發(fā)布時(shí)間：2018-04-30 18:45

  本文選題：膠質(zhì)瘤 + HDGF　； 參考：《南方醫(yī)科大學(xué)》2014年碩士論文

【摘要】：研究背景與目的 膠質(zhì)瘤是中樞神經(jīng)系統(tǒng)最常見的、預(yù)后較差的原發(fā)性惡性腫瘤,占顱內(nèi)腫瘤的50%-60%,即使給予傳統(tǒng)的手術(shù)聯(lián)合放、化療的綜合治療,低級別膠質(zhì)瘤病人的平均存活時(shí)間僅為3-5年,而高級別膠質(zhì)瘤為1-2年。其治療一直是神經(jīng)外科領(lǐng)域的研究熱點(diǎn),膠質(zhì)瘤的傳統(tǒng)治療策略是在手術(shù)盡可能全切除的基礎(chǔ)上,采用多種手段殺滅殘存瘤細(xì)胞或抑制其增殖。但即使是相同病理類型和相同WHO級別的膠質(zhì)瘤患者,其預(yù)后也存在很大差異,治療上的差異是一方面,但膠質(zhì)瘤內(nèi)在的生物學(xué)特性,特別是分子水平的不同是關(guān)鍵所在。 肝癌衍生生長因子(hepatoma-derived growth factor, HDGF)是從人肝癌細(xì)胞系HUH-7培養(yǎng)液中分離出一種的肽類物質(zhì)。大量研究發(fā)現(xiàn)HDGF在多種惡性腫瘤中高表達(dá),具有促進(jìn)細(xì)胞增殖、促進(jìn)血管生成等多種生理作用。HDGF在多種惡性腫瘤中系高表達(dá),如有研究表明HDGF在正常的肝細(xì)胞、肝癌細(xì)胞及內(nèi)皮細(xì)胞中均有表達(dá),且在胞漿及胞核中都有分布,癌組織中的HDGF表達(dá)水平明顯高于癌周正常組織,腫瘤細(xì)胞核HDGF表達(dá)水平與患者的AFP水平呈正相關(guān)關(guān)系、與腫瘤的分化程度呈負(fù)相關(guān)關(guān)系；在乳腺癌中HDGF核表達(dá)程度和腫瘤的分期、分級及增殖密切相關(guān),在細(xì)胞水平上,腺病毒轉(zhuǎn)染高表達(dá)HDGF乳腺癌細(xì)胞中E鈣粘蛋白表達(dá)降低而波形蛋白表達(dá)增高,從而誘導(dǎo)上皮細(xì)胞向間葉細(xì)胞的轉(zhuǎn)化(EMT過程),使得乳腺癌的侵襲性及轉(zhuǎn)移能力增強(qiáng)；在惡性程度較高的口腔癌中,HDGF呈現(xiàn)高表達(dá),HDGF核表達(dá)的程度與口腔癌病理分期、分級及腫瘤壞死程度呈正相關(guān)。 HDGF在膠質(zhì)瘤中鮮有研究,且其在膠質(zhì)瘤中的具體功能尚未明確,本研究首先通過免疫組化方法明確HDGF在膠質(zhì)瘤組織中的表達(dá)特性；進(jìn)一步通過構(gòu)建穩(wěn)定低表達(dá)HDGF膠質(zhì)瘤細(xì)胞系,探討HDGF表達(dá)沉默后對于膠質(zhì)瘤細(xì)胞系生物學(xué)行為的影響及其所涉及的具體信號通路,將有助于進(jìn)一步揭示膠質(zhì)瘤的發(fā)病機(jī)理及預(yù)后,并有可能為今后深入探討膠質(zhì)瘤的發(fā)生發(fā)展機(jī)制和今后的臨床防治提供新的依據(jù)。 研究內(nèi)容與方法 1.膠質(zhì)瘤及正常腦組織中HDGF表達(dá)鑒定 ①利用RT-PCR檢測HDGF在膠質(zhì)瘤及正常腦組織中mRNA表達(dá)水平。 ②利用Western blot檢測HDGF在膠質(zhì)瘤及正常腦組織中蛋白表達(dá)水平。 ③免疫組化檢測膠質(zhì)瘤及正常腦組織中HDGF的表達(dá)情況。 2.穩(wěn)定低表達(dá)HDGF膠質(zhì)瘤細(xì)胞株的功能研究在人膠質(zhì)瘤細(xì)胞株U251、U87中,采用慢病毒載體技術(shù)將HDGF沉默表達(dá),同時(shí)設(shè)立陰性對照組,并利用RT-PCR及Western blot檢測其干擾效率。通過平板克隆實(shí)驗(yàn)、MTT法、EdU實(shí)驗(yàn)、劃痕實(shí)驗(yàn)、Transwell小室遷移實(shí)驗(yàn)、Boyden小室侵襲實(shí)驗(yàn)等檢測干擾HDGF后對膠質(zhì)瘤細(xì)胞株生長、周期、侵襲、遷移等方面的影響。 3. HDGF介導(dǎo)的機(jī)制研究通過細(xì)胞功能實(shí)驗(yàn)我們發(fā)現(xiàn),干擾HDGF表達(dá)后細(xì)胞生長、侵襲及遷移能力均降低。