本文選題：miR-139-5p + Cdc42�。� 參考：《蘇州大學》2016年博士論文

【摘要】：骨肉瘤是一種起源于間葉組織的骨骼系統(tǒng)惡性腫瘤,其發(fā)病率和死亡率在原發(fā)性骨腫瘤中均居首位。骨肉瘤多發(fā)于15-25周歲的青少年,其發(fā)展進程快,轉移及復發(fā)率高,患者生存旅較低,行單一手術切除術治療的患者5年生存率僅為15-20%,已成為青少年健康的一大威脅。隨著醫(yī)療技術的迅猛發(fā)展,新輔助放化療聯(lián)合保肢術替代截肢術成為骨肉瘤治療的主要外科手段,雖然患者預后水平有所提高,但放化療并不具有靶向性,并不能有效清除腫瘤細胞,患者術后復發(fā)率較高,且保肢術后還需輔助骨組織重建術,價格昂貴,給患者帶來一定的經(jīng)濟壓力。目前,骨肉瘤新型治療手段如免疫療法、介入治療、中醫(yī)藥治療及基因靶向治療成為攻克骨肉瘤的突破口。其中基因靶向治療可靶向在骨肉瘤發(fā)展進程中起重要功能的癌相關基因,從而抑制腫瘤細胞增殖、遷移和侵襲等惡性生物學特性,而成為有效治愈骨肉瘤的新希望。因此,進一步揭示骨肉瘤發(fā)生發(fā)展中的分子機制全貌,探索新的分子治療靶點,為基因靶向治療提供理論依據(jù)和數(shù)據(jù)支持,具有重要的臨床意義和科學價值。隨著第二代高通量測序技術的成熟和廣泛應用,針對腫瘤組織和細胞的測序數(shù)據(jù)如外顯子測序、轉錄組測序、miRNAs測序、lnc RNA測序和單細胞測序數(shù)據(jù)等為基因靶向治療的研究提供了可靠的數(shù)據(jù)支持,腫瘤學研究由此迎來了“數(shù)據(jù)爆炸”時代。在當今大數(shù)據(jù)時代,一系列整合了大量腫瘤樣本的基因測序數(shù)據(jù)及臨床數(shù)據(jù)的數(shù)據(jù)庫如TCGA、Oncomine等也應運而生,被廣泛的應用到腫瘤學的研究中來。TCGA數(shù)據(jù)庫是當今最大的數(shù)據(jù)庫,其涵蓋全球范圍內29種類型的腫瘤超過1萬例樣本的外顯子測序數(shù)據(jù)、SNP數(shù)據(jù)、CMV數(shù)據(jù)及全面的臨床數(shù)據(jù),成為腫瘤學研究的一把利劍。目前圍繞TCGA數(shù)據(jù)庫展開的相關研究發(fā)表在《Science》、《Nature》、《PNS》等一系列重量級科學刊物。但利用TCGA大數(shù)據(jù)進行骨肉瘤的研究則未見報道。因此,在當今大數(shù)據(jù)時代,如何運用腫瘤大數(shù)據(jù)對骨肉瘤進行深入的研究,進一步完善骨肉瘤發(fā)生發(fā)展的分子機制,成為當今腫瘤學研究的一大趨勢。microRNAs是一類長度約為21-23nt的在物種間具有高度保守性的非編碼RNA,之前的研究認為miRNA是一種不具備功能的基因轉錄的“垃圾產(chǎn)物”,隨著深入的研究,人們逐漸發(fā)現(xiàn),miRNA可以6-8個堿基不完全互補配對的方式與靶基因3’UTR區(qū)域結合,發(fā)揮對基因表達負向調控的作用。因此,miRNA在調控細胞的各項生理功能如增殖、分化、凋亡衰老方面具有重要的功能。并于2002年被《Science》雜志評為十大科技突破第一名。目前在哺乳動物中已鑒定出的miRNA多達上千條序列,并且仍不斷有新的miRNAs被發(fā)現(xiàn)。近年來,隨著對miRNA在腫瘤學研究的不斷深入,人們逐漸發(fā)現(xiàn)腫瘤中有許多miRNA對癌相關基因具有重要的調控作用,在腫瘤的發(fā)生發(fā)展中扮演著重要的角色,被認為是治療腫瘤的潛在的分子靶點。因此,進一步探索和研究在骨肉瘤發(fā)生發(fā)展中起關鍵性調控作用的miRNAs,將對于進一步明確骨肉瘤發(fā)生發(fā)展中伴隨的分子機制,以及探索新的分子治療靶點具有重要的科學意義。第一部分基于TCGA腫瘤數(shù)據(jù)分析miR-139在骨肉瘤中的表達及其表觀調控機制研究在本部分的研究中,我們利用TCGA腫瘤數(shù)據(jù)庫中的骨肉瘤miRNA芯片數(shù)據(jù),篩選在骨肉瘤中發(fā)生顯著差異表達的miRNAs,發(fā)現(xiàn)發(fā)生顯著下調表達的miRNAs有70條,發(fā)生顯著上調表達的miRNAs有115條。在顯著上調的miRNAs中,miR-139-5p是下調最為顯著且未在骨肉瘤中有報道的miRNA。我們采用q RT-PCR檢測了骨肉瘤組織及細胞系中miR-139-5p的表達,結果進一步說明miR-139-5p在骨肉瘤中發(fā)生了下調表達。為了探究miR-139-5p在骨肉瘤中發(fā)生下調表達的分子機制,我們采用CHIP實驗檢測了miR-139啟動子區(qū)組蛋白的甲基化及乙�；揎椙闆r發(fā)現(xiàn),miR-139在骨肉瘤中的下調表達是由miR139啟動子區(qū)組蛋白H3K27、H3K9甲基化水平上調,H3K4甲基化水平下調以及H3乙�；较抡{所介導的。此外,我們結合TCGA數(shù)據(jù)庫中骨肉瘤樣本的臨床數(shù)據(jù),分析了miR-139-5p表達與患者生存期的關系發(fā)現(xiàn),miR-139-5p高表達患者的生存期顯著高于低表達患者。通過以上結果,我們初步推斷miR-139-5p在骨肉瘤發(fā)生發(fā)展中具有重要的作用。第二部分miR-139-5p對骨肉瘤惡行生物學表型的調控作用及其分子機制研究為了研究miR-139-5p在骨肉瘤發(fā)生發(fā)展中的作用,我們首先采用q RT-PCR檢測了miR-139-5p mimics的轉染效率。結果顯示,轉染miR-139-5p mimics可顯著提高骨肉瘤細胞MG63及U20S中miR-139-5p水平。接下來,我們采用CCK8實驗檢測了miR-139-5p對骨肉瘤增殖的影響發(fā)現(xiàn),miR-139-5p可顯著抑制骨肉瘤的增殖。采用Transwell檢測miR-139-5p對骨肉瘤細胞遷移和侵襲的影響發(fā)現(xiàn),miR-139-5p可顯著抑制骨肉瘤細胞的遷移和侵襲。此外,構建裸鼠皮下抑制瘤模型,體內過表達miR-139-5p后發(fā)現(xiàn),miR-139-5p可顯著抑制瘤體生長。因此,我們得出結論:miR-139-5p可顯著抑制骨肉瘤的發(fā)生發(fā)展。為了探究miR-139-5p發(fā)揮抑瘤作用的分子機制,我們首先采用Targetscan預測了miR-139-5p的靶基因發(fā)現(xiàn),miR-139-5p可靶向Cdc42 m RNA 3’UTR序列。