本文選題：骨肉瘤 + 肌細(xì)胞增強(qiáng)因子2D��； 參考：《吉林大學(xué)》2017年博士論文

【摘要】：骨肉瘤是青少年及成人中最常見的原發(fā)性惡性骨腫瘤,進(jìn)展迅速,早期即出現(xiàn)轉(zhuǎn)移。每年全世界的發(fā)病率約為4/105,易發(fā)生于生長較快的青年人,嚴(yán)重威脅著患者的身心健康。當(dāng)前骨肉瘤的治療手段仍以手術(shù)治療聯(lián)合系統(tǒng)放化療為主,基因治療、免疫治療、分子靶向治療等研究雖取得了一定進(jìn)展,但在臨床應(yīng)用前仍需建立可靠的動物模型同時進(jìn)行標(biāo)準(zhǔn)化的臨床試驗(yàn),因此療效尚不明確。再者,已有大量研究表明許多因素均會影響骨肉瘤的發(fā)生發(fā)展,如基因突變、染色體異常、環(huán)境因素、微小RNA(microRNA,miRNA)等;還有粘附因子、凋亡異常、耐藥性等也會影響骨肉瘤的治療與轉(zhuǎn)移,使得骨肉瘤的徹底治療、死亡率降低變得尤為困難。因此,明晰骨肉瘤發(fā)生發(fā)展的分子生物學(xué)機(jī)制并利用其發(fā)生發(fā)展過程中特征的分子標(biāo)志物早期預(yù)警、診斷及治療對改善預(yù)后至關(guān)重要。然而當(dāng)今關(guān)于骨肉瘤的潛在分子發(fā)病機(jī)制仍知之甚少,有待進(jìn)一步探究。最近,轉(zhuǎn)錄因子-肌細(xì)胞增強(qiáng)因子2(Myocyte enhancer factor 2,MEF2)家族被發(fā)現(xiàn)與人類多種腫瘤的發(fā)生發(fā)展密切相關(guān)。肌細(xì)胞增強(qiáng)因子2D(Myocyte enhancer factor 2D,MEF2D)能夠?qū)υS多類型癌癥細(xì)胞的致瘤性發(fā)揮一定的促進(jìn)作用,已明確為白血病、肝癌、惡性膠質(zhì)瘤、結(jié)直腸癌和肺癌等惡性腫瘤的致癌基因。然而,它在骨肉瘤的產(chǎn)生和發(fā)展過程中是否也能發(fā)揮相同或類似的作用尚不明確,國內(nèi)外研究未見相關(guān)報(bào)道。我們特別感興趣的一點(diǎn)是,在肯定MEF2D過度表達(dá)在加快惡性腫瘤進(jìn)程中發(fā)揮的作用之后,某些能夠控制MEF2D基因過表達(dá)的miRNA也意外地被發(fā)現(xiàn)。因此,在我們通過體內(nèi)外研究驗(yàn)證了MEF2D過表達(dá)對骨肉瘤的體內(nèi)生長及骨肉瘤細(xì)胞的增殖活性和細(xì)胞周期都有一定的促進(jìn)作用后,繼而深入探究了能夠作用于MEF2D表達(dá)并對其具有抑制作用的miR-144,以期為骨肉瘤患者尋找新的治療策略提供指導(dǎo)方向。研究目的:觀察MEF2D在骨肉瘤中的表達(dá)變化和功能特點(diǎn),探討MEF2D表達(dá)水平對骨肉瘤細(xì)胞及正常成骨細(xì)胞增殖活性與細(xì)胞周期的影響,明晰MEF2D促進(jìn)骨肉瘤細(xì)胞致瘤的具體機(jī)制,并進(jìn)一步探索可作用于mef2d基因并抑制其表達(dá)的mirna,從而為臨床工作中尋找骨肉瘤新的治療靶點(diǎn)提供方向。研究方法:1.mef2d在人骨肉瘤組織中的表達(dá)變化研究收集吉林大學(xué)第一醫(yī)院等三家醫(yī)院12例臨床骨肉瘤組織及少量癌旁正常組織標(biāo)本,提取腫瘤組織和對照組總rna和蛋白質(zhì),利用qrt-pcr、免疫組化和免疫印跡檢測標(biāo)本中mef2d基因和蛋白的表達(dá)情況。2.mef2d表達(dá)水平對骨肉瘤細(xì)胞及正常成骨細(xì)胞增殖能力的影響研究針對相應(yīng)u2os、saos2骨肉瘤細(xì)胞和hfob1.19正常成骨細(xì)胞,利用rna干擾技術(shù)或基因過表達(dá)技術(shù)沉默或者過表達(dá)mef2d,通過mtt法觀察mef2d表達(dá)水平對不同細(xì)胞增殖活性的影響。3.mef2d表達(dá)水平與骨肉瘤生長相關(guān)性的體內(nèi)研究按前述方法分別用慢病毒lv-shmef2d-1(5×107pfu/mlin200μl),lv-shmef2d-2(5×107pfu/mlin200μl),lv-scrambled(5×107pfu/mlin200μl)感染u2os骨肉瘤細(xì)胞,同時分別用腺病毒ad-mef2d(5×107pfu/mlin200μl),ad-gfp(5×107pfu/mlin200μl)感染hfob1.19正常成骨細(xì)胞。隨機(jī)選取30只6周齡的雄性balb/c裸鼠,移植部位選擇右側(cè)前肢腋窩處,定位后皮下注射總體積約為100μl的5×105個慢病毒感染的u2os細(xì)胞或者腺病毒感染的hfob1.19正常成骨細(xì)胞。在注射后35天內(nèi)定期測量腫瘤直徑并計(jì)算腫瘤體積。整個動物實(shí)驗(yàn)嚴(yán)格按照實(shí)驗(yàn)動物保護(hù)指南進(jìn)行。所有動物實(shí)驗(yàn)均經(jīng)吉林大學(xué)第二醫(yī)院動物研究倫理審查委員會審查通過。4.mef2d表達(dá)水平影響骨肉瘤細(xì)胞及正常成骨細(xì)胞周期進(jìn)程的機(jī)制研究我們進(jìn)一步利用流式細(xì)胞術(shù)探究了感染慢病毒lv-shmef2d-1和lv-scrambled的u2os和saos2骨肉瘤細(xì)胞的細(xì)胞周期進(jìn)程以明確mef2d過表達(dá)加速骨肉瘤細(xì)胞增殖的具體機(jī)制。同時,我們還檢測了腺病毒ad-mef2d和ad-gfp感染正常成骨細(xì)胞hfob1.19后的細(xì)胞周期情況,對過表達(dá)mef2d成骨細(xì)胞的細(xì)胞周期進(jìn)程進(jìn)行了評估。5.mir-144通過調(diào)控mef2d表達(dá)對骨肉瘤的抑制作用研究5.1通過文獻(xiàn)檢索和mirna及靶基因數(shù)據(jù)庫targetscanhuman的生物信息學(xué)分析,最終發(fā)現(xiàn)mef2dmrna的3'utr存在mir-144的mirna識別元件(mirnarecognitionelement,mre),它可能會抑制骨肉瘤的進(jìn)程。5.2應(yīng)用qrt-pcr法分別檢測不同骨肉瘤細(xì)胞(u2os、saos2、hos、khos、p1、p2)和正常成骨細(xì)胞hfob1.19中mef2d和相應(yīng)mir-144的表達(dá)水平。繼而以mef2d表達(dá)水平為橫坐標(biāo),mir-144表達(dá)水平為縱坐標(biāo)描繪散點(diǎn)圖,用以評估m(xù)ir-144表達(dá)水平與mef2d表達(dá)水平之間是否存在線性關(guān)系。