(jiàn)miR-17和miR-19b對(duì)信號(hào)通路的貢獻(xiàn)占了絕大部分。兩者參與了多條信號(hào)通路,與腫瘤密切相關(guān)的有環(huán)境信息的信號(hào)轉(zhuǎn)導(dǎo),細(xì)胞的運(yùn)動(dòng)性、生長(zhǎng)與死亡及細(xì)胞通訊,多種腫瘤相關(guān)通路等。同時(shí)前期發(fā)現(xiàn)miR-19b的改變倍數(shù)及表達(dá)量顯著高于miR-17,因此將miR-19b挑出進(jìn)行后續(xù)功能研究。 6.鼻咽癌細(xì)胞CNE1-LMP1中hsa-miR-19b功能初探 hsa-miR-19b阻斷后,細(xì)胞增殖下降(5pmol組抑制率為20.45%,11pmol組為44.50%)；細(xì)胞周期阻滯于G1,hsa-miR-19b阻斷后G1期細(xì)胞百分比明顯增加,而細(xì)胞凋亡明顯增加；hsa-miR-19b阻斷后細(xì)胞的遷移、侵襲能力下降。同時(shí),其靶基因SOCS1蛋白表達(dá)明顯升高,使STAT3磷酸化水平下降。 7.鼻咽癌組織中LMP1與hsa-miR-19b的表達(dá)及與臨床病理特征的關(guān)系 NPC組織中LMP1蛋白陽(yáng)性表達(dá)率為60.95%(28/46), hsa-miR-19b的表達(dá)量為68.27±69.00；LMP1蛋白表達(dá)及hsa-miR-19b表達(dá)均與腫瘤分期和淋巴結(jié)轉(zhuǎn)移相關(guān)(P0.05)。同時(shí)LMP1蛋白表達(dá)與hsa-miR-19b表達(dá)相關(guān)(r=0.390,P0.05)。 結(jié)論 1.鼻咽癌細(xì)胞系CNE1與其LMP1穩(wěn)定轉(zhuǎn)染細(xì)胞系CNE1-LMP1的oncomiRs表達(dá)譜存在差異。 2.LMP1能調(diào)節(jié)鼻咽癌細(xì)胞系oncomiRs的表達(dá),使miRNAs的總體表達(dá)水平升高,其可能機(jī)制為通過(guò)其轉(zhuǎn)錄激活功能促進(jìn)miRNAs的編碼基因表達(dá)miRNAs。 3.LMP1可能調(diào)節(jié)鼻咽癌細(xì)胞系oncomiRs的表達(dá),可以成為其發(fā)揮病毒癌基因作用的另一重要的通路。 4.在8個(gè)差異表達(dá)較大的miRNA分子中,hsa-miR-17和hsa-miR-19b的靶基因?qū)?xì)胞信號(hào)通路的貢獻(xiàn)最大,其參與的信號(hào)轉(zhuǎn)導(dǎo)、細(xì)胞的運(yùn)動(dòng)、生長(zhǎng)與死亡、細(xì)胞通訊的信號(hào)通路、腫瘤相關(guān)信號(hào)通路與腫瘤的發(fā)生發(fā)展密切相關(guān)。 5. hsa-miR-19b能促進(jìn)鼻咽癌細(xì)胞生長(zhǎng)與增殖、抑制細(xì)胞凋亡；其作用的可能途徑有：通過(guò)抑制其靶基因SOCS1而抑制STAT3信號(hào)通路。hsa-miR-19b還能促進(jìn)細(xì)胞遷移和侵襲。 6.鼻咽部低分化鱗狀細(xì)胞癌組織中存在LMP1和hsa-miR-19b的表達(dá)。 7.鼻咽部低分化鱗狀細(xì)胞癌組織中,LMP1可能參與了hsa-miR-19b的表達(dá)調(diào)控。 8.LMP1和hsa-miR-19b可以作為鼻咽部低分化鱗狀細(xì)胞癌的分期及轉(zhuǎn)移的診斷分子標(biāo)記。
[Abstract]:Background and purpose
Nasopharyngeal carcinoma is one of the most common malignant tumors in southern and Southeast Asia, and has obvious regional distribution characteristics. The close relationship with EB virus.LMP1 is a viral oncogene expressed in nasopharyngeal carcinoma cells with EBV II latent infection. He can promote the transformation of epithelial cells and can activate the downstream genes through the signal pathways such as NF- kappa B, p38, JNK and so on. At the same time, it can regulate the expression of miRNAs in the lymphoma cells of EBV type III latent infection, and maintain the latent infection state of the virus through the regulation of the target gene of miRNAs, and affect the biological behavior of the tumor and so on.
