發(fā)布時間：2018-04-05 02:03

  本文選題：膠質瘤　切入點：細胞增殖　出處：《河北醫(yī)科大學》2016年博士論文

【摘要】：膠質瘤是人類中樞神經(jīng)系統(tǒng)中最為常見的原發(fā)性惡性腫瘤,約占顱內腫瘤的40%~60%。目前對膠質瘤患者普遍采用手術切除聯(lián)合術后放化療等綜合治療方法。雖然近年來,神經(jīng)影像技術、顯微外科技術以及放化療治療方案等多方面均取得了突飛猛進的發(fā)展,但對于膠質瘤患者,尤其是高級別的膠質瘤患者,預后仍然不佳。膠質母細胞瘤(WHOⅣ級)患者術后復發(fā)率仍接近100%,中位生存時間少于1年。文獻報道,低級別膠質瘤患者平均生存時間為3~5年,而高級別患者則是1~2年。治療效果的不佳主要是由于膠質瘤細胞具有高度侵襲、增殖、遷移能力以及凋亡抑制的特性,決定了膠質瘤不可能單純通過外科方法得到治愈,而目前的放化療治療也無法滿意控制膠質瘤的發(fā)展。因此,深入了解膠質瘤發(fā)生發(fā)展機制,研究靶向藥物以特異性地抑制甚至滅活殘存瘤細胞,是未來膠質瘤治療的方向。目前已經(jīng)發(fā)現(xiàn)許多與腫瘤相關的基因及蛋白因子,有些已經(jīng)研究的比較深入,一部分新型抗腫瘤藥物已應用臨床并顯著改善預后。但是針對膠質瘤的藥物研究大多仍處于實驗的初級階段,仍需進一步研究探索。mi RNA即微小RNA(microRNA),是一類新近發(fā)現(xiàn)的、內源性、非蛋白質編碼RNA,因其在各種病理生理過程中的強大作用逐漸受到重視。文獻指出,miR-95-3p在直腸癌、胰腺癌、乳腺癌及前列腺癌等癌癥中具有致癌作用�？紤]到miR-95-3p尚未在膠質瘤細胞中進行過研究,故在本實驗中我們選取miR-95-3p作為對象,并通過MTT實驗,流式細胞技術以及Transwell實驗探討其對于膠質瘤的作用。CELF2(CUGBP-and ETR-3-like family)為一組RNA連接蛋白,包含眾多與基因轉錄后調控相關的蛋白。研究表明,CELF2編碼基因位于10號染色體上,該染色體在60%的低級別膠質瘤中呈單體型,并在80%的高級別膠質瘤中部分缺失,我們因此猜測CELF2與膠質瘤的發(fā)生發(fā)展可能相關。由于CELF2出現(xiàn)在Targetscan的預測結果中,我們進一步研究其與miR-95-3p的關系。實驗中我們通過熒光素酶報告基因實驗確定mir-95-3p與celf2的靶向作用關系,并分析兩者表達量的相關性進一步證實兩者相關性。最后通過復活實驗證實mir-95-3p對膠質瘤的作用是通過靶向調控celf2引起的。第一部分mir-95-3p在人腦膠質瘤組織中的表達及其與膠質瘤病理級別的相關性目的:研究mir-95-3p在人腦膠質瘤組織中的表達,并分析mir-95-3p的表達與膠質瘤病理級別的關系。方法:1組織標本的采集:35例膠質瘤樣本及15例非腫瘤腦組織樣本均于2014年采集自河北醫(yī)科大學第二醫(yī)院神經(jīng)外科。包括19名女性,31名男性,年齡從18至68歲,共收集膠質瘤樣本35例,其中Ⅰ級膠質瘤4例、ii級5例、iii級17例、iv級9例,均由術中切除獲得。15例非腫瘤腦組織樣本來自于對嚴重的腦外傷患者進行的顱內減壓術。診斷結果均由2位病理醫(yī)師根據(jù)who分級指導得出。所有樣本在采集后立即保存至-80℃液氮中。2樣本mir-95-3p表達水平的測定:反轉錄定量聚合酶鏈反應(qrt-pcr)方法測定35例膠質瘤樣本以及15例非腫瘤腦組織樣本中的mir-95-3p含量。3相關性分析:應用t檢驗分析膠質瘤中mir-95-3p含量與膠質瘤級別之間的關系。結果:1qrt-pcr結果:膠質瘤組織與非腫瘤腦組織中mir-95-3p表達量具有顯著性差異。與對照非腫瘤腦組織相比,膠質瘤組織中mir-95-3p含量顯著升高,差別具有統(tǒng)計學意義(p0.001)。2t檢驗結果:低級別膠質瘤(whoⅠ、Ⅱ級)、高級別膠質瘤(whoⅢ、Ⅳ級)及非腫瘤腦組織中mir-95-3p表達量具有顯著性差異。在高級別膠質瘤組織中mir-95-3p的含量較低級別更高。結論:1mir-95-3p在人腦膠質瘤組織中高表達,且其表達量隨著膠質瘤級別的升高而升高。高級別膠質瘤mir-95-3p的表達量要高于低級別膠質瘤,差別具有統(tǒng)計學意義。2mir-95-3p的表達水平與膠質瘤的級別呈顯著的正相關,提示mir-95-3p可能成為膠質瘤臨床分級的分子標志物。第二部分mir-95-3p對膠質瘤細胞生物學活性的影響目的:研究mir-95-3p對u87和u251細胞的增殖、侵襲、凋亡及細胞周期等方面的影響。方法:1培養(yǎng)u87和u251細胞系用于體外功能學實驗。向實驗組中轉染mir-95-3paso以降低細胞內mir-95-3p的表達。對照組轉染ctrlaso。2進行mtt實驗研究降低mir-95-3p表達后膠質瘤細胞增殖能力的變化。3進行流式細胞實驗研究降低mir-95-3p表達后膠質瘤細胞周期及凋亡能力的變化。4進行transwell實驗研究降低mir-95-3p表達后膠質瘤細胞侵襲能力的變化。結果:1qrt-pcr結果顯示,轉染mir-95-3paso后,u87及u251細胞內mir-95-3p的表達量顯著降低(p0.05)。2mtt實驗結果顯示,降低mir-95-3p表達后,u87及u251細胞增殖能力顯著降低(p0.05)。3流式細胞實驗結果顯示,降低mir-95-3p表達后,u87及u251細胞周期無明顯改變,凋亡增殖能力顯著增高(p0.05)。4transwell實驗結果顯示,降低mir-95-3p表達后,u87及u251細胞侵襲能力顯著降低(p0.05)。結論:降低mir-95-3p表達,可以使u87及u251細胞增殖及侵襲能力顯著降低,凋亡能力顯著增高,細胞周期無明顯差別。mir-95-3p可以影響膠質瘤細胞的增殖、侵襲及凋亡水平。第三部分celf2為mir-95-3p的下游靶基因目的:尋找mir-95-3p的下游作用靶點,進一步了解mir-95-3p對膠質瘤生物學影響的作用機制。方法:1使用在線工具targetscan預測mir-95-3p的下游作用靶點,并根據(jù)文獻資料篩選結果。2雙熒光素酶報告基因實驗驗證mir-95-3p與celf2的靶向作用關系。3應用反轉錄定量聚合酶鏈反應(qrt-pcr)及蛋白質免疫印跡(westernblot)方法檢測mir-95-3p與celf2在u87及u251細胞中的表達量,并分析兩者的相關性。結果:1根據(jù)targetscan的預測結果,并結合相關文獻資料,猜測celf2上可能存在mir-95-3p的靶向作用位點。2相對于mir-95-3p反義寡核苷酸(mir-95-3paso),對照組中共轉染mir-95-3p與ctrlaso可以顯著抑制熒光素酶活性,而突變靶位點后此抑制作用消失。3mir-95-3p與celf2在u87及u251中的表達量呈負相關。結論:celf2的mrna中存在mir-95-3p在膠質瘤中的靶向作用位點。第四部分mir-95-3p通過調控celf2影響膠質瘤細胞增殖、侵襲、凋亡等的生物學活性目的:證實mir-95-3p對膠質瘤的生物學活性影響是通過調控celf2而完成的。方法:1向u251細胞內轉染mir-95-3paso后,同時轉染小干擾rna(smallinterferingrna,sirna),以降低細胞中celf2的含量。2進行mtt實驗,實驗組共轉染mir-95-3paso與celf2sirna,對照組共轉染mir-95-3p與ctrlsirna,檢測u251細胞增殖能力的改變。3進行流式細胞實驗,實驗組共轉染mir-95-3paso與celf2sirna,對照組共轉染mir-95-3p與ctrlsirna,檢測u251細胞凋亡能力的改變。4進行transwell實驗,實驗組共轉染mir-95-3paso與celf2sirna,對照組共轉染mir-95-3p與ctrlsirna,檢測u251細胞侵襲能力的改變。1 Western blot實驗證實轉染CELF2 siRNA后,U251細胞內CELF2含量顯著降低(P0.05)。2 MTT實驗結果顯示,相對于對照組,實驗組中U251細胞增殖能力明顯降低(P0.05)。3流式細胞實驗結果顯示,相對于對照組,實驗組中U251細胞凋亡能力明顯增高(P0.05)。4 Transwell實驗結果顯示,相對于對照組,實驗組中U251細胞侵襲能力明顯降低(P0.05)。結論:miR-95-3p是通過調控CELF2的表達而影響膠質瘤增殖、凋亡、侵襲能力改變的。