5.3依次以mir-144模擬劑轉(zhuǎn)染u2os骨肉瘤細(xì)胞,mir-144抑制劑轉(zhuǎn)染hfob1.19正常成骨細(xì)胞。24h之后,用westernblot檢測u2os骨肉瘤細(xì)胞和hfob1.19正常成骨細(xì)胞中mef2d蛋白的表達(dá)情況。5.4分別將野生型和突變型mef2d3'utr插入到熒光素酶表達(dá)載體pmir-report中,分別為pmir-report-mef2d-3utr和pmir-report-mef2d-3utr-m,然后將其分別轉(zhuǎn)染u2os骨肉瘤細(xì)胞系和hfob1.19正常成骨細(xì)胞系。之后,我們再用mir-144mimics轉(zhuǎn)染u2os骨肉瘤細(xì)胞、mir-144inhibitors轉(zhuǎn)染hfob1.19正常成骨細(xì)胞,通過檢測其表達(dá)熒光素酶的情況,明確mir-144是否能夠抑制mef2d的表達(dá)。研究結(jié)果:1.mef2d基因和蛋白在骨肉瘤組織中呈過度表達(dá)。通過qrt-pcr、免疫組化及免疫印跡證實(shí)在12例人骨肉瘤組織及癌旁正常組織標(biāo)本中,mef2d基因和蛋白在其中10例骨肉瘤組織標(biāo)本中的表達(dá)量顯著高于瘤旁正常組織,差異有統(tǒng)計(jì)學(xué)意義。2.mef2d表達(dá)水平與骨肉瘤細(xì)胞的增殖活性密切相關(guān)。利用mtt法分析研究了mef2d表達(dá)水平對骨肉瘤細(xì)胞及正常成骨細(xì)胞增殖能力的影響。結(jié)果表明,mef2d表達(dá)水平越高,骨肉瘤細(xì)胞增殖率越高,并且mef2d表達(dá)水平和細(xì)胞增殖率呈正相關(guān)。與此同時,沉默mef2d能夠降低u2os和saos2細(xì)胞的增殖率,mef2d過表達(dá)能夠升高h(yuǎn)fob1.19細(xì)胞的增殖率。3.體內(nèi)改變mef2d表達(dá)水平影響骨肉瘤裸鼠移植瘤的生長。建立移植有u2os骨肉瘤細(xì)胞或hfob1.19正常成骨細(xì)胞的異種動物模型,通過lv-shmef2d-1和lv-shmef2d-2轉(zhuǎn)染沉默裸鼠mef2d基因的表達(dá),通過ad-mef2d轉(zhuǎn)染高表達(dá)mef2d基因,用游標(biāo)卡尺定期測量腫瘤大小并計(jì)算體積。結(jié)果表明在u2os細(xì)胞中,mef2d沉默能延緩骨肉瘤裸鼠移植瘤的生長;而在hfob1.19細(xì)胞中,mef2d過表達(dá)能夠加速骨肉瘤裸鼠移植瘤的生長。4.mef2d表達(dá)水平和骨肉瘤細(xì)胞的周期進(jìn)展密切相關(guān)。在明晰了過表達(dá)mef2d對骨肉瘤的細(xì)胞增殖與體內(nèi)生長的促進(jìn)作用之后,利用流式細(xì)胞術(shù)研究mef2d表達(dá)水平對骨肉瘤細(xì)胞及正常成骨細(xì)胞細(xì)胞周期的影響。流式細(xì)胞術(shù)結(jié)果表明在u2os和saos2細(xì)胞中,下調(diào)mef2d表達(dá)水平增加了細(xì)胞在g2/m期中的百分比,誘導(dǎo)了細(xì)胞周期的g2/m期阻滯。與此相對應(yīng)的是,在hfob1.19細(xì)胞中,mef2d過表達(dá)降低了細(xì)胞在g2/m期中的百分比,加快細(xì)胞周期的g2/m期過渡。通過qrt-pcr定量分析發(fā)現(xiàn),在u2os和saos2細(xì)胞中,mef2d沉默可引起g2/m細(xì)胞周期調(diào)控蛋白-rprm和cdkn1a明顯升高。相反,在hfob1.19細(xì)胞中,mef2d過度表達(dá)則引起g2/m細(xì)胞周期調(diào)控蛋白-rprm和cdkn1a明顯降低。5.mir-144通過下調(diào)mef2d表達(dá)對骨肉瘤的生長發(fā)揮抑制作用。鑒于mef2d過表達(dá)對骨肉瘤細(xì)胞增殖活性和細(xì)胞周期的抑制作用,進(jìn)一步研究mef2d在其中的調(diào)控機(jī)制。通過在線數(shù)據(jù)庫的篩選,提示mir-144可能是調(diào)控mef2d表達(dá)的關(guān)鍵mirna。通過qrt-pcr定量分析得出mir-144表達(dá)水平在u2os骨肉瘤細(xì)胞中減少,并與mef2d表達(dá)水平呈負(fù)相關(guān)。免疫印跡結(jié)果顯示mir-144mimics降低了u2os細(xì)胞中mef2d蛋白的表達(dá)水平,而mir-144inhibitors上調(diào)了hfob1.19細(xì)胞中mef2d蛋白的表達(dá)水平。熒光素酶檢測顯示,將合成的mir-144mimics轉(zhuǎn)染u2os細(xì)胞后,極大地抑制了pmir-report-mef2d-3utr熒光素酶的表達(dá),但不會影響pmir-report-mef2d-3utr-m(p0.01);而mir-144inhibitors則增加了正常成骨細(xì)胞中pmir-report-mef2d-3utr熒光素酶的表達(dá),但對突變株沒有影響(p0.01)。這說明mir-144是通過下調(diào)mef2d表達(dá)來抑制骨肉瘤的生長。研究結(jié)論:1.mef2d在骨肉瘤組織及細(xì)胞中均呈高表達(dá),與骨肉瘤發(fā)生發(fā)展具有密切相關(guān)性,可作為骨肉瘤的候選致癌基因。2.mef2d在mir-144的調(diào)控下通過抑制rprm和cdkn1a加速骨肉瘤細(xì)胞的G2/M期過渡而促進(jìn)骨肉瘤的發(fā)展。因此,mi R-144減少可能是骨肉瘤中MEF2D高表達(dá)的原因,或可作為治療骨肉瘤的新靶點(diǎn)。創(chuàng)新點(diǎn):1.首次對MEF2D在骨肉瘤臨床標(biāo)本中的表達(dá)特點(diǎn)進(jìn)行了探討,驗(yàn)證了MEF2D與骨肉瘤發(fā)生發(fā)展之間的關(guān)系,證實(shí)MEF2D是骨肉瘤的候選致癌基因。2.首次研究了MEF2D促進(jìn)骨肉瘤發(fā)生發(fā)展的分子機(jī)制,并明確了其與腫瘤抑制因子miR-144的關(guān)系,證實(shí)miR-144是通過調(diào)控MEF2D表達(dá)對骨肉瘤發(fā)揮抑制作用。這為骨肉瘤的早期診斷及治療提供了一個新思路,值得進(jìn)一步探究。
