本文選題：神經(jīng)母細(xì)胞瘤 + Survivin��； 參考：《山東大學(xué)》2014年博士論文

【摘要】：研究背景： 神經(jīng)母細(xì)胞瘤(Neuroblastoma, NB)是發(fā)生在兒童和嬰兒中最常見的惡性顱外實(shí)體腫瘤之一,其起病部位隱匿,臨床治療困難,尤其對于進(jìn)展期NB患兒,生存率仍然維持在20%-30%,復(fù)發(fā)率居高不下。因此,對神經(jīng)母細(xì)胞瘤的生物學(xué)、遺傳學(xué)特性及具體發(fā)病機(jī)制進(jìn)行深入研究,對尋找新的腫瘤基因治療方法、提高NB患兒的治愈率和改善患兒的遠(yuǎn)期預(yù)后具有重要的臨床價(jià)值。 Survivin蛋白屬于凋亡抑制蛋白家族,在多種惡性腫瘤中均被發(fā)現(xiàn)高表達(dá),提示其可能在腫瘤發(fā)病機(jī)制中起重要作用。Survivin可能參與NB的發(fā)生、發(fā)展、演變的過程,它不僅可能是判斷NB預(yù)后的重要參考指標(biāo),也可能成為NB基因治療中的一個(gè)理想靶點(diǎn)。YM155是水溶survivi特異抑制劑,體內(nèi)外均可特異性地抑制survivin的表達(dá),具有強(qiáng)大的抗腫瘤功效,同時(shí)可增加常見腫瘤對化療、放療的敏感性。Survivin在NB腫瘤細(xì)胞的增殖、凋亡、遷移和轉(zhuǎn)移等過程中究竟扮演著什么調(diào)控角色?而YM155作用于NB腫瘤細(xì)胞的效果如何呢?在體內(nèi)、體外研究應(yīng)用中YM155是否能發(fā)揮對NB腫瘤細(xì)胞的順鉑化療增敏作用呢?本課題通過體內(nèi)外實(shí)驗(yàn)相互結(jié)合,進(jìn)一步研究Survivin和其抑制劑YM155與NB的關(guān)系,以期為NB靶向治療尋找新的靶點(diǎn)。 第一部分Survivin ASONDN對神經(jīng)母細(xì)胞瘤細(xì)胞遷移和侵襲的影響目的 將Survivin的反義寡核苷酸以不同濃度轉(zhuǎn)染入人神經(jīng)母細(xì)胞瘤細(xì)胞株SK-N-SH,觀察Survivin對SK-N-SH增殖、凋亡、遷移和侵襲的影響。 方法 設(shè)計(jì)并合成Survivin的反義寡核苷酸(ASODN),以脂質(zhì)體為載體,以不同濃度轉(zhuǎn)染入體外培養(yǎng)的人神經(jīng)母細(xì)胞瘤細(xì)胞株SK-N-SH;采用RT-PCR和Westernblot分析經(jīng)過不同濃度Survivin ASODN干擾后SK-N-SH細(xì)胞中Survivin mRNA和蛋白表達(dá)水平；應(yīng)用MTT法檢測不同濃度Survivin ASODN對細(xì)胞的生長抑制作用,流式細(xì)胞儀檢測轉(zhuǎn)染后的細(xì)胞凋亡率；用Transwell實(shí)驗(yàn)分析Survivin ASODN對SK-N-SH細(xì)胞體外遷移力和侵襲力的影響。 結(jié)果 不同濃度Survivin ASODN作用于SK-N-SH細(xì)胞48h后,Survivin mRNA表達(dá)均明顯下調(diào),與空白對照組、脂質(zhì)體轉(zhuǎn)染對照組及正義寡核苷酸SODN組比較,有顯著的差異(P0.05),且抑制作用呈現(xiàn)劑量依賴性,以濃度為800nmol/L時(shí)的作用最明顯。