因此,采用Western blot定量檢測細(xì)胞侵襲及生長相關(guān)蛋白的表達(dá),如β-catenin、Vimentin、E-cadherin. N-cadherin及PI3K/Akt、TGF-beta信號通路相關(guān)蛋白。 4.替莫唑胺(TMZ)敏感性檢測及IC50測定首先IC50定義是膠質(zhì)瘤細(xì)胞株生長被抑制一半時(shí)替莫唑胺的濃度。接下來,為了研究HDGF基因是否影響藥物敏感性,將干擾HDGF組和對照組分別在替莫唑胺濃度為25μM、50μM、100μM、200μM和400μM的培養(yǎng)基中培養(yǎng)48個(gè)小時(shí),隨后用MTT法對細(xì)胞生長進(jìn)行檢測并測定IC50。 結(jié)果 1.膠質(zhì)瘤及正常腦組織中HDGF表達(dá)鑒定①根據(jù)RT-PCR結(jié)果,可發(fā)現(xiàn)HDGF在膠質(zhì)瘤組織中表達(dá)較正常腦組織明顯上調(diào)(P0.0001)。 ②Western blot實(shí)驗(yàn)結(jié)果顯示,與正常腦組織比較,HDGF在膠質(zhì)瘤組織中上調(diào),其差異有統(tǒng)計(jì)學(xué)意義(P0.01) ③免疫組化結(jié)果表明,與正常腦組織比較,HDGF在膠質(zhì)瘤組織中顯著上調(diào)(P0.001),且在大多數(shù)細(xì)胞中HDGF為核表達(dá),少數(shù)也在細(xì)胞漿中表達(dá)。此外,根據(jù)組織標(biāo)本的臨床資料的統(tǒng)計(jì)分析,不同性別、年齡、組織學(xué)分型患者HDGF表達(dá)程度無顯著差異(P值分別為0.395、0.513和0.573)。但膠質(zhì)瘤組織WHO級別越高,HDGF表達(dá)越高(P0.01),即HDGF表達(dá)程度與膠質(zhì)瘤的惡性程度相關(guān)。 2.穩(wěn)定低表達(dá)HDGF膠質(zhì)瘤細(xì)胞株的功能研究為了研究HDGF在膠質(zhì)瘤細(xì)胞中的功能,我們選取了經(jīng)典的U251、U87細(xì)胞株,構(gòu)建穩(wěn)定低表達(dá)HDGF的慢病毒載體,包裝成成熟的慢病毒,轉(zhuǎn)染膠質(zhì)瘤細(xì)胞株。隨后,采用blot實(shí)驗(yàn)對比干擾HDGF組及對照組細(xì)胞HDGF蛋白表達(dá)情況,在干擾組中HDGF表達(dá)明顯下調(diào)(P0.001)。鑒定完干擾效率后,采用兩株細(xì)胞的干擾HDGF組及陰性對照組細(xì)胞進(jìn)行細(xì)胞功能實(shí)驗(yàn)。采用平板克隆實(shí)驗(yàn)和MTT法檢測兩組細(xì)胞的體外增殖能力的差異。兩種實(shí)驗(yàn)的結(jié)果均顯示,下調(diào)HDGF表達(dá)后,與陰性對照組相比,兩株細(xì)胞的干擾組的體外增殖能力均明顯減弱。統(tǒng)計(jì)學(xué)分析表明,兩組間細(xì)胞的增殖能力差異具有統(tǒng)計(jì)學(xué)意義(P0.001)。 接下來,為了剖析干擾組細(xì)胞增殖能力改變的原因,我們采用EdU實(shí)驗(yàn)檢測兩組細(xì)胞中處于細(xì)胞周期S期的細(xì)胞的數(shù)量。結(jié)果顯示,干擾組的S期細(xì)胞較對照組減少,其差異具有統(tǒng)計(jì)學(xué)意義(P0.01)。這一結(jié)果也從側(cè)面證明了干擾HDGF組細(xì)胞較對照組細(xì)胞的增殖能力減弱。 采用劃痕實(shí)驗(yàn)及Transwell小室遷移實(shí)驗(yàn)檢測沉默表達(dá)HDGF后細(xì)胞的體外遷移能力。Transwell小室遷移實(shí)驗(yàn)結(jié)果顯示,將HDGF沉默后,干擾組細(xì)胞穿過膜的細(xì)胞數(shù)顯著減少,提示干擾組的細(xì)胞遷移能力明顯減弱,差異具有顯著性；同樣,劃痕實(shí)驗(yàn)也得到了一樣的結(jié)果(P0.001)。 為了檢測干擾組細(xì)胞的侵襲能力的變化,我們采用了Boyden小室侵襲實(shí)驗(yàn)。結(jié)果顯示,兩組細(xì)胞均有穿透基質(zhì)膠向下侵襲的現(xiàn)象,并在聚碳酸酯膜上可見腫瘤細(xì)胞形態(tài)改變。與陰性對照組相比,干擾組穿過膜的細(xì)胞明顯減少,其體外侵襲能力降低(P0.001)。 