[Abstract]:Glioma is the human central nervous system is the most common primary malignant tumor, accounnting 40%~60%. of glioma patients commonly used surgery chemotherapy and other comprehensive treatment method of resection. Although in recent years, neuroimaging techniques, microsurgical technique and chemoradiotherapy achieved etc. the rapid development, but for glioma patients, especially in patients with high grade gliomas, the prognosis is still poor. Glioblastoma (WHO IV) recurrence rate is close to 100%, the median survival time of less than 1 years. The literature reported that patients with low grade gliomas the average survival time was 3~5 however, patients with high grade is 1~2 years. The poor treatment effect is mainly due to glioma cells with high invasion, proliferation, migration and apoptosis characteristics, determines the glioma may not only by Methods surgical cure and chemotherapy in the treatment of current cannot satisfy the development control of glioma. Therefore, in-depth understanding of the occurrence and development mechanism of glioma research, targeted drugs to specifically inhibit or inactivate the residual tumor cells, glioma is the future direction of the treatment. It was found that many tumor related genes and some of the proteins, has been more in-depth, part of a new antitumor drug has clinical application and improve the prognosis. But research on drugs of glioma are still in the primary stage of the experiment, further research is needed to explore the.Mi RNA micro RNA (microRNA), is a newly discovered endogenous non protein. RNA encoding, because of its powerful role in various pathophysiological processes has attracted much attention. The literature pointed out, miR-95-3p in rectal cancer, pancreatic cancer, breast cancer and prostate cancer and other cancers. Taking into account the carcinogenic effect. MiR-95-3p has not been in glioma cells studied in this experiment, we select miR-95-3p as the object, and through the MTT experiment to investigate the effect of.CELF2 glioma cells and Transwell (CUGBP-and ETR-3-like family) flow experiment for a group of RNA binding protein related protein regulation, including many of the post transcriptional gene. The results show that the CELF2 encoding gene is located on chromosome 10, the chromosome haplotype was in low grade glioma in 60%, and 80% in the high grade gliomas excalation, so I guess the occurrence and development of CELF2 and glioma may be related. Because CELF2 appear in the prediction results in Targetscan, we further study the relationship with miR-95-3p. In our experiment by luciferase reporter assay and determine mir-95-3p targeting celf2, and analysis The expression of correlation further confirmed the relationship between them. Finally, the resurrection experiments confirmed that the effect of mir-95-3p on glioma is caused by celf2 to control the target. Part 1 expression of mir-95-3p in human glioma tissues and its correlation with the pathological grade of glioma Objective: To study the expression of mir-95-3p in human glioma tissues, and analysis the relationship between mir-95-3p expression