SK-N-SH細(xì)胞經(jīng)200、400、800lmol/L Survivin ASODN轉(zhuǎn)染48h后,Survivin蛋白表達(dá)較空白對照組、脂質(zhì)體轉(zhuǎn)染對照組及正義寡核苷酸SODN組明顯下降(P0.05),且抑制作用呈現(xiàn)劑量依賴性,以濃度為800nmol/L時(shí)的作用最明顯。 不同濃度Survivin ASODN轉(zhuǎn)染入SK-N-SH細(xì)胞后,可不同程度地抑制該腫瘤細(xì)胞的生長增殖,相同作用時(shí)間下各濃度ASODN轉(zhuǎn)染組細(xì)胞抑制率均顯著高于空白對照組、脂質(zhì)體轉(zhuǎn)染對照組和正義寡核苷酸SODN組(P0.05)。相同濃度(800nmol/L)下Survivin ASODN隨著時(shí)間的增加其抑制作用明顯增強(qiáng),有著較為明顯的時(shí)效關(guān)系,48h抑制率升至最高。 各Survivin ASODN轉(zhuǎn)染組細(xì)胞凋亡率均明顯高于空白對照組、脂質(zhì)體轉(zhuǎn)染對照組和SODN轉(zhuǎn)染組(P0.05),且細(xì)胞的凋亡率隨著Survivin ASODN濃度增加而增加,呈劑量依賴關(guān)系,以800nmol/L時(shí),其促進(jìn)細(xì)胞調(diào)亡的作用最強(qiáng)。相同濃度(800nmol/L) Survivin ASODN轉(zhuǎn)染SK-N-SH細(xì)胞后,細(xì)胞凋亡率48h達(dá)高峰,72h后開始下降,表明Survivin ASODN對SK-N-SH細(xì)胞凋亡的促進(jìn)作用呈一定的時(shí)間依賴性,最佳作用時(shí)間48h。 細(xì)胞遷移和侵襲實(shí)驗(yàn)中,轉(zhuǎn)染作用24、48、72h后,各Survivin ASODN轉(zhuǎn)染組遷移穿膜細(xì)胞數(shù)和侵襲穿膜細(xì)胞數(shù)均明顯減少,與空白對照組、脂質(zhì)體轉(zhuǎn)染對照組、SODN對照組間比較,有顯著的差異(P0.05),且呈現(xiàn)一定的劑量和時(shí)間依賴性,以濃度為800nmol/L時(shí)的作用最明顯,最佳作用時(shí)間為48h。結(jié)論 Survivin ASODN能通過特異性抑制SK-N-SH細(xì)胞中Survivin mRN及蛋白的表達(dá),誘導(dǎo)SK-N-SH細(xì)胞凋亡,抑制腫瘤增殖,并降低SK-N-SH細(xì)胞的侵襲和遷移能力。 第二部分YM155對神經(jīng)母細(xì)胞瘤細(xì)胞遷移和侵襲的影響 目的 探討Survivin抑制劑YM155對人神經(jīng)母細(xì)胞瘤細(xì)胞株SK-N-SH增殖、凋亡、遷移和侵襲的影響及其作用機(jī)制。 方法 用不同濃度YM155處理SK-N-SH,采用RT-PCR和Western blot分析經(jīng)處理后SK-N-SH細(xì)胞中Survivin mRNA和蛋白表達(dá)水平；應(yīng)用MTT法檢測處理后細(xì)胞的生長抑制作用,流式細(xì)胞儀檢測處理后的細(xì)胞凋亡率,用Transwell實(shí)驗(yàn)分析YM155對SK-N-SH細(xì)胞體外遷移力和侵襲力的影響。 結(jié)果 SK-N-SH細(xì)胞經(jīng)不同濃度YM155處理后,10-500nmol/LYM155處理組SK-N-SH細(xì)胞中Survivin mRNA、蛋白表達(dá)均明顯下降(P0.05),且該作用呈劑量依賴性,隨YM155濃度增加,細(xì)胞中Survivin mRNA、蛋白表達(dá)隨之下降。以100nmol/L YM155處理SK-N-SH細(xì)胞12、24、48、72h后,SK-N-SH細(xì)胞中Survivin蛋白表達(dá)均明顯下降(P0.05),且此抑制作用呈現(xiàn)時(shí)間依賴性。 