3. HDGF介導(dǎo)的機(jī)制研究 根據(jù)細(xì)胞功能結(jié)果可見,干擾HDGF表達(dá)后,膠質(zhì)瘤細(xì)胞的增殖能力、遷移能力及侵襲能力均下降。為了進(jìn)一步研究HDGF調(diào)控膠質(zhì)瘤發(fā)生發(fā)展的機(jī)制,我們采用western blot檢測了與腫瘤增殖、遷移、侵襲相關(guān)蛋白及PI3K/AKT、 TGF-beta信號通路。結(jié)果如下： ①Western blot定量分析表明,較陰性對照組相比,干擾組的侵襲、遷移相關(guān) 蛋白表達(dá)除了E-cadherin無明顯變化外,beta-catenin, vimentin、N-cadherin 均下降(P0.05)。 ②采用Western blot檢測增殖相關(guān)的經(jīng)典信號通路PI3K/AKT和TGF-beta,結(jié)果表明：下調(diào)HDGF后,PI3K、AKT總蛋白及磷酸化的PI3K、AKT亦下調(diào)(P0.05); TGF-beta通路中,TGF-beta、c-myc、CCND1、p16及p21蛋白表達(dá)均減弱(P0.05)。 4.替莫唑胺(TMZ)敏感性檢測及ICso測定 將干擾HDGF組和對照組分別在替莫唑胺濃度為25μM、50μM、100μM、200pM和400μM的培養(yǎng)基中培養(yǎng)48小時(shí),隨后用MTT法對細(xì)胞生長進(jìn)行檢測,結(jié)果顯示：與正常生長的細(xì)胞相比,U251干擾組細(xì)胞在含有不同替莫唑胺濃度的培養(yǎng)基中分別被抑制9.4%、15.0%、35.3%、49.4%、67.2%,U251對照組細(xì)胞分別被抑制3.7%、6.5%、13.9%、28.9%、43.9%,兩組間差異有統(tǒng)計(jì)學(xué)意義(P0.05)；U87干擾組分別被抑制11.8%、14.8%、27.5%、37.1%、49.7%,U87對照組細(xì)胞分別被抑制2.7%、4.3%、12.3%、17.5%、32.5%,兩組間差異亦有統(tǒng)計(jì)學(xué)意義(P0.05)。隨后測定的IC50為：U251干擾組202.5,對照組487.3；U87干擾組406.3,對照組808.4。 討論 從本研究的結(jié)果中可知,HDGF在膠質(zhì)瘤組織中系高表達(dá),且以核表達(dá)為主,與腫瘤的惡性程度呈正相關(guān)。細(xì)胞功能實(shí)驗(yàn)顯示,下調(diào)HDGF基因后,膠質(zhì)瘤細(xì)胞株U251、U87的增殖能力、侵襲能力及遷移能力均下降。為進(jìn)一步闡明HDGF調(diào)控膠質(zhì)瘤發(fā)生發(fā)展的機(jī)制,我們檢測了大量與細(xì)胞增殖、細(xì)胞周期、侵襲、遷移相關(guān)的蛋白,從中發(fā)現(xiàn),HDGF可能通過PI3K/AKT及TGF-beta兩條通路共同作用來調(diào)控膠質(zhì)瘤的發(fā)生發(fā)展。此外,HDGF沉默表達(dá)后,beta-catenin、vimentin、N-cadherin等侵襲相關(guān)蛋白亦出現(xiàn)沉默表達(dá),提示HDGF可能參與調(diào)控與上皮間質(zhì)轉(zhuǎn)化(Epithelial-to-Mesenchymal Transition, EMT)過程。最后,我們檢測了HDGF對膠質(zhì)瘤藥物敏感性的影響,可以發(fā)現(xiàn)當(dāng)下調(diào)HDGF基因時(shí),膠質(zhì)瘤細(xì)胞株U251、U87對于藥物替莫唑胺的敏感性上升,由此可見HDGF可能與膠質(zhì)瘤的藥物耐藥性有關(guān)。綜上所述,HDGF作為一個(gè)癌基因,擁有一個(gè)復(fù)雜的調(diào)控機(jī)制,本研究發(fā)現(xiàn)HDGF可能通過PI3K/AKT及TGF-beta兩條通路的共同作用來調(diào)控膠質(zhì)瘤的發(fā)生發(fā)展,可能參與上皮間質(zhì)轉(zhuǎn)化過程,且與藥物的耐藥性相關(guān),揭示HDGF的具體調(diào)控機(jī)制有助于闡明腫瘤的發(fā)生發(fā)展機(jī)制,并有可能成為藥物治療的一個(gè)新的靶點(diǎn)。
[Abstract]:Background and purpose of study