and pathological grade of glioma. Methods: 1 tissue specimens collected: 35 cases of glioma samples and 15 cases of non tumor brain tissue samples were collected in 2014 from the second hospital of Hebei Medical University, Department of neurosurgery. Including 19 women, 31 men, aged from 18 to 68 years, a total of 35 cases of glioma samples, including 4 cases of glioma, 5 cases of grade II, III grade 17 cases, 9 cases of grade IV, were obtained by resection of.15 cases of non tumor brain tissue samples from the patients with severe traumatic brain injury Intracranial decompression performed. According to the WHO grading diagnosis results by 2 pathologists. All the samples that guide preservation to the level of mir-95-3p expression were detected by.2 -80 C in liquid nitrogen immediately after collection: reverse transcription polymerase chain reaction (qRT-PCR) analysis of.3 correlation of mir-95-3p content in 35 cases of glioma and 15 cases of non tumor samples brain tissue samples: application of t test method to analyze the relationship between the content of mir-95-3p in glioma and glioma grade. Results: 1qrt-pcr results: a significant difference of mir-95-3p expression of glioma and non tumor brain tissues. Compared with non tumor brain tissue, the content of mir-95-3p in glioma tissues increased significantly. The difference was statistically significant (p0.001).2t test results: low grade gliomas (who I, II) and high grade gliomas (who III, IV) and non tumor brain tissue of mir-95-3p expression The difference is significant. The content of mir-95-3p in high grade glioma tissues of the lower level higher. Conclusion: high expression of 1mir-95-3p in human glioma tissues, and its expression increased with the glioma grade. The expression of mir-95-3p in high grade gliomas than in low grade gliomas, a significant positive expression was statistically significant difference.2mir-95-3p and glioma grade, suggesting that mir-95-3p may become a molecular marker for glioma clinical classification. The second part: the effect of mir-95-3p on glioma cells Objective: To study the biological activity of mir-95-3p and U251 on U87 cell proliferation, invasion, apoptosis and cell cycle and other aspects of the method. 1: the culture of U87 and U251 cells for in vitro functional experiments. The experimental group was transfected with mir-95-3paso to reduce the expression of mir-95-3p in cells transfected with ctrlaso.2 in the control group MTT experimental study on reducing the change of.3 expression of mir-95-3p glioma cell proliferation by flow cytometry experiments of experimental study of Transwell decreased after glioma cell invasion of the expression of mir-95-3p decreased.4 mir-95-3p expression in glioma cell cycle and apoptosis ability. Results: 1qrt-pcr results showed that after mir-95-3paso transfection, expression U87 and U251 cells significantly decreased mir-95-3p (P0.05).2mtt experimental results show that the decreased expression of mir-95-3p, U87 and U251 Cell proliferation ability decreased significantly (P0.05).3 flow cytometry results showed that decreased expression of mir-95-3p, U87 and U251 no significant changes in the cell cycle, proliferation apoptosis significantly increased (P0.05).4transwell the experimental results show that the reduced expression of mir-95-3p, U87 and the invasion ability of U251 cells was significantly decreased (P0.05). Conclusion: the decreased expression of mir-95-3p, can make u 87 and U251 Cell Proliferation and invasion ability decreased significantly, the apoptosis increased significantly, there was no significant difference in cell cycle of.Mir-95-3p can affect the glioma cell proliferation, invasion and apoptosis level. The third part celf2 is the downstream target genes of mir-95-3p Objective: to find out the mir-95-3p downstream targets, to further understand the mechanism of mir-95-3p effect on glioma biology. Methods: 1 using the online tool targetscan to predict downstream effect of mir-95-3p target, and screening results of mir-95-3p and celf2 to verify the.2 dual luciferase assay targeting.3 by reverse transcription polymerase chain reaction (qRT-PCR) based on the literature and Western blot (Westernblot) method to detect mir-95-3p and celf2 expression in U87 and U251 cells, and to analyze the relationship between them. Results: 1 according to the prediction results of targetscan, and combined with the relevant Literature, guess mir-95-3p might exist on celf2 targeting sites of.2 compared with mir-95-3p antisense oligonucleotide (mir-95-3paso), the control group transfected with mir-95-3p and ctrlaso can significantly inhibit the luciferase activity, and mutation of target sites of this inhibition of the expression of.3mir-95-3p and celf2 disappeared in U87 and in U251 was negatively correlated. Conclusion: mir-95-3p in glioma targeting sites of celf2 mRNA in mir-95-3p. The fourth part through the regulation of celf2 proliferation effect of glioma cell invasion, apoptosis and biological activity Objective: To study the effects of biological activity of mir-95-3p on glioma is completed by the regulation of celf2. Methods: 1 to U251 cells after transfection of mir-95-3paso. At the same time, transfection of small interfering RNA (smallinterferingrna, siRNA), in order to reduce the content of.2 in celf2 cells by MTT experiment, the experimental group were transfected into mir-95-3paso and CE Lf2sirna, the control group were transfected into mir-95-3p and ctrlsirna, U251 to detect the changes of cell proliferation..3 flow cytometry experiment, the experimental group were transfected into mir-95-3paso and celf2sirna, the control group were transfected into mir-95-3p and ctrlsirna, U251 apoptosis detection ability change.4 Transwell experiment, the experimental group were transfected into mir-95-3paso and celf2sirna, CO transfected control group mir-95-3p ctrlsirna and.1 Western blot, change the experimental invasion ability of U251 cells were detected by CELF2 siRNA after transfection confirmed, CELF2 in U251 cells was significantly reduced (P0.05).2 MTT experimental results show that compared with the control group, U251 cell proliferation in experimental group was significantly lower (P0.05).3 flow cytometry results showed that compared with the control U251 group, apoptosis in experimental group was significantly increased (P0.05).4 Transwell experimental results show that compared with the control group, U251 cell infiltration in the experimental group The attack ability was significantly reduced (P0.05). Conclusion: miR-95-3p affects the proliferation, apoptosis, and invasion of glioma by regulating the expression of CELF2.

【學位授予單位】：河北醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R739.41

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