[Abstract]:Osteosarcoma is the most common primary malignant bone tumor in adolescents and adults, with rapid progress and early metastasis. The incidence of osteosarcoma is about 4/105 every year. It is easy to occur in young people with faster growth, and it is a serious threat to the physical and mental health of the patients. Although some progress has been made in the study of treatment, immunotherapy and molecular targeting therapy, a reliable animal model still needs to be established and standardized clinical trials are still needed before clinical application. Therefore, the curative effect is not clear. Often, environmental factors, small RNA (microRNA, miRNA), and adhesion factors, abnormal apoptosis and drug resistance also affect the treatment and metastasis of osteosarcoma, which makes the radical treatment of osteosarcoma and the reduction of mortality become particularly difficult. Therefore, the molecular biological mechanism of osteosarcoma development is clarifying and the characteristics of the development process are used. Early warning of submarkers, diagnosis and treatment are essential to improve the prognosis. However, little is known about the potential molecular pathogenesis of osteosarcoma today. It remains to be further explored. Recently, the transcription factor - the Myocyte enhancer factor 2 (MEF2) family has been found to be closely related to the development of a variety of human tumors. 2D (Myocyte enhancer factor 2D, MEF2D) can play a certain role in the tumorigenicity of many types of cancer cells. It has been identified as the oncogene of leukemia, liver cancer, malignant glioma, colorectal cancer and lung cancer. However, it can also play a role in the process of the production and development of osteosarcoma. The role of the same or similar is not clear, and there is no related report at home and abroad. One of our particular interest is that some miRNA, which can control the overexpression of MEF2D genes, have been discovered unexpectedly after affirming the role of overexpression of MEF2D in accelerating the process of malignant tumor. Therefore, we have verified the MEF2D in our body and body. Over expression can promote the growth of osteosarcoma in vivo and the proliferation and cell cycle of osteosarcoma cells, and then explore the miR-144 which can play a role in MEF2D expression and have inhibitory effect on the osteosarcoma, in order to provide guidance for the osteosarcoma patients to find new therapeutic strategies. Objective: To observe the MEF2D in bone. The expression changes and functional characteristics in sarcomas are used to explore the effect of MEF2D expression on the proliferation and cell cycle of osteosarcoma cells and normal osteoblasts, and to clarify the specific mechanism of MEF2D to promote osteosarcoma cells, and to further explore the function of the MEF2D gene and inhibit the miRNA of the osteosarcoma, so as to find bone meat for clinical work. Research methods: study methods: study methods: 1.mef2d expression in human osteosarcoma tissue, 12 cases of clinical osteosarcoma and a small number of normal tissue specimens were collected