為了進一步探究miR-139-5p對Cdc42 m RNA 3’UTR序列的靶向作用,我們構建了Cdc42m RNA 3’UTR區(qū)45-52位點的Luciferase雙熒光報告載體,轉染miR-139-5p后發(fā)現(xiàn)miR-139-5p可顯著抑制熒光生成。以上結果說明miR-139-5p可靶向Cdc42 m RNA3’UTR 45-52位點。為了進一步探究miR-139-5p對Cdc42是否有負向調控作用及其作用機制,我們檢測了轉染miR-139-5p后,骨肉瘤細胞Cdc42 m RNA及蛋白的表達發(fā)現(xiàn),miR-139-5p并不抑制Cdc42 m RNA水平,可顯著抑制Cdc42蛋白的表達。通過以上結果,我們得出結論:miR-139-5p可通過抑制Cdc42 m RNA的翻譯從而對Cdc42基因表達起負向調控作用。第三部分Cdc42對骨肉瘤惡行生物學表型的調控作用研究在本部分中,我們探究了Cdc42基因在骨肉瘤中的表達及其對骨肉瘤惡性生物學表型的調控作用。首先分析了TCGA數(shù)據(jù)庫中骨肉瘤RNA-Seq數(shù)據(jù)發(fā)現(xiàn),Cdc42m RNA并未在骨肉瘤中發(fā)生差異表達,采用q RT-PCR及Westernblot分別檢測了骨肉瘤組織和細胞系中Cdc42 m RNA和蛋白表達發(fā)現(xiàn),Cdc42 m RNA并未在骨肉瘤中發(fā)生差異表達,但Cdc42蛋白在骨肉瘤中發(fā)生了顯著的上調表達。以上結果說明,Cdc42在骨肉瘤中發(fā)生顯著的上調表達,其上調表達主要發(fā)生在轉錄后的調控,miR-139-5p作為Cdc42轉錄后的調控因子,在調控Cdc42表達上具有重要的作用。接下來我們探究了Cdc42對骨肉瘤細胞增殖和遷移的影響。CCK8結果顯示,沉默Cdc42表達可顯著抑制骨肉瘤細胞的增殖;劃痕實驗結果顯示,Cdc42沉默后,骨肉瘤細胞的遷移能力降低。通過以上結果,我們得出Cdc42可促進骨肉瘤細胞的增殖和分化。綜上所述,miR-139-5p在骨肉瘤發(fā)生發(fā)展中發(fā)揮著重要的作用,具體表現(xiàn)為通過負向調控Cdc42基因的表達,從而抑制骨肉瘤的發(fā)生發(fā)展,可以作為治療骨肉瘤潛在的分子靶點。
[Abstract]:Osteosarcoma is a malignant tumor of the skeletal system derived from interleaf tissue. The incidence and mortality of osteosarcoma are the first in primary bone tumors. Osteosarcoma often occurs in adolescents aged 15-25 years, with rapid development, high metastasis and recurrence rate and low survival. The 5 year survival rate of patients treated with single hand surgery is only 15-20%, With the rapid development of medical technology, with the rapid development of medical technology, the combination of neoadjuvant radiotherapy and chemotherapy combined with limb salvage has become the main surgical method for osteosarcoma. Although the prognosis of the patients is improved, the radiotherapy and chemotherapy is not targeted, and the tumor cells can not be effectively removed, and the recurrence rate of the patients is higher. It is also necessary to assist the reconstruction of bone tissue after limb salvage, which is expensive and brings some economic pressure to the patients. At present, the new treatment of osteosarcoma, such as immunotherapy, interventional therapy, Chinese medicine treatment and gene targeting therapy, has become the breakthrough of osteosarcoma. Gene targeting therapy can be used to play an important role in the process of osteosarcoma development. The function of cancer related genes, thus inhibiting tumor cell proliferation, migration and invasion and other malignant biological characteristics, and become a new hope to effectively cure osteosarcoma. Therefore, further reveal the molecular mechanism of osteosarcoma development, explore new molecular therapeutic targets, provide theoretical basis and data support for gene targeting therapy. Important clinical significance and scientific value. With