本文關(guān)鍵詞： 膠質(zhì)瘤 NF-κB通路 DNA損傷 治療抵抗　出處：《大連醫(yī)科大學(xué)》2014年博士論文　論文類型：學(xué)位論文

【摘要】：腦膠質(zhì)瘤是最常見的中樞神經(jīng)系統(tǒng)惡性腫瘤,具有高發(fā)病率、高度侵襲性、高死亡率的特點(diǎn)。該腫瘤通過對整個(gè)大腦的廣泛入侵表現(xiàn)出了持續(xù)的惡性進(jìn)展特點(diǎn),并對傳統(tǒng)的放療具有抵抗力,故臨床上治療十分棘手。 近年研究表明,術(shù)后腫瘤細(xì)胞對放療不敏感與NF-κB信號通路活性增高有關(guān)。腫瘤的放射治療一般是通過損傷DNA,誘導(dǎo)細(xì)胞凋亡,阻斷細(xì)胞增殖從而消除腫瘤細(xì)胞。DNA損傷激活的NF-κB信號通路誘導(dǎo)細(xì)胞凋亡是放療的主要作用機(jī)制之一。但是NF-κB通路在DNA損傷誘導(dǎo)的凋亡反應(yīng)中是一把雙刃劍,具有雙重作用,其促進(jìn)細(xì)胞凋亡的同時(shí),還將誘導(dǎo)抗凋亡基因的表達(dá)。一旦NF-KB活性異常增高或者持續(xù)活化,則表現(xiàn)出抗凋亡作用,通過誘導(dǎo)抗凋亡及促進(jìn)細(xì)胞增殖相關(guān)靶基因的表達(dá),包括Bcl-2家族,Survivin,COX-2,Cyclin D1,AKT及EGFR等,導(dǎo)致腫瘤細(xì)胞周期進(jìn)程加快,抗凋亡能力增強(qiáng),侵襲及轉(zhuǎn)移能力增強(qiáng),從而對放療產(chǎn)生抗性。由于NF-κB介導(dǎo)的下游靶基因有很大一部分是細(xì)胞正常生命進(jìn)程所需要的,因此廣譜阻斷NF-κB意味著很多不良反應(yīng)的產(chǎn)生。理想的NF-κB抑制劑應(yīng)是能特異性作用于腫瘤細(xì)胞,而非正常細(xì)胞,從而達(dá)到精確清除腫瘤細(xì)胞的目的。不同組織來源的腫瘤細(xì)胞對DNA損傷的耐受性及反應(yīng)性不同,對放療的敏感性也不同。DNA損傷誘導(dǎo)的NF-KB信號通路起抗凋亡作用還是促凋亡作用具有一定的組織特異性。因此深入探討特定條件誘導(dǎo)NF-KB通路的分子機(jī)理、調(diào)控機(jī)制及其組織特異性,有利于我們針對NF-κB在腫瘤放療耐受中的作用,提出特異而有效的個(gè)體化治療方案。 本研究著眼于膠質(zhì)瘤對放療不敏感這一臨床問題,擬在膠質(zhì)瘤細(xì)胞系T98G及U87MG中探討NF-KB通路與基于DNA損傷誘導(dǎo)的膠質(zhì)瘤放療不敏感的作用機(jī)制,以期為有效的膠質(zhì)瘤放療提供理論依據(jù)。 實(shí)驗(yàn)用細(xì)胞輻照儀處理人膠質(zhì)瘤細(xì)胞系T98G及U87MG,以模擬DNA損傷環(huán)境。研究發(fā)現(xiàn)膠質(zhì)瘤細(xì)胞系T98G及U87MG對DNA損傷誘導(dǎo)的細(xì)胞凋亡及增殖抑制不敏感,但抑制NF-κB活性則增強(qiáng)其對DNA損傷的敏感性。分子機(jī)制研究發(fā)現(xiàn),DNA損傷能顯著增強(qiáng)膠質(zhì)瘤細(xì)胞中NF-κB的活性,導(dǎo)致NF-KB介導(dǎo)的靶基因,包括Bcl-κL, Cyclin Dl, Survivin,及IL-8等高表達(dá),從而增強(qiáng)腫瘤細(xì)胞抗凋亡活性,促進(jìn)腫瘤生長。利用分子生物學(xué)研究手段,發(fā)現(xiàn)DNA損傷可增強(qiáng)NEMO的SUMO化修飾。NEMO的SUMO化修飾是細(xì)胞核內(nèi)的DNA損傷信號激活細(xì)胞核外的NF-κB信號通路傳導(dǎo)的限速步驟,因此增強(qiáng)NEMO的SUMO化修飾對于DNA損傷誘導(dǎo)的NF-KB活化至關(guān)重要。進(jìn)一步研究發(fā)現(xiàn),NF-κB活化可促進(jìn)miR-181b表達(dá)升高,而miR-181b可靶向去SUMO化酶SENP2,使其表達(dá)下降,降低了SENP2催化的NEMO去SUMO化修飾,從而促使NF-KB保持持續(xù)活化狀態(tài)。而miR-181b有望成為提高膠質(zhì)瘤放射治療效果的新靶點(diǎn)。 第一部分：DNA損傷激活人腦膠質(zhì)瘤細(xì)胞NF-κB信號通路 目的：探討人膠質(zhì)瘤細(xì)胞T98G,U87MG對DNA損傷誘導(dǎo)的細(xì)胞凋亡及增殖抑制是否敏感,及其與NF-κB信號通路的關(guān)系。 