from three hospitals, such as No.1 Hospital of Jilin University, and the total RNA and protein in the tumor tissue and control group were extracted, and qRT-PCR, immunohistochemistry and Western blotting were used. The effect of the expression of MEF2D gene and protein in the samples on the proliferation of osteosarcoma cells and normal osteoblasts by.2.mef2d expression level, the study aimed at corresponding U2OS, saos2 osteosarcoma cells and hfob1.19 normal osteoblasts. The RNA interference technique or gene overexpression technique was used to silence or overexpress MEF2D, and the MEF2D table was observed by MTT method. In vivo studies on the effects of levels of.3.mef2d on the growth of different cell proliferation and osteosarcoma growth in vivo, respectively, using lentivirus lv-shmef2d-1 (5 x 107pfu/mlin200 Mu L), lv-shmef2d-2 (5 * 107pfu/mlin200 Mu L), lv-scrambled (5 * 107pfu/mlin200 micron L) infected with U2OS osteosarcoma cells, and adenovirus ad-me, respectively. F2D (5 * 107pfu/mlin200 Mu L), Ad-GFP (5 * 107pfu/mlin200 Mu L) infected normal osteoblasts of hfob1.19. 30 6 week old male balb/c nude mice were randomly selected. The transplant site selected the axillary fossa of the right forelimb, and then subcutaneous injection of 5 x 105 lentivirus infected U2OS cells or adenovirus infected hfob1.19 normal osteogenesis after localization. Cells. The diameter of the tumor and the volume of the tumor were regularly measured within 35 days after the injection. The whole animal experiment was carried out strictly in accordance with the guide of experimental animal protection. All animal experiments were examined by the animal research ethics committee of the second hospital of Jilin University to examine the effects of the.4.mef2d expression level on the osteosarcoma cells and normal osteoblast cycles. We further explored the cell cycle process of U2OS and saos2 osteosarcoma cells infected with lentivirus lv-shmef2d-1 and lv-scrambled by flow cytometry to clarify the specific mechanism of MEF2D overexpression to accelerate the proliferation of osteosarcoma cells. At the same time, we also detected HF of adenosis ad-mef2d and Ad-GFP infection normal osteoblast HF. The cell cycle status after ob1.19, evaluation of the cell cycle process over expression of MEF2D osteoblasts and the inhibitory effect of.5.mir-144 on osteosarcoma by regulating MEF2D expression 5.1 through bibliographic information analysis of literature retrieval and miRNA and target gene database targetscanhuman, it is found that mef2dmrna 3'UTR exists mir-144 MI. The RNA identification element (mirnarecognitionelement, MRE), which may inhibit the process of osteosarcoma,.5.2 use qRT-PCR to detect the expression level of different osteosarcoma cells (U2OS, saos2, HOS, khos, P1, P2) and the normal osteoblast hfob1.19 and corresponding expressions. The standard portrayed the scatter plot to assess whether there is a linear relationship between mir-144 expression