the mature and extensive application of the second generation high-throughput sequencing technology, the research on tumor tissue and cell sequencing data, such as exon sequencing, transcriptional sequencing, miRNAs sequencing, LNC RNA sequencing and single cell sequencing data, provides reliable data support for gene targeting therapy, oncology In today's big data age, a series of data databases such as TCGA and Oncomine, which integrate a large number of tumor samples, such as TCGA, and clinical data, are also widely used in oncology research to be the largest database today, covering the global scope. Exon sequencing data, SNP data, CMV data, and comprehensive clinical data of 29 types of internal tumor types have become a sharp sword in oncology research. A series of scientific publications on , , , etc. are published around the TCGA database. However, osteosarcoma with large TCGA data is used for osteosarcoma. Therefore, in today's big data age, how to use tumor large data to study osteosarcoma, further improve the molecular mechanism of osteosarcoma development, and become a major trend in oncology research today.MicroRNAs is a class of highly conserved non coded R with a length of about 21-23nt. NA, previous studies suggest that miRNA is a "junk product" that does not have functional gene transcription. With further research, people have gradually found that miRNA can combine the 6-8 base pairs with the target gene 3 'UTR region to play the role in the negative regulation of gene expression. Therefore, miRNA regulates every cell in the cell. Physical function, such as proliferation, differentiation and apoptosis, has important functions. In 2002, it was first named ten major scientific and technological breakthroughs in magazine. At present, up to thousands of miRNA sequences have been identified in mammals, and new miRNAs has been found. In recent years, with the deepening of oncology research on miRNA, people We have gradually found that many miRNA plays an important role in the regulation of cancer related genes and plays an important role in the development of cancer. It is considered as a potential molecular target for cancer treatment. Therefore, further exploration and study of the regulatory role of the key role of miRNAs in the development of osteosarcoma will be further clear. The molecular mechanism associated with the development of the osteosarcoma and the exploration of new molecular therapeutic targets are of great scientific significance. Part 1 based on the analysis of TCGA tumor data, the expression of miR-139 in osteosarcoma and its apparent regulation mechanism are studied in this part, and we use the number of miRNA chips in the osteosarcoma in the TCGA tumor database. According to the screening of significant