經(jīng)YM155處理72h后,SK-N-SH細(xì)胞增殖受到不同程度的抑制,抑制率均明顯高于空白對照組(P0.05),且抑制率隨著YM155濃度(10-500nmol/L)增加而增加,呈劑量依賴關(guān)系。100nmol/L YM155作用12、24、48、72h后,SK-N-SH細(xì)胞增殖受到不同程度的抑制,YM155組細(xì)胞抑制率均明顯高于空白對照組(P0.05),且細(xì)胞的抑制率隨著YM155作用時(shí)間延長而增加,呈時(shí)間依賴關(guān)系。 經(jīng)YM155處理72h后,SK-N-SH細(xì)胞凋亡率受到不同程度影響,凋亡率均明顯高于空白對照組(P0.05),且細(xì)胞的凋亡率隨著YM155濃度(10-500nmol/L)增加而增加,呈劑量依賴關(guān)系。100nmol/L YM155作用12、24、48、72h后,SK-N-SH細(xì)胞凋亡率逐漸增加,明顯高于空白對照組,呈時(shí)間依賴關(guān)系。 細(xì)胞遷移和侵襲實(shí)驗(yàn)中,10-500nmol/L YM155作用于SK-N-SH細(xì)胞12、24、48、72h后,腫瘤細(xì)胞遷移穿膜細(xì)胞數(shù)和侵襲穿膜細(xì)胞數(shù)明顯減少,與空白對照組比較,有顯著的差異(P0.05),亦呈現(xiàn)劑量和時(shí)間依賴性。結(jié)論 YM155作為特異性的Survivin抑制劑,可能通過下調(diào)NB腫瘤細(xì)胞中Survivin的表達(dá),抑制腫瘤細(xì)胞的增殖,并可誘導(dǎo)腫瘤細(xì)胞凋亡,降低其遷移和侵襲能力。 第三部分YM155對神經(jīng)母細(xì)胞瘤細(xì)胞的順鉑化療增敏作用研究 目的 研究聯(lián)合應(yīng)用YM155和順鉑對人神經(jīng)母細(xì)胞瘤細(xì)胞細(xì)胞株SK-N-SH增殖、凋亡的影響,探討YM155對順鉑化療敏感性的影響及其作用機(jī)制。 方法 分別用順鉑、YM155、YM155聯(lián)合順鉑處理SK-N-SH,應(yīng)用MTT法檢測處理后細(xì)胞的生長抑制作用,流式細(xì)胞儀檢測處理后的細(xì)胞凋亡率,采用Western blot分析經(jīng)過處理后SK-N-SH細(xì)胞中Survivin蛋白表達(dá)水平。結(jié)果 YM155聯(lián)合順鉑(0.05,1,2μmol/L)作用于SK-N-SH細(xì)胞12～72h,細(xì)胞抑制率出現(xiàn)逐漸升高的趨勢,與單獨(dú)YM155組、單獨(dú)順鉑組、對照組比較,差異具有顯著性(P0.05)。不同濃度(0.05,1,2μmol/L)順鉑聯(lián)合YM155作用72h,各組SK-N-SH細(xì)胞的抑制率比較,差異無統(tǒng)計(jì)學(xué)意義(P0.05),YM155可以增加SK-N-SH細(xì)胞對順鉑的敏感性,細(xì)胞生長的抑制作用加強(qiáng),即使減少順鉑的使用劑量也可以達(dá)到明顯的抗腫瘤作用。 順鉑聯(lián)合YM155作用于SK-N-SH細(xì)胞12-72h,細(xì)胞凋亡率均明顯增高,明顯高于單獨(dú)YM155組、單獨(dú)順鉑組、對照組,差異具有顯著性(P0.05)。作用72h時(shí),不同濃度順鉑(0.05,1,2u mol/L)聯(lián)合YM155作用SK-N-SH細(xì)胞的凋亡率比較,差異無顯著性(P0.05),說明YM155對順鉑的化療增敏作用明顯,可以增加SK-N-SH細(xì)胞對順鉑的敏感性,有效誘導(dǎo)細(xì)胞凋亡,減少化療中順鉑的使用劑量。 