Gliomas are the most common and poor prognosis primary malignant tumors of the central nervous system , accounting for 50 - 60 % of the intracranial tumors , and the average survival time of the patients with low grade glioma is only 3 - 5 years , and the high - grade glioma is 1 - 2 years .

The expression level of HDGF in normal liver cells , liver cancer cells and endothelial cells was significantly higher than that in normal tissues , and the expression level of HDGF in cancer tissues was significantly higher than that in normal tissues .
The expression of E - cadherin and the expression of E - cadherin in human breast cancer cells were closely related to the level of expression of E - cadherin in human breast cancer . The expression of E - cadherin in human breast cancer cells was decreased , and the expression of P - cadherin increased , thus inducing the transformation of epithelial cells to mesenchymal cells ( EMT process ) , which resulted in increased invasion and metastasis ability of breast cancer .
HDGF was highly expressed in the higher malignant degree of oral cancer , and the level of HDGF was positively correlated with pathological stage , grade and tumor necrosis degree of oral cancer .

The specific function of HDGF in glioma was not clear . First , the expression of HDGF in glioma tissues was determined by immunohistochemistry .
Furthermore , by constructing the stable low - expression HDGF glioma cell line , the effects of HDGF on the biological behavior of glioma cell lines and the specific signal pathways involved will be discussed , which will help to further reveal the pathogenesis and prognosis of glioma .

Study contents and methods

Expression of HDGF in glioma and normal brain tissue

( 1 ) The mRNA expression level of HDGF in human glioma and normal brain tissue was detected by RT - PCR .

2 . Western blot was used to detect the expression level of HDGF in human glioma and normal brain tissue .

( 3 ) The expression of HDGF in glioma and normal brain tissues was detected by immunohistochemistry .

2 . The function of stable low - expression HDGF glioma cell line was studied in human glioma cell lines U251 and U87 , and the interference efficiency was detected by RT - PCR and Western blot . The effects of HDGF on growth , cycle , invasion and migration of glioma cell line were studied by means of plate cloning , MTT assay , EdU experiment , scratch test , Transwell chamber migration experiment , Boyden chamber invasion experiment and so on .

