【摘要】：肺癌是一種致死性惡性疾病,因其預(yù)后差、發(fā)病率還逐年增加,對(duì)它的研究也在大量開(kāi)展。即便如此,其發(fā)生、發(fā)展的分子機(jī)制仍然沒(méi)有完全被闡明。最近有報(bào)導(dǎo)稱,肌細(xì)胞增強(qiáng)因子2D(myocyte enhancer factor 2D,MEF2D)可以促進(jìn)肝癌的生長(zhǎng),但是尚不明確其在肺癌中是否也存在相同或類似的作用。同時(shí),根據(jù)現(xiàn)有研究所示,MEF2D激活及過(guò)表達(dá)促進(jìn)腫瘤進(jìn)程的機(jī)制是多樣的。有趣的是,這些研究在證實(shí)MEF2D可以促進(jìn)腫瘤進(jìn)程的同時(shí),或多或少都發(fā)現(xiàn)了一些可以抑制MEF2D基因過(guò)表達(dá)的微小RNA(micro RNA,mi RNA)。在證實(shí)了MEF2D對(duì)肺癌細(xì)胞的增殖、凋亡和侵襲能力均有影響后,我們想要進(jìn)一步研究可以作用于MEF2D基因并抑制其表達(dá)的mi RNA。為此,我們查閱了大量文獻(xiàn),并求助于mi RNA及目標(biāo)基因的在線數(shù)據(jù)庫(kù),最終發(fā)現(xiàn),在MEF2Dm RNA的3'UTR上,有一種mi R-218的mi RNA識(shí)別元件(micro RNA recognition element,MRE),而mi R-218可能會(huì)抑制肺癌的進(jìn)程。因此,我們將mi R-218對(duì)MEF2D表達(dá)的影響作為了第二步研究的目標(biāo)。因此我們?cè)O(shè)計(jì)了既有區(qū)別又相互關(guān)聯(lián)的兩個(gè)子實(shí)驗(yàn)研究mi R-218及MEF2D與肺癌的關(guān)聯(lián)。為了探討在非小細(xì)胞肺癌(non-small cell lung cancer,NSCLC)中,MEF2家族的表達(dá)特點(diǎn)。我們首先重點(diǎn)研究MEF2D表達(dá)對(duì)非小細(xì)胞肺癌的增殖、凋亡及侵襲能力的影響。我們運(yùn)用q PCR的方法,研究30例非小細(xì)胞肺癌患者肺組織及正常組織中,MEF2家族四種基因的表達(dá)情況。使用免疫印跡法比較MEF2D在肺癌組織及正常組織中的表達(dá)情況。應(yīng)用免疫熒光染色,明確MEF2D基因所表達(dá)的蛋白在肺癌和正常細(xì)胞中的分布情況。在正常肺組織細(xì)胞高表達(dá)MEF2D及沉默腫瘤細(xì)胞MEF2D的表達(dá)后,通過(guò)transwell試驗(yàn)驗(yàn)證MEF2D對(duì)細(xì)胞侵襲性的影響;通過(guò)Brd U試驗(yàn)及ki67表達(dá)情況來(lái)驗(yàn)證MEF2D對(duì)細(xì)胞增殖率的影響;通過(guò)流式細(xì)胞技術(shù)來(lái)驗(yàn)證MEF2D對(duì)細(xì)胞凋亡的影響。最后,建立肺癌細(xì)胞異種移植小鼠動(dòng)物模型,將表達(dá)MEF2D發(fā)夾結(jié)構(gòu)的慢病毒載體和對(duì)照載體注射到小鼠肺癌組織中。通過(guò)定期測(cè)量腫瘤的大小和重量,來(lái)驗(yàn)證MEF2D對(duì)肺癌體內(nèi)試驗(yàn)?zāi)[瘤增殖情況的影響。通過(guò)免疫組織化學(xué)技術(shù)驗(yàn)證腫瘤切片中MEF2D和ki67的表達(dá)情況,側(cè)面反應(yīng)MEF2D對(duì)腫瘤增殖能力的影響。同時(shí),用TUNEL試驗(yàn)來(lái)檢測(cè)體內(nèi)實(shí)驗(yàn)?zāi)[瘤細(xì)胞的凋亡情況。q PCR試驗(yàn)證實(shí),與正常組織與正常細(xì)胞相比,肺癌組織和肺癌細(xì)胞中的MEF2D的m RNA表達(dá)量顯著提高,而MEF2A和MEF2C的表達(dá)水平?jīng)]有顯著差異,實(shí)驗(yàn)中沒(méi)有檢測(cè)到MEF2B的表達(dá)。免疫印跡試驗(yàn)證實(shí),MEF2D蛋白在肺癌組織和細(xì)胞中異常高表達(dá)。免疫熒光染色提示,MEF2D主要存在于肺癌細(xì)胞系A(chǔ)549細(xì)胞核內(nèi),而在正常肺MRC-5細(xì)胞中,MEF2D在細(xì)胞核內(nèi)的表達(dá)比A549細(xì)胞要低,但在細(xì)胞質(zhì)中的表達(dá)卻高于A549細(xì)胞。Transwell試驗(yàn)表明,MEF2D表達(dá)水平的增加可以提高M(jìn)RC-5細(xì)胞的侵襲性;Brd U試驗(yàn)和ki67表達(dá)情況均表明,MEF2D的過(guò)表達(dá)能夠提高M(jìn)RC-5細(xì)胞的增殖率。轉(zhuǎn)染靶向抑制MEF2D的si RNA后,Brd U試驗(yàn)和ki67表達(dá)情況都表明,腫瘤細(xì)胞增殖率明顯降低;通過(guò)流式細(xì)胞檢測(cè)證實(shí),沉默MEF2D后,腫瘤細(xì)胞凋亡率增加;transwell試驗(yàn)表明,轉(zhuǎn)染MEF2Dsi RNA可降低A549和H460細(xì)胞的侵襲性。在小鼠肺癌細(xì)胞異種移植動(dòng)物模型的相關(guān)實(shí)驗(yàn)也證實(shí)了,注射Lv-scrambled質(zhì)粒的組織MEF2D廣泛表達(dá),而注射Lv-sh MEF2D質(zhì)粒組,其表達(dá)則受到抑制;用TUNEL試驗(yàn)來(lái)檢測(cè)同一腫瘤的細(xì)胞凋亡情況,發(fā)現(xiàn)注射了Lv-sh MEF2D質(zhì)粒組呈現(xiàn)明顯的陽(yáng)性染色。綜合以上實(shí)驗(yàn)結(jié)果,抑制MEF2D能夠抑制小鼠體內(nèi)肺癌的生長(zhǎng)。