level and MEF2D expression level.5.3 transfection of U2OS osteosarcoma cells with mir-144 simulant, mir-144 inhibitor transfected to hfob1.19 normal osteoblast.24h, and Westernblot detection of U2OS osteosarcoma cells and hfob1.19 normal osteoblasts by Westernblot The expression situation.5.4 inserted wild and mutant mef2d3'utr into the luciferase expression vector pmir-report, respectively pmir-report-mef2d-3utr and pmir-report-mef2d-3utr-m, and then transfected them to U2OS osteosarcoma cell lines and hfob1.19 normal osteoblast lines respectively. Then, we transfected the U2OS osteosarcoma cells with mir-144mimics. Mir-144inhibitors transfected hfob1.19 normal osteoblasts. By detecting its expression of luciferase, it is clear whether mir-144 can inhibit the expression of MEF2D. The results: the 1.mef2d gene and protein were overexpressed in the osteosarcoma tissue. Through qRT-PCR, immunohistochemistry and immunization were confirmed in 12 human osteosarcoma tissues and adjacent to cancer. In the normal tissue specimens, the expression of MEF2D gene and protein in 10 cases of osteosarcoma was significantly higher than that of normal tissue adjacent to the tumor. The difference was statistically significant between the expression level of.2.mef2d and the proliferation activity of osteosarcoma cells. The proliferation of MEF2D expressed by MTT was analyzed and the proliferation of osteosarcoma cells and normal osteoblasts was studied. The results showed that the higher the expression level of MEF2D, the higher the proliferation rate of osteosarcoma cells, and the positive correlation between the MEF2D expression level and the cell proliferation rate. At the same time, silent MEF2D can reduce the proliferation rate of U2OS and saos2 cells, and MEF2D overexpression can increase the proliferation rate of fob1.19 cells in.3. and change the level of MEF2D expression to influence bone. The growth of sarcoma transplanted tumor in nude mice. A xenograft model of U2OS osteosarcoma cells or hfob1.19 normal osteoblasts was established. The expression of MEF2D gene in nude mice was transfected by lv-shmef2d-1 and lv-shmef2d-2. The high expression of MEF2D gene was transfected by ad-mef2d. The size of the tumor was measured with the vernier caliper and the volume was calculated. The results showed that the tumor size was measured and the volume was calculated. In U2OS cells, MEF2D silencing can delay the growth of osteosarcoma xenografts in nude mice. In hfob1.19 cells, MEF2D overexpression can accelerate the growth of.4.mef2d expression level of osteosarcoma xenografts and the progression of osteosarcoma cells. The promotion of cell proliferation and growth in bone sarcomas by MEF2D is clarified. After use, flow cytometry was used to study the effect of MEF2D expression on the cell cycle of osteosarcoma cells and normal osteoblasts. Flow cytometry results showed that down regulation of MEF2D expression in U2OS and saos2 cells increased the percentage