differential expression of miRNAs in osteosarcoma, there were 70 significant down-regulation miRNAs and 115 significant up-regulated miRNAs. In a significantly up-regulated miRNAs, miR-139-5p was the most significant down-regulation and was not reported in osteosarcoma. We used Q RT-PCR to detect osteosarcoma tissues and fines. The expression of miR-139-5p in the cell lines further indicated that miR-139-5p was downregulated in osteosarcoma. In order to explore the molecular mechanism of the down-regulation of miR-139-5p in osteosarcoma, we detected the methylation and acetylation of the histone in the miR-139 promoter region by CHIP test, and miR-139 was found in the osteosarcoma. The expression is mediated by the miR139 promoter histone H3K27, the up regulation of H3K9 methylation level, the downregulation of H3K4 methylation level and the downregulation of H3 acetylation. In addition, we combine the clinical data of the osteosarcoma samples in the TCGA database to analyze the relationship between the expression of miR-139-5p and the survival period of the patients, and the birth of the patients with high expression of miR-139-5p. The survival time is significantly higher than that of the low expression patients. Through the above results, we preliminarily deduce that miR-139-5p plays an important role in the development of osteosarcoma. Second the role of miR-139-5p in the regulation of the biological phenotype of osteosarcoma and its molecular mechanism are studied to study the role of miR-139-5p in the development of osteosarcoma. Q RT-PCR was used to detect the transfection efficiency of miR-139-5p mimics. The results showed that the transfection of miR-139-5p mimics could significantly increase the miR-139-5p level in osteosarcoma cells MG63 and U20S. Next, we detected miR-139-5p on the proliferation of osteosarcoma by CCK8 experiment, and miR-139-5p could significantly inhibit the proliferation of osteosarcoma. The effect of miR-139-5p on the migration and invasion of osteosarcoma cells found that miR-139-5p could significantly inhibit the migration and invasion of osteosarcoma cells. In addition, the subcutaneous tumor model of nude mice was constructed, and after the overexpression of miR-139-5p in the body, miR-139-5p could significantly inhibit the growth of the tumor. Therefore, we conclude that miR-139-5p can significantly inhibit osteosarcoma. Development. In order to explore the molecular mechanism of miR-139-5p playing a tumor suppressor, we first used Targetscan to predict the target gene discovery of miR-139-5p, and miR-139-5p can target the Cdc42 m RNA 3 'UTR sequence. In order to further explore the target of miR-139-5p to Cdc42 m RNA 3' sequence, we construct 45-52 bits. Luciferase double fluorescent report carrier, miR-139-5p