3 . The mechanism of HDGF - mediated mechanism was found to decrease the cell growth , invasion and migration ability after interfering with HDGF expression . Therefore , Western blot was used to quantitatively detect the invasion and growth - related protein expression , such as 尾 - catenin , Vimentin , E - cadherin . N - cadherin and PI3 , TGF - beta signaling pathway related proteins .

4 . The IC50 determination of temozolomide ( TMZ ) was first defined as the concentration of temozolomide when the growth of glioma cell line was inhibited by half . Next , in order to study whether the HDGF gene affected drug sensitivity , the interference HDGF group and the control group were cultured for 48 hours in the medium of temozolomide concentration of 25 . m u.M , 50 . m u.M , 100 . m u.M , 200 . m u.M and 400 . m u.M , respectively , and then the cell growth was detected and the IC50 was determined by MTT assay .

Results

1 . The expression of HDGF in human glioma and normal brain tissue was determined ( 1 ) According to the results of RT - PCR , it was found that the expression of HDGF in glioma tissues was significantly higher than that in normal brain tissue ( P < 0 . 0001 ) .

The results of Western blot showed that HDGF was up - regulated in glioma tissues compared with normal brain tissue ( P0.01 ) .

In addition , the higher the WHO grade of glioma , the higher the level of HDGF , the higher the expression of HDGF ( P0.01 ) , that is , the degree of HDGF was correlated with the degree of malignancy of glioma .

2 . In order to study the function of HDGF in glioma cells , we selected classical U251 and U87 cell lines , constructed a slow virus vector stably expressing HDGF , packaged into mature lentivirus and transfected glioma cell line .

The results showed that the S phase cells of the interfering group decreased significantly compared with the control group ( P0.01 ) . The results also showed that the proliferation ability of the cells from the interfering HDGF group was weakened compared with the control group .

Transwell small cell migration experiment showed that the number of cells passing through the membrane decreased significantly after the silencing of HDGF , suggesting that the cell migration ability of the interfering group was significantly decreased , and the difference was significant .
Similarly , the same results were obtained in the scratch experiment ( P0.001 ) .

In order to detect the invasion ability of interfering group cells , we used Boyden ' s cell invasion experiment . The results showed that both groups had the phenomenon of penetrating matrix glue and the morphological changes of tumor cells were seen on the polycarbonate membrane . Compared with the negative control group , the cells of the interference group decreased significantly , and the invasion ability in vitro was decreased ( P0.001 ) .

3 . Mechanism of HDGF - mediated Mechanism

In order to further study the mechanism of HDGF in the development of glioma , Western blot was used to detect the proliferation , migration , invasion - related protein and the 3 - 3 / 3 - 1 , TGF - beta signaling pathway .

Western blot analysis showed that compared with the negative control group , the invasion and migration of the interference group were related .

In addition to E - cadherin , the expression of 尾 - catenin , vimentin , N - cadherin

Both decreased ( P0.05 ) .

2 . Western blot was used to detect the proliferation - related classical signal pathway of PI3 - 3 and TGF - beta . The results showed that , after downregulating the HDGF , the total protein and the phosphorylation of PI3 - 3 were down - regulated ( P0.05 ) , and the expression of TGF - beta , c - myc , CCND1 , p16 and p21 protein in TGF - beta pathway decreased ( P0.05 ) .

4 . Temozolomide ( TMZ ) Sensitivity Detection and Determination of ICso

Cell growth was detected by MTT assay . The results showed that U251 cells were inhibited by 9 . 4 % , 15.0 % , 35 . 3 % , 49.4 % , 67.2 % in culture medium containing different temozolomide concentration , and that of U251 control group were inhibited by 3 . 7 % , 6 . 5 % , 13.9 % , 28 . 9 % and 43.9 % , respectively .
U87 interfered group was inhibited 11.8 % , 14.8 % , 27.5 % , 37.5 % , 49.7 % , U87 control group cells were inhibited 2.7 % , 4.3 % , 12.3 % , 17.5 % , 32.5 % , respectively . The IC50 of U251 interference group was 202.5 and 487.3 % in U251 interference group .
U87 interfered group 406.3 , control group 808.4 .

discuss

In conclusion , HDGF may be involved in regulating the development of glioma . In conclusion , HDGF may be involved in regulating and regulating the development of glioma . In conclusion , HDGF may be involved in regulating and regulating the development of glioma . In conclusion , HDGF may be involved in regulating and regulating the development of glioma .

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

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