我們進(jìn)一步研究了mi R-218與MEF2D表達(dá)的關(guān)系,及其對(duì)非小細(xì)胞肺癌生物學(xué)行為的影響;以及mi R-218是否直接作用于MEF2D。我們分別將野生型和突變型MEF2D的3'UTR插入到一種熒光素酶表達(dá)載體中,將其分別轉(zhuǎn)染肺癌細(xì)胞系及正常肺細(xì)胞系。之后,用mi R-218的mimic轉(zhuǎn)染肺癌細(xì)胞并用inhibitor轉(zhuǎn)染正常細(xì)胞系,通過(guò)其表達(dá)熒光素酶的情況,來(lái)證實(shí)其對(duì)目標(biāo)基因MEF2D表達(dá)情況的影響。另外,應(yīng)用q PCR和免疫印跡方法,分別檢測(cè)不同mi R-218豐度下,肺癌細(xì)胞系及正常肺組織細(xì)胞中MEF2D的表達(dá)情況,從而協(xié)助明確mi R-218對(duì)MEF2D表達(dá)情況的影響。收集10例臨床非小細(xì)胞肺癌患者的肺癌樣本,同時(shí)收集相應(yīng)患者的血清,對(duì)其肺癌中MEF2D表達(dá)水平進(jìn)行q PCR檢測(cè),同時(shí)測(cè)量其血清中mi R-218的水平,用以比較兩者之間是否存在線性關(guān)系。用pc DNA-MEF2D(表達(dá)MEF2D m RNA的載體,不受mi R-218調(diào)控)和mi R-218 mimics同時(shí)轉(zhuǎn)染A549細(xì)胞和正常肺細(xì)胞。在不同時(shí)間點(diǎn)計(jì)數(shù)細(xì)胞以計(jì)算其增殖率。同時(shí),利用流式細(xì)胞術(shù)測(cè)定不同組細(xì)胞凋亡情況,并對(duì)不同組細(xì)胞進(jìn)行Transwell試驗(yàn)以明確其侵襲能力的變化。我們發(fā)現(xiàn)將合成的mi R-218 mimics轉(zhuǎn)染A549細(xì)胞后,將極大的抑制野生型熒光素酶表達(dá)載體熒光素酶的表達(dá),但不會(huì)影響突變型熒光素酶的表達(dá)。同樣,mi R-218 inhibitor增加了正常肺纖維母細(xì)胞中熒光素酶的表達(dá),對(duì)突變型無(wú)影響。q PCR和蛋白印跡方法也證實(shí),mi R-218 mimic能夠降低肺癌細(xì)胞中MEF2D的表達(dá)水平。而mi R-218 inhibitor可以使正常細(xì)胞MEF2D的表達(dá)增加。另外,對(duì)臨床肺癌樣本中MEF2D行q PCR檢驗(yàn),同時(shí)對(duì)比相應(yīng)患者血清mi R-218水平,結(jié)果也發(fā)現(xiàn)mi R-218跟MEF2D的表達(dá)水平存在負(fù)相關(guān)。之后,用pc DNA-MEF2D和mi R-218同時(shí)轉(zhuǎn)染肺癌細(xì)胞系,發(fā)現(xiàn)mi R-218并沒(méi)有抑制MEF2D的過(guò)表達(dá)。通過(guò)流式細(xì)胞術(shù)也證實(shí),即便已經(jīng)轉(zhuǎn)染了mi R-218的A549細(xì)胞,其細(xì)胞凋亡仍然被過(guò)表達(dá)的MEF2D所抑制。Transwell試驗(yàn)也表明,轉(zhuǎn)染了mi R-218 mimics的肺癌細(xì)胞中,MEF2D的過(guò)表達(dá)仍能顯著增強(qiáng)肺癌細(xì)胞的侵襲性。通過(guò)以上的實(shí)驗(yàn),我們認(rèn)為在非小細(xì)胞肺癌組織和細(xì)胞中,存在MEF2D的過(guò)表達(dá)。MEF2D除了具有促進(jìn)肺癌細(xì)胞增殖和侵襲的能力,其過(guò)度表達(dá)還能夠增強(qiáng)肺癌細(xì)胞的存活能力。因此,我們可以推斷,MEF2D可能是非小細(xì)胞肺癌的一種致癌基因。抑制其表達(dá),可以控制非小細(xì)胞肺癌的發(fā)生和發(fā)展,提示MEF2D可能會(huì)成為非小細(xì)胞肺癌治療的新靶點(diǎn)。同時(shí),我們也發(fā)現(xiàn)mi R-218跟MEF2D的表達(dá)水平存在負(fù)相關(guān),MEF2D是腫瘤抑制因子mi R-218的目標(biāo)基因。同時(shí),單純轉(zhuǎn)染mi R-218mimic而不抑制MEF2D表達(dá)對(duì)腫瘤無(wú)抑制作用,從而證明了mi R-218是通過(guò)減少M(fèi)EF2D表達(dá)來(lái)抑制肺癌細(xì)胞生長(zhǎng)。
[Abstract]:Lung cancer is a fatal malignant disease. Because of its poor prognosis, the incidence of lung cancer is increasing year by year, and its research is also being carried out. Even so, the molecular mechanism of its occurrence and development is still not fully elucidated. Recently, it has been reported that the 2D (myocyte enhancer factor 2D, MEF2D) can promote the growth of liver cancer, but it is still possible to promote the growth of liver cancer. It is not clear whether it has the same or similar role in lung cancer. According to existing research, the mechanisms of MEF2D activation and overexpression are diverse. Interestingly, these