of cells in g2/m phase and induced the g2/m phase block in the cell cycle. This corresponds to that in hfob1 In.19 cells, the over expression of MEF2D reduces the percentage of cells in the g2/m phase and speeds up the g2/m transition in the cell cycle. Through qRT-PCR quantitative analysis, it is found that MEF2D silencing can cause the g2/m cell cycle regulation protein -rprm and CDKN1A to rise obviously in U2OS and saos2 cells. Cyclical regulatory proteins -rprm and CDKN1A significantly reduce the inhibitory effect of.5.mir-144 on the growth of osteosarcoma by down regulation of MEF2D. In view of the inhibitory effect of MEF2D overexpression on the proliferation and cell cycle of osteosarcoma cells, the regulatory mechanism of MEF2D is further studied. Through screening in a line database, it is suggested that mir-144 may be adjusted. The key mirna. for controlling MEF2D expression showed that the expression level of mir-144 decreased in U2OS osteosarcoma cells and was negatively correlated with the level of MEF2D expression. The results of immunoblotting showed that mir-144mimics decreased the expression level of MEF2D protein in U2OS cells, while mir-144inhibitors increased the expression of MEF2D protein in hfob1.19 cells. Level. Luciferase assay showed that the transfection of the synthesized mir-144mimics to U2OS cells greatly inhibited the expression of pmir-report-mef2d-3utr luciferase, but did not affect pmir-report-mef2d-3utr-m (P0.01), and mir-144inhibitors increased the expression of pmir-report-mef2d-3utr luciferase in normal osteoblasts, but to the mutant strain. It does not affect (P0.01). This indicates that mir-144 inhibits the growth of osteosarcoma by down regulation of MEF2D. Conclusion: 1.mef2d is highly expressed in osteosarcoma tissues and cells, and is closely related to the development of osteosarcoma, and can be used as a candidate oncogene of osteosarcoma by inhibiting RPRM and CDKN1A under the control of mir-144. The G2/M transition of the rapid osteosarcoma cells promotes the development of osteosarcoma. Therefore, the decrease of MI R-144 may be the cause of high expression of MEF2D in osteosarcoma, or can be used as a new target for the treatment of osteosarcoma. Innovation: 1. for the first time, the expression of MEF2D in the clinical specimens of osteosarcoma was discussed, which verified the development between MEF2D and osteosarcoma. It is confirmed that MEF2D is the candidate oncogene.2. of osteosarcoma for the first time to study the molecular mechanism of MEF2D to promote osteosarcoma development, and to clarify its relationship with the tumor suppressor factor miR-144, which confirms that miR-144 plays an inhibitory effect on osteosarcoma through the regulation of MEF2D expression, which provides a new diagnosis and treatment for osteosarcoma. The idea is worth further exploring.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R738.1

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