方法：應(yīng)用電離輻射處理T98G及U87MG細(xì)胞誘導(dǎo)DNA損傷。免疫熒光檢測DNA損傷標(biāo)志物H2AX-γ來判斷DNA損傷效果。劃痕實(shí)驗(yàn)檢測細(xì)胞劃痕愈合能力；流式細(xì)胞儀檢測細(xì)胞凋亡；MTT檢測細(xì)胞增殖；Real-time PCR檢測NF-KB調(diào)控的與腫瘤生長及轉(zhuǎn)移相關(guān)的靶基因的表達(dá)水平；雙熒光素酶報(bào)告系統(tǒng)檢測NF-κB的活性；Western blot檢測p-IκBα、IKBα、p50及p65水平；免疫熒光檢測DNA損傷處理后T98G細(xì)胞中p65是否入核。 結(jié)果：電離輻射處理T98G細(xì)胞,能造成DNA損傷；DNA損傷不影響膠質(zhì)瘤細(xì)胞T98G的劃痕愈合能力,不誘導(dǎo)其凋亡；用Bay11抑制NF-κB活性后,T98G細(xì)胞的劃痕愈合能力下降,細(xì)胞增殖受抑制；抑制NF-κB活性能下調(diào)T98G細(xì)胞中DNA損傷誘導(dǎo)的腫瘤抗性基因,包括CyclinD1、Bcl-xL、Survivin及IL-8的表達(dá)；DNA損傷能激活膠質(zhì)瘤細(xì)胞T98G及U87MG細(xì)胞中NF-κB信號通路傳導(dǎo),促進(jìn)IκBα磷酸化及降解,從而釋放NF-KB使其入核。 結(jié)論：1、人膠質(zhì)瘤細(xì)胞系T98G及U87MG對DNA損傷不敏感。抑制NF-κB活性后,敏感性增強(qiáng)。 2、DNA損傷激活人膠質(zhì)瘤細(xì)胞系T98G及U87MG中NF-KB信號通路。 第二部分：miR-181b通過靶向SENP2正調(diào)控DNA損傷誘導(dǎo)的NF-κB通路活性 目的：探討DNA損傷增強(qiáng)人膠質(zhì)瘤細(xì)胞T98G及U87MG中NF-KB通路活性的分子機(jī)制。 方法：應(yīng)用免疫沉淀技術(shù)檢測DNA損傷后NEMO的SUMO化修飾；利用軟件預(yù)測NEMO的去SUMO化酶SENP2上microRNA的作用靶點(diǎn)；雙熒光素酶報(bào)告系統(tǒng)及Western blot檢測SENP23'UTR是否含有miR-181b的作用靶點(diǎn)；MicroRNA特異的real-time PCR檢測DNA損傷處理前后U87MG細(xì)胞中microRNA表達(dá)量的變化；雙熒光素酶報(bào)告系統(tǒng)檢測miR-181b對NF-κB通路活性的調(diào)控。 結(jié)果：DNA損傷能促進(jìn)U87MG細(xì)胞中NEMO的SUMO化修飾；軟件預(yù)測顯示去SUMO化酶SENP2的3’UTR含有miR-181b作用位點(diǎn)；雙熒光素酶報(bào)告系統(tǒng)及Western blot證實(shí)miR-181b可以靶向SENP2,使其表達(dá)降低：DNA損傷后miR-181b表達(dá)升高；過表達(dá)的miR-181b會進(jìn)一步增強(qiáng)DNA損傷誘導(dǎo)的NF-κB通路活性。 結(jié)論：1、DNA損傷能促進(jìn)膠質(zhì)瘤細(xì)胞中NEMO的SUMO化修飾。 2、DNA損傷后,miR-181b表達(dá)升高,miR-181b可靶向于去SUMO化酶SENP2,使其表達(dá)降低,而不能抑制NEMO的SUMO化修飾,從而進(jìn)一步增強(qiáng)NF-κB舌性。
[Abstract]:Glioma is the most common malignant tumors of the central nervous system, with high incidence, highly invasive, high mortality. The tumor through extensive invasion of whole brain showed malignant progression characteristics continuously, and the traditional radiotherapy resistant, so clinical treatment is very difficult.