studies have found that some of the MEF2D can inhibit the overexpression of MEF2D genes at the same time that the cancer process can be promoted. RNA (micro RNA, MI RNA). After confirming the effect of MEF2D on the proliferation, apoptosis and invasion of lung cancer cells, we want to further study the function of the MEF2D gene and inhibit the MI RNA. of its expression. We have consulted a large number of documents and resorted to the online database of MI RNA and target genes. On the 3'UTR of NA, there is a mi RNA identification element of MI R-218 (micro RNA recognition element, MRE), and MI may inhibit the process of lung cancer. The association with lung cancer. To investigate the expression of the MEF2 family in non-small cell lung cancer (NSCLC), we first focus on the effect of MEF2D expression on the proliferation, apoptosis and invasion of non-small cell lung cancer. We used Q PCR to study lung tissue and normal tissue in 30 patients with non-small cell lung cancer. The expression of four genes in the MEF2 family. The expression of MEF2D in lung cancer tissues and normal tissues was compared by immunoblotting. The distribution of the protein expressed by the MEF2D gene in lung cancer and normal cells was determined by immunoblotting. The expression of MEF2D in normal lung tissue and the expression of MEF2D in the silent tumor cells were expressed in normal lung tissue. The effect of MEF2D on cell invasiveness was verified by Transwell test, and the effect of MEF2D on cell proliferation rate was verified by Brd U test and Ki67 expression, and the effect of MEF2D on cell apoptosis was verified by flow cytometry. Finally, the rat model of xenotransplantation of lung cancer cells was established, and the lentivirus expressing MEF2D hairpin structure would be expressed. The carrier and control vector were injected into the lung cancer tissue in mice. The effect of MEF2D on the tumor proliferation in lung cancer was verified by measuring the size and weight of the tumor. The expression of MEF2D and Ki67 in the tumor slices and the effect of side reaction of MEF2D on the proliferation of tumor were verified by immunohistochemistry. At the same time, TUNE was used. L test to detect the apoptosis of tumor cells in vivo,.Q PCR test confirmed that the expression of M RNA in lung cancer tissues and lung cancer cells increased significantly compared with normal tissues and normal cells, but there was no significant difference in the expression level of MEF2A and MEF2C, and the expression of MEF2B was not detected in the experiment. Western blot test confirmed that MEF2D, MEF2D, MEF2D, and MEF2D. The protein is