MiRNAs a new, endogenous, non protein encoded small RNA molecule, with about 22 nucleotides long, exerting the regulation of gene expression after transcriptional gene expression,.MiRNAs, which inhibits the translation or degradation of target mRNA through miRISC, and regulates cell development, differentiation, proliferation, apoptosis, and metabolites. Some of these miRNAs have oncogenes and tumor suppressor. The function of the gene, known as the oncogene miRNAs (oncomiRs), plays an important role in the biological behavior of the tumor.
Through high throughput screening by miRNA chip, identifying differentially expressed miRNAs molecules, especially oncomiRs molecules, can fully understand the molecular mechanism of tumor development and development, and more accurately classify and prognosis the tumor. Find out the differential expression: after miRNA, multiple target gene prediction software can be used to predict the target gene. It is of great significance to understand its biological function. Recently, some scholars have predicted the biological function of differential expression of miRNA by means of the signal pathway involved in the expression of the target gene of miRNA in the differential expression of the nasopharyngeal carcinoma tissue from the normal tissue adjacent to the cancer, and found that they can interfere with the target gene to interfere with the biological behavior of the tumor. Related signaling pathways play an important role in tumor growth and proliferation, apoptosis, metastasis and angiogenesis.
The functional study of miRNA and the results of bioinformatics prediction can be carried out by transfection of miRNA mimics, antagomiRs or miRNA inhibitor to induce or reverse the function of miRNA, to study or verify the function of the miRNA molecule in the cell. The effectiveness of the transfection can be confirmed by the change of the expression level of the target gene. The related target genes are expressed to explore the specific mechanism of its function.
The purpose of this study was to investigate the effect of LMP1 on the expression of miRNA in nasopharyngeal carcinoma cells and to explore its effect on the biological behavior of nasopharyngeal carcinoma. By comparing the latent membrane protein 1 (latent membrane protein 1, LMP1) of the nasopharyngeal carcinoma cell line CNE1 and its EB virus (latent membrane protein 1, LMP1), the oncogene micro RNA (oncogenic microRNAs) was steadily transfected into the cell line CNE1-LMP1. Rs) the difference of expression profiles and the effect of LMP1 on the expression of CNE1oncomiRs in nasopharyngeal carcinoma cell line of EBV type II latent infection. And through bioinformatics analysis, the key molecules of cell biological function were found, and the effects on the biological behavior of nasopharyngeal carcinoma were investigated by antagomiRs blocking and in nasopharyngeal carcinoma tissue. The expression of LMP1 and its correlation with clinicopathological characteristics were detected, and its significance in nasopharyngeal carcinoma tissues was discussed.
Method
1. the expression and differential expression profiles of the stable transfected cell line oncomiRs of nasopharyngeal carcinoma cell line CNE1 and its EBV LMP1 were detected by a membrane based microRNA chip containing 132 oncomiRs molecules. Real-time quantitative PCR detection was used to verify the expression of miRNAs molecules with a large difference (up to 2 times), and the results were analyzed to verify the chip detection. The reliability of the result.
2. the miRNA molecular function was used to predict the online tool DIANA-mirPath to analyze the known signal pathways involved in the differential expression of miRNA, the Kyoto gene and the genome Encyclopedia (KEGG) signal pathway, to clarify the biological functions of their participation.
3. the hsa-miR-19b in nasopharyngeal carcinoma cell CNE1-LMP1 was blocked by hsa-miR-19b knockdown probe, and the effects on cell cycle, proliferation, apoptosis, cell migration and invasion were analyzed, and the effect on the target gene protein SOCS1 and STAT3 (Signal transducer and activator of transcription 3) signal pathway to explore nasopharyngeal carcinoma preliminarily. The function and mechanism of hsa-miR-19b in cells.
4. the hsa-miR-19b molecules with more distinct differences in expression were obtained by selection of chip and qRT-PCR. Real-time quantitative PCR was used to detect the most differentially expressed hsa-miR-19b expression in 46 cases of nasopharyngeal carcinoma, and the expression of LMP1 in 46 nasopharyngeal carcinoma tissues was detected by immunohistochemistry in situ, and the correlation between the expression of LMP1 and the expression of LMP1 in 46 cases of nasopharyngeal carcinoma was investigated. The relationship between the two expressions and clinicopathological features was discussed, and the significance of its expression as diagnostic molecular marker was discussed.
Result
OncomiRs expression profile of 1.CNE1
Of the 132 oncomiRs contained in the chip, 21 of the oncomiRs molecules were detected in CNE1, of which 4 were highly expressed (the ratio of expression to the internal reference RUN48 was greater than 1), and 17 of the low expression (the expression and the RUN48 ratio of the internal reference were less than 1).
OncomiRs expression profiles of 2. CNE1-LMP1
Of the 132 oncomiRs contained in the chip, 30 were detected in NE1-LMP1, of which 7 were highly expressed (the ratio of expression and the RUN48 ratio of the internal reference was greater than 1), and 23 of the low expression (the expression and the RUN48 ratio of the internal reference were less than 1).