Recent studies show that postoperative tumor cells to radiation and NF- B pathway activity increased. Radiotherapy is usually through injury DNA cell apoptosis induced by blocking cell proliferation, thereby eliminating tumor cell.DNA damage and activation of NF- B signaling pathway induced apoptosis is one of the main mechanisms of radiotherapy. But the NF- B pathway in apoptosis induced by DNA damage response is a double-edged sword, has a dual role, which promote cell apoptosis at the same time, will also induce the expression of anti apoptotic genes. Once the abnormal increase of NF-KB activity or sustained activation, showed anti apoptosis effect, through the expression of anti apoptosis and promote cell proliferation induced by the relevant target genes, including Bcl-2 family, Survivin, COX-2, Cyclin, D1, AKT and EGFR, leading to tumor cell cycle progression and enhance the anti apoptosis ability, enhance the ability of invasion and metastasis, thus Resistant to radiotherapy. As the downstream target genes of NF- kappa B mediated by a large part of the required normal cellular processes, thus blocking the NF- spectrum K B means a lot of adverse reactions. NF- B inhibitors ideal should be specific to tumor cells, but not normal cells. To achieve the precise clear tumor cells. Different tolerance and reactivity of various tumor cells to DNA damage, sensitivity to radiotherapy is different NF-KB signaling pathway.DNA damage induced by the anti apoptosis or apoptosis is tissue specific. So to explore molecular mechanism of NF-KB pathway induced by specific conditions the regulatory mechanisms and tissue specificity, we can according to the role of NF- K B in the radiotherapy of tumor tolerance, put forward specific and effective individualized treatment plan.
This study focuses on the clinical problem of glioma which is not sensitive to radiotherapy. We intend to explore the mechanism of NF-KB pathway and insensitivity to DNA damage induced glioma radiotherapy in glioma cell line T98G and U87MG, in order to provide a theoretical basis for effective glioma radiotherapy.