YM155聯(lián)合順鉑(0.05,1,2μmol/L)組和單獨(dú)YM155組的Survivin蛋白表達(dá)均被完全抑制,而單獨(dú)順鉑組和對照組Survivin蛋白表達(dá)均無明顯變化。順鉑單獨(dú)作用SK-N-SH細(xì)胞,對Survivin蛋白表達(dá)無抑制作用。結(jié)論 YM155對順鉑的增敏作用機(jī)制可能與YM155特異性地抑制凋亡抑制蛋白Survivin的表達(dá)密切相關(guān)。 第四部分YM155對神經(jīng)母細(xì)胞瘤裸鼠移植瘤模型順鉑增敏作用研究目的 建立神經(jīng)母細(xì)胞瘤荷瘤鼠模型,進(jìn)一步評價(jià)體內(nèi)YM155對順鉑化療敏感性的影響。方法 建立神經(jīng)母細(xì)胞瘤荷瘤鼠模型,在腫瘤及腫瘤周圍分別注射順鉑、YM155及YM155聯(lián)合順鉑,觀察用藥3周時(shí)間內(nèi)移植瘤生長情況,計(jì)算腫瘤體積；處死老鼠后,剝離腫瘤稱重,計(jì)算抑瘤率(IR),進(jìn)行腫瘤組織常規(guī)病理檢查,采用TUNEL法觀察腫瘤組織中細(xì)胞凋亡的情況,應(yīng)用RT-PCR法和免疫組織化學(xué)法檢測腫瘤組織中survivin mRNA和蛋白質(zhì)表達(dá)水平。結(jié)果 各實(shí)驗(yàn)組給藥3周后,處死裸鼠,剝?nèi)∧[瘤并稱重,計(jì)算抑瘤率。結(jié)果表明,順鉑+YM155組的腫瘤重量明顯輕于其余兩組,而抑瘤率明顯高于順鉑組及YM155組(P0.01),用藥治療的3周期間,順鉑(cispatin)+YM155組的腫瘤體積增長明顯放緩,其曲線最低,與YM155組、順鉑組和對照組比較,均有顯著性差異(P0.05)。順鉑和YM155對NB裸鼠移植瘤生長均具有一定抑制作用,兩者聯(lián)合應(yīng)用能更有效抑制NB裸鼠移植瘤生長,明顯優(yōu)于單獨(dú)使用順鉑或YM155。 用藥結(jié)束后檢測四組腫瘤組織中細(xì)胞凋亡的情況,發(fā)現(xiàn)順鉑+YM155組的細(xì)胞凋亡指數(shù)AI最高,次之是YM155組,其次是順鉑組。順鉑+YM155組的AI明顯高于YM155組、順鉑組和對照組(P0.05),而YM155組的AI也明顯高于順鉑組。這說明順鉑和YM155均能誘導(dǎo)NB的腫瘤細(xì)胞發(fā)生凋亡,但YM155的作用更顯著,且兩者聯(lián)合應(yīng)用時(shí),能更有效地誘導(dǎo)腫瘤細(xì)胞凋亡,明顯優(yōu)于單獨(dú)使用順鉑或YM155。 YM155組和順鉑+YM155的裸鼠移植瘤中survivin mRNA表達(dá)顯著下降,明顯低于對照組和順鉑組(P0.05),而對照組和順鉑組比較,差異無顯著性(P0.05)。 免疫組織化學(xué)檢測結(jié)果顯示,各組裸鼠移植瘤組織中均發(fā)現(xiàn)不同程度的survivin蛋白陽性表達(dá),其陽性表達(dá)主要位于細(xì)胞漿或細(xì)胞膜。對照組和順鉑組中有大量強(qiáng)陽性的survivin蛋白表達(dá),YM155組和順鉑+YM155的survivin陽性表達(dá)率明顯降低,survivin陽性表達(dá)的強(qiáng)度和區(qū)域面積均較對照組和順鉑組明顯降低。結(jié)論 YM155聯(lián)合順鉑應(yīng)用可能是治療NB的一個(gè)有效的新方法。
[Abstract]:Background of Study :