can significantly inhibit fluorescence generation after transfection of miR-139-5p. The above results show that miR-139-5p can target Cdc42 m RNA3 'UTR 45-52 site. In order to further explore the negative regulation of miR-139-5p on Cdc42 and its mechanism of action, we detected osteosarcoma after miR-139-5p transfection. The expression of Cdc42 m RNA and protein found that miR-139-5p did not inhibit the Cdc42 m RNA level and could significantly inhibit the expression of Cdc42 protein. Through the above results, we concluded that miR-139-5p can be used to regulate the expression of the gene by inhibiting the translation of Cdc42 m RNA. The third part of the biological phenotype of osteosarcoma is the biological phenotype of osteosarcoma. In this part, we explored the expression of Cdc42 gene in osteosarcoma and its regulatory role in the malignant biological phenotype of osteosarcoma. First, we analyzed the RNA-Seq data of osteosarcoma in the TCGA database, and Cdc42m RNA was not expressed differently in osteosarcoma, and the bone was detected by Q RT-PCR and Westernblot, respectively. The expression of Cdc42 m RNA and protein in sarcomas and cell lines found that Cdc42 m RNA did not express differential expression in osteosarcoma, but the expression of Cdc42 protein in osteosarcoma was significantly up-regulated. The above results indicated that Cdc42 was significantly up-regulated in osteosarcoma, and its up regulation was mainly regulated after transcriptional regulation, miR-139-5p As a regulatory factor after Cdc42 transcriptional regulation, it plays an important role in regulating the expression of Cdc42. Then we explored the effect of Cdc42 on the proliferation and migration of osteosarcoma cells..CCK8 results showed that silent Cdc42 expression significantly inhibited the proliferation of osteosarcoma cells; the scratch test showed that the migration ability of osteosarcoma cells after Cdc42 was silent. Through the above results, we conclude that Cdc42 can promote the proliferation and differentiation of osteosarcoma cells. To sum up, miR-139-5p plays an important role in the development of osteosarcoma, which is manifested by negative regulation of the expression of Cdc42 gene, thus inhibiting the occurrence and development of osteosarcoma, and can be used as a potential molecular target for the treatment of osteosarcoma. Point.

【學位授予單位】：蘇州大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R738.1

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7 曹慶選;李文華;曹來賓;夏寶樞;;中藥治愈骨肉瘤的中醫(yī)研究與影像學對照[A];第十次全國中西醫(yī)結合影像學術研討會暨全國中西醫(yī)結合影像學研究與診斷學習班資料匯編[C];2009年

8 王英;肖艦;陳曉華;;骨肉瘤病人癌性疼痛的護理體會[A];全國腫瘤護理學術交流暨專題講座會議論文匯編[C];2003年

9 陳秋;王達輝;閔若良;馬巍;;大段異體骨治療兒童骨肉瘤的初步應用[A];2005'中國修復重建外科論壇論文匯編[C];2005年

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