With the treatment of human glioma cell line T98G and U87MG cell irradiator experiment to simulate the damage environment. DNA glioma cell lines T98G and U87MG on DNA damage insensitive cell apoptosis and proliferation induced by the discovery, but the inhibition of NF- kappa B activity enhances their sensitivity to DNA damage. The molecular mechanism study found that DNA damage can significantly enhance the glioma cells NF- kappa B activity leads to target genes mediated by NF-KB, including Cyclin Dl, Bcl- kappa L, Survivin, and high expression of IL-8, so as to enhance the anti apoptosis activity of tumor cells, promote tumor growth. The use of molecular biology research methods, found that DNA damage can be enhanced SUMO modification of SUMO modification of.NEMO NEMO is the rate limiting step in DNA damage signaling within the nucleus activation of NF- kappa B signaling pathway of the cell nucleus, thus enhance the NEMO modification of SUMO is essential for activation of DNA damage induced by NF-KB. Further studies showed that NF- B activation can promote the expression of miR-181b increased, while miR-181b can be targeted to the SUMO enzyme SENP2, which decreased the expression of SENP2, reduce the catalytic NEMO to SUMO modification, so as to promote the sustained activation of NF-KB. MiR-181b is expected to become a new target to improve the treatment effect of radial glia.
Part one: DNA injury activates NF- kappa B signaling pathway in human glioma cells
Objective: To investigate whether human glioma cells T98G, U87MG are sensitive to apoptosis and proliferation inhibition induced by DNA damage, and their relationship with the NF- kappa B signaling pathway.
Methods: application of ionizing radiation treated T98G and U87MG cells induced by DNA damage. Immunofluorescence detection of DNA injury markers to determine H2AX- gamma DNA damage effect. Cell scratch scratch assay. Healing; cell apoptosis was detected by flow cytometry to detect the cell proliferation; MTT; detection of NF-KB regulation of Real-time PCR and tumor growth and metastasis related gene the level of expression of the dual luciferase reporter assay; NF- kappa B activity; Western blot detection of p-I kappa B alpha, alpha IKB, P50 and p65; immunofluorescence detection of DNA damage in p65 treated T98G cells into the nucleus.
Results: T98G cells were treated with ionizing radiation, can cause DNA damage; DNA damage does not affect the T98G glioma cells scratch healing ability, does not induce apoptosis; inhibition of NF- kappa B activity by Bay11 after T98G cell wound healing ability, inhibition of cell proliferation; inhibition of NF- kappa B induced down-regulation of DNA activity tumor resistance gene in T98G cells, including CyclinD1, Bcl-xL, expression of Survivin and IL-8; DNA injury can activate T98G glioma cells and U87MG cells in NF- kappa B signaling pathway, promoting I kappa B alpha phosphorylation and degradation, thereby releasing the NF-KB into the nucleus.
Conclusion: 1, human glioma cell lines T98G and U87MG are insensitive to DNA damage. The sensitivity of NF- kappa B activity is enhanced.
2, DNA damage activates the NF-KB signaling pathway in the human glioma cell line T98G and U87MG.
The second part: miR-181b regulates the activity of NF- kappa B pathway induced by DNA damage through target SENP2
Objective: To investigate the molecular mechanism of DNA injury to enhance the activity of NF-KB pathway in human glioma cells, T98G and U87MG.
Methods: using immunoprecipitation technique to detect SUMO modification of NEMO DNA after injury; prediction of NEMO to target SUMO SENP2 microRNA enzyme by software; target whether dual luciferase reporter system and Western blot detection of SENP23'UTR containing miR-181b and MicroRNA; specific real-time PCR to detect DNA damage in U87MG cell the expression of microRNA; dual luciferase reporter assay miR-181b regulation of NF- B pathway activity.
Results: DNA injury can promote the modification of SUMO NEMO in U87MG cells; software predictive display to SUMO enzyme SENP2 3 UTR containing miR-181b binding sites; dual luciferase reporter system and Western blot confirmed that miR-181b can target SENP2, which decreased the expression of DNA: the expression of miR-181b increased after injury; overexpression of miR-181b would further enhanced NF- B pathway activity induced by DNA.
Conclusion: 1, DNA damage can promote the SUMO modification of NEMO in glioma cells.
2, after DNA injury, the expression of miR-181b is increased. MiR-181b can target SUMO de SENP2, reduce its expression, but not inhibit SUMO modification of NEMO, thereby further enhance the tongue nature of NF- kappa B.

【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R739.41

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