highly expressed in the tissues and cells of lung cancer. Immunofluorescence staining suggests that MEF2D mainly exists in the nucleus of lung cancer cell line A549, while in normal lung MRC-5 cells, the expression of MEF2D in the nucleus is lower than that of A549 cells, but the expression in cytoplasm is higher than that of the A549 cell.Transwell test that the expression of MEF2D is increased. Addition of addition can improve the invasiveness of MRC-5 cells; Brd U test and Ki67 expression showed that the overexpression of MEF2D could increase the proliferation rate of MRC-5 cells. After transfection of Si RNA to the targeting of MEF2D, Brd U test and Ki67 expression showed that the proliferation rate of the tumor cells decreased obviously; through flow cytometry confirmed that the tumor was fine after silence. The apoptosis rate increased; Transwell test showed that transfection of MEF2Dsi RNA could reduce the invasiveness of A549 and H460 cells. Related experiments in the xenotransplantation animal model of lung cancer cells in mice also confirmed that the tissue MEF2D of the injected Lv-scrambled plasmid was widely expressed, while the expression of the Lv-sh MEF2D plasmid group was inhibited, and the TUNEL test was used to detect the expression of the Lv-scrambled plasmid. It was found that the Lv-sh MEF2D plasmid group showed positive positive staining in the same tumor cell apoptosis. The inhibition of MEF2D could inhibit the growth of lung cancer in mice. We further studied the relationship between MI R-218 and the expression of MEF2D, and the effect on the biological behavior of non small cell lung cancer; and mi R-218 In MEF2D., we inserted the wild and mutant MEF2D 3'UTR into a luciferase expression vector, respectively, and transfected them to lung cancer cell lines and normal lung cell lines respectively. Then, the lung cancer cells were transfected with MI R-218 mimic and transfected with inhibitor to normal cell lines. The expression of luciferase expression was confirmed by the expression of luciferase. The effect on the expression of target gene MEF2D. In addition, Q PCR and immunoblotting were used to detect the expression of MEF2D in lung cancer cell lines and normal lung tissue cells under different mi R-218 abundances, and to help clarify the effect of MI R-218 on MEF2D expression. 