OncomiRs differential expression profiles of 3.CNE1 and CNE1-LMP1
By comparing the difference of miRNAs (oncomiRs) expression profiles between CNE1 and LMP1 stable transfected cell line CNE1-LMP1, CNE1 detected 21 oncomiRs molecules, and 30 in CNE1-LMP1, indicating that LMP1 could regulate the expression of miRNAs. Compared with CNE1, the total expression of the molecule increased in CNE1-LMP1, and 9 in the CNE1-LMP1. Specific expression in MP1. Analysis of 21 miRNA molecules expressed by co expression found that 8 slightly decreased in CNE1-LMP1 and 13 expressions rising, of which 7 miRNA molecules raised up to two times higher than 7: hsa-miR-19b, hsa-miR-17-3p, hsa-miR-22, hsa-miR-149, hsa-miR-150, hsa-miR-188 and hsa-miR-205.9 in CNE1-LMP1. In A, hsa-miR-122a was highly expressed, and its relative expression was greater than 1.. In summary, the overall level of miRNA expression in CNE1-LMP1 increased.
4. qRT-PCR validation of differentially expressed miRNA molecules in two cell lines
Through the fluorescence quantitative RT-RCR detection, 7 (hsa-miR-19b, hsa-miR-17-3p, hsa-miR-22, hsa-miR-149, hsa-miR-150, hsa-miR-188 and hsa-miR-205) were detected by the fluorescence quantitative detection. The difference of the difference between the detection results of the chip detection was related to the difference of the results of qRT-RCR detection (r=0.970, P=0.000). The two methods of detection were detected. The fruit is the same.
5. DIANA-mirPath signaling pathways and functional prediction of differential expression of miRNA
The number of target genes associated with the cell signaling pathway was predicted by software, and 95 of the 8 miRNA molecules expressed differently were predicted to participate in 44 of the signaling pathway targets, 53 miR-19b and 4 of the other 6. This shows that the contribution of miR-17 and miR-19b to the signaling pathway is most. Signal transduction is closely related to the tumor, including signal transduction of environmental information, cell motility, growth and death, cell communication, and multiple tumor related pathways. At the same time, the change multiple and expression of miR-19b were found to be significantly higher than that of miR-17, so miR-19b was selected for follow-up study.
6. hsa-miR-19b function in nasopharyngeal carcinoma cell CNE1-LMP1
After hsa-miR-19b blockage, cell proliferation decreased (the inhibition rate of group 5pmol was 20.45%, group 11pmol was 44.50%), cell cycle was blocked in G1, the percentage of cells in G1 phase increased obviously after hsa-miR-19b blocking, and cell apoptosis increased obviously; cell migration and invasion energy decreased after hsa-miR-19b blocking. Meanwhile, the expression of SOCS1 protein in target gene increased obviously. The phosphorylation level of STAT3 is reduced.
7. expression of LMP1 and hsa-miR-19b in nasopharyngeal carcinoma and its relationship with clinicopathological characteristics
The positive expression rate of LMP1 protein in NPC tissue was 60.95% (28/46), and the expression of hsa-miR-19b was 68.27 + 69. The expression of LMP1 protein and hsa-miR-19b expression were related to the tumor stage and lymph node metastasis (P0.05), and the expression of LMP1 protein was associated with the expression of hsa-miR-19b (r=0.390, P0.05).
conclusion
1. oncomiRs expression profiles of nasopharyngeal carcinoma cell line CNE1 and its LMP1 transfected cell line CNE1-LMP1 were different.
2.LMP1 can regulate the expression of oncomiRs in nasopharyngeal carcinoma cell line and increase the overall expression level of miRNAs. The possible mechanism is to promote the expression of miRNAs. in the miRNAs gene through its transcriptional activation function.
3.LMP1 may regulate the expression of oncomiRs in nasopharyngeal carcinoma cell line, and it can become another important pathway to play the role of viral oncogene.
4. of the 8 highly differentially expressed miRNA molecules, the target genes of hsa-miR-17 and hsa-miR-19b have the greatest contribution to the cell signaling pathway, and their involvement in signal transduction, cell movement, growth and death, cell communication signaling pathways, and tumor related signaling pathways are closely related to the development of tumor development.
5. hsa-miR-19b can promote the growth and proliferation of nasopharyngeal carcinoma cells and inhibit cell apoptosis. The possible pathways are: inhibition of the target gene SOCS1 and the inhibition of the STAT3 signaling pathway.Hsa-miR-19b can also promote cell migration and invasion.
6. the expression of LMP1 and hsa-miR-19b in nasopharyngeal poorly differentiated squamous cell carcinoma.
7. in nasopharyngeal poorly differentiated squamous cell carcinoma, LMP1 may be involved in the regulation of hsa-miR-19b expression.
8.LMP1 and hsa-miR-19b can be used as diagnostic markers for staging and metastasis of poorly differentiated squamous cell carcinoma of the nasopharynx.
【學(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R739.63

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