Neuroblastomas ( NB ) is one of the most common malignant extracranial solid tumors in children and infants . It is difficult for clinical treatment . Especially for children with advanced stage NB , the survival rate is still maintained between 20 % and 30 % , the recurrence rate is high . Therefore , it is important to search for new tumor gene therapy methods , improve the curative rate of NB children and improve the long - term prognosis of children .

Survivin protein belongs to the family of apoptosis - inhibiting proteins , and is highly expressed in many malignant tumors . It suggests that it may play an important role in the pathogenesis of NB . Survivin may play an important role in the development and evolution of NB tumor cells .

Objective : To investigate the effect of survivin ASONDN on the migration and invasion of neuroblastomas .

Survivin antisense oligonucleotides were transfected into human glioma cell line SK - N - SH at different concentrations , and the effects of Survivin on proliferation , apoptosis , migration and invasion of SK - N - SH were observed .

method

Survivin antisense oligonucleotides ( ASODN ) were designed and synthesized . The expression of Survivin mRNA and protein in SK - N - SH cells was determined by RT - PCR and Western blot .
MTT assay was used to detect the inhibitory effect of survivin ASODN on cell growth , and the apoptosis rate was detected by flow cytometry .
The effects of survivin ASODN on the in vitro migration and invasion of SK - N - SH cells were analyzed by Transwell experiment .

Results

The expression of Survivin mRNA was down - regulated after 48 h of SK - N - SH cells with different concentrations of Survivin ASODN . Compared with control group , liposome - transfected control group and sense oligonucleotide SODN group , the expression of Survivin decreased significantly ( P0.05 ) .

After transfected into SK - N - SH cells with different concentrations of Survivin ASODN , the growth and proliferation of the tumor cells were inhibited to some extent , and the inhibitory rates of ASODN - transfected group were significantly higher than those in the control group ( P0.05 ) .

Survivin ASODN transfected SK - N - SH cells with the same concentration ( 800 nmol / L ) .

After 24 , 48 and 72 h transfection , the number of migration and invasion - through membrane cells of survivin ASODN transfected group were significantly decreased compared with control group , liposome - transfected control group and SODN control group .

Survivin ASODN can specifically inhibit the expression of Survivin mRN and protein in SK - N - SH cells , induce apoptosis of SK - N - SH cells , inhibit tumor proliferation , and reduce the invasion and migration ability of SK - N - SH cells .

The effect of the second part YM155 on the migration and invasion of glioma cells

Purpose

Objective To investigate the effects of survivin inhibitor YM155 on proliferation , apoptosis , migration and invasion of human glioma cell line SK - N - SH and its mechanism of action .

method

SK - N - SH was treated with different concentrations of YM155 . The expression of Survivin mRNA and protein in SK - N - SH cells was analyzed by RT - PCR and Western blot .
The effect of YM155 on the in vitro migration and invasion of SK - N - SH cells was investigated by MTT assay .

Results

The expression of Survivin mRNA and protein in SK - N - SH cells decreased significantly ( P0.05 ) , and the expression of Survivin in SK - N - SH cells decreased significantly ( P0.05 ) .

The inhibition rate of SK - N - SH cells was significantly higher than that in the control group ( P0.05 ) , and the inhibition rate of SK - N - SH cells was significantly higher than that in the blank control group ( P0.05 ) .