10 cases of lung cancer samples from patients with non small cell lung cancer were collected. At the same time, the serum of the corresponding patients was collected, and the expression level of MEF2D in the lung cancer was detected by Q PCR, and the level of MI R-218 in the serum was measured to compare the linear relationship between them. PC DNA-MEF2D (the carrier of MEF2D m RNA, not regulated by Mi R-218) and the normal lung cells were transfected at the same time. The cell proliferation rate was counted at different time points. At the same time, the cell apoptosis in different groups was measured by flow cytometry, and the changes in the invasion ability of different groups were determined by Transwell test. We found that the transfection of synthetic mi R-218 mimics to A549 cells would greatly inhibit the expression of wild type luciferase. The expression of luciferase did not affect the expression of mutant luciferase. Similarly, MI R-218 inhibitor increased the expression of luciferase in normal lung fibroblasts. There was no effect on.Q PCR and Western blotting on mutagenesis. Mi R-218 mimic could reduce the expression level of MEF2D in lung cancer cells. Mi R-218 inhibitor. To increase the expression of MEF2D in normal cells. In addition, the Q PCR test of MEF2D in the clinical lung cancer samples and the serum mi R-218 level of the corresponding patients were compared. The results also showed that there was a negative correlation between the expression level of MI R-218 and MEF2D. Then, the lung cancer cell lines were transfected with PC DNA-MEF2D and MI. Through flow cytometry, it was also confirmed that even if the transfected mi R-218 A549 cells were still transfected with the expressed MEF2D, the.Transwell test also showed that the overexpression of MEF2D still significantly enhanced the invasiveness of lung cancer cells in the transfected mi R-218 mimics lung cancer cells. The overexpression of MEF2D in the tissues and cells of non-small cell lung cancer has the ability to promote the proliferation and invasion of lung cancer cells, and its overexpression can also enhance the viability of lung cancer cells. Therefore, we can deduce that MEF2D may be a oncogene in non-small cell lung cancer. The occurrence and development of lung cancer suggest that MEF2D may be a new target for the treatment of non-small cell lung cancer. At the same time, we also found that there is a negative correlation between the expression level of MI R-218 and MEF2D, MEF2D is the target gene of the tumor suppressor factor mi R-218. Meanwhile, the simple transfection of MI R-218mimic without inhibiting the expression of MEF2D has no inhibitory effect on the tumor, thus proving that the expression of MEF2D has no inhibitory effect on the tumor. Mi R-218 inhibits the growth of lung cancer cells by reducing MEF2D expression.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R734.2

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