The apoptosis rate of SK - N - SH cells increased with the increase of YM155 ( 10 - 500 nmol / L ) . The apoptosis rate of SK - N - SH cells increased gradually with the concentration of YM155 ( 10 - 500 nmol / L ) .

In the experiment of cell migration and invasion , 10 - 500 nmol / L YM155 acts on SK - N - SH cells at 12 , 24 , 48 and 72 h , and the number of cell - penetrating cells and the number of invasive and penetrating cells in tumor cells decreased significantly . Compared with the blank control group , there was a significant difference ( P0.05 ) , and the dose and time - dependence were also presented .

YM155 , as a specific Survivin inhibitor , may inhibit the expression of Survivin in NB tumor cells , inhibit the proliferation of tumor cells , and induce tumor cell apoptosis and reduce its migration and invasion ability .

The effect of the third part YM155 on the cisplatin - chemotherapy sensitization of neuroblastoid cells

Purpose

To investigate the effect of YM155 and cisplatin on the proliferation and apoptosis of human glioma cell line SK - N - SH , and to investigate the effect of YM155 and cisplatin on the sensitivity of cisplatin chemotherapy and its mechanism .

method

SK - N - SH was treated with cisplatin , YM155 , YM155 and cisplatin respectively . The growth inhibition of treated cells was determined by MTT assay . The expression of Survivin in SK - N - SH cells was analyzed by Western blot analysis .

YM155 combined cisplatin ( 0.05 , 1 , 2 渭mol / L ) on SK - N - SH cells for 12 - 72h , and the inhibition rate of the cells increased gradually . Compared with control group alone , the inhibition rate of SK - N - SH cells increased significantly ( P0.05 ) , and YM155 could increase the sensitivity of SK - N - SH cells to cisplatin and enhance the inhibition of cell growth .

The apoptosis rate of SK - N - SH cells was significantly higher than that of YM155 alone ( P0.05 ) .

Survivin protein expression was completely inhibited by YM155 combined with cisplatin ( 0.05 , 1 , 2渭mol / L ) and single YM155 alone .

The mechanism of sensitization of YM155 to cisplatin may be closely related to the inhibition of the expression of Survivin in YM155 .

Objective : To study the effect of the fourth part YM155 on the cisplatin sensitization in the nude mice transplanted tumor

The effect of YM155 in vivo on the sensitivity of cisplatin chemotherapy was further evaluated .

The tumor and tumor were injected with cisplatin , YM155 and YM155 respectively to observe the growth of transplanted tumor within 3 weeks , and the tumor volume was calculated .
After the mice were killed , the tumor was weighed , the tumor inhibition rate ( IR ) was calculated , the tumor tissue was examined by routine pathology , and the expression level of survivin mRNA and protein in tumor tissues was detected by TUNEL method .

The results showed that the tumor weight of cisplatin + YM155 group was significantly lower than that of cisplatin group and YM155 group ( P0.01 ) . The results showed that the tumor volume of cisplatin + YM155 group was significantly slower than that of cisplatin group and YM155 group ( P0.01 ) .

It was found that the AI of the cisplatin + YM155 group was higher than that in the group YM155 , the cisplatin group and the control group ( P0.05 ) , but the AI of the group YM155 was significantly higher than that in the cisplatin group .

Survivin mRNA expression was significantly lower in YM155 and cisplatin + YM155 nude mice than that in control group and cisplatin group ( P0.05 ) , but there was no significant difference between control group and cisplatin group ( P0.05 ) .

The positive expression of survivin was found to be significantly lower in the control group and the cisplatin group than in the control group and the cisplatin group . Conclusion The positive expression of survivin in the control group and the cisplatin group was significantly lower than that in the control group and the cisplatin group .

The combination of YM155 and cisplatin may be an effective new method for the treatment of NB .
【學(xué)位授予單位】：山東大學(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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