【摘要】：膠質瘤是起源于神經膠質細胞、發(fā)病率最高的顱內腫瘤,占惡性腦腫瘤的80%以上。WHO根據膠質瘤的病理類型將其分為四個等級,其中I級和II級為低級別膠質瘤,III級和IV級為高級別膠質瘤。其中IV級多形性膠質母細胞瘤(Glioblastoma multiforme,GBM)是最具侵襲性的中樞神經系統(tǒng)原發(fā)腫瘤,約占原發(fā)惡性腦腫瘤的46.1%�；颊叩�5年存活率僅為5.1%。目前主要通過放化療以及手術切除等方法進行治療,但效果并不理想。因此,尋找新的治療手段是當前神經科學領域亟待解決的重要問題。神經膠質瘤的發(fā)病原因尚不明了,多種因素包括遺傳因素、電離輻射和職業(yè)化學暴露等在膠質瘤的發(fā)生中可能具有重要作用。此外,已有研究表明多種病毒如乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、人乳頭瘤病毒(HPV)、EB病毒(EBV)等與原發(fā)性肝癌、宮頸癌以及鼻咽癌的發(fā)生密切相關。近年來,陸續(xù)有在膠質瘤組織中檢出的病毒包括有人巨細胞病毒(HCMV)、EBV、人皰疹病毒6型(HHV-6)、猴空泡病毒40(SV40)和猿猴肉瘤病毒(WMSV)等的報道,但大都為西方的研究資料。由于遺傳背景、生存環(huán)境的不同,且疾病的病因譜也不盡相同,積累我國膠質瘤與病毒感染的研究資料非常必要。前期我們關注了皰疹病毒與膠質瘤發(fā)生的關系,79例膠質瘤腦組織HHV抗原的初步檢測結果顯示:膠質瘤組織中單純皰疹病毒1、2的陽性率與對照腦組織無明顯差別,EBV陽性率較低,未檢出水痘-帶狀皰疹病毒和HHV-8,但HCMV和HHV-6的檢出率明顯高于對照組,故本研究主要關注我國漢族人群中HCMV和HHV-6在膠質瘤組織中的檢出率及其與疾病發(fā)生的可能關聯(lián)。一.HCMV在膠質瘤發(fā)生中的可能作用HCMV屬皰疹病毒科β亞科,是人皰疹病毒家族中基因組最大的病毒�；蚪M為雙鏈DNA,長約180~240kb。HCMV基因組表達呈現(xiàn)一定的時序性,分即刻早期(IE)、早期(E)和晚期(L)基因,共編碼227種病毒蛋白,其中結構蛋白pp65在感染早期和晚期均有豐富表達,易于檢測。HCMV在人群中的感染率高達60~90%,而且一旦感染終生攜帶。HCMV感染具有潛伏-再激活的特點,可引起多種臨床病癥。2002年,Cobbs等首次發(fā)現(xiàn)膠質瘤組織中HCMV IE1抗原的表達率高達99%,提出HCMV感染與膠質瘤發(fā)生密切。在隨后的十幾年間,不同研究小組在膠質瘤組織中陸續(xù)檢出HCMV抗原和核酸,包括有pp65、g B、pp28、pp71、p52/76k D、US28、UL55、UL123等,進一步支持Cobbs的實驗結果和結論。然而,另外有研究在膠質瘤組織中并未檢測到HCMV抗原或核酸,因而HCMV感染與膠質瘤的關系存在爭議。目前認為出現(xiàn)以上不同研究結果的原因可能包括有不同的組織標本制備方法、不同的檢測指標和方法、不同的研究人群等。以往我們在79例膠質瘤組織中發(fā)現(xiàn)HCMV pp65蛋白和DNA的表達陽性率分別為65.8%(52/79)和54.4%(43/79),且HCMV的陽性率和表達水平與膠質瘤的病理級別成正比。因此,結合以往的報道,我們認為HCMV在膠質瘤發(fā)生發(fā)展過程中發(fā)揮重要作用,但HCMV以何種機制參與膠質瘤的進展有待進一步闡明。已知血管生成是腫瘤生長和轉移的必要條件,HCMV可通過與一些關鍵信號通路的相互作用參與血管生成的調節(jié),進而參與膠質瘤的惡性表型。STAT3是信號轉導及轉錄激活蛋白(signal transducer and activator of transcription,STAT)家族的重要成員。STAT3在人體的正常組織及細胞中有少許表達,被磷酸化后激活形成二聚體,是胚胎發(fā)育、分化,特別是神經干細胞和星形膠質細胞發(fā)育的重要調節(jié)因子。在腫瘤組織及細胞中STAT3異常高表達,可參與腫瘤細胞的惡性侵襲和轉移。但HCMV是否通過激活STAT3信號通路參與膠質瘤的發(fā)生與發(fā)展,尚待進一步研究。膠質瘤是高度血管化的腫瘤,豐富的新生血管是膠質瘤生長、侵襲和轉移的重要病理學基礎,這一過程受多種血管生成因子調控,如血管內皮生成因子(VEGF)、血管生成素(Angiopoietin,Ang)以及endocan。其中,endocan是一個分子量為50k Da的硫酸皮膚素蛋白聚糖,主要由血管內皮細胞分泌,生理條件下,endocan在血液中的水平極低,其功能與細胞的粘附、炎癥反應有關。部分炎癥因子和VEGF可以刺激內皮細胞分泌endocan。已有研究發(fā)現(xiàn),endocan在腫瘤組織和腫瘤病人血液中表達增加。在裸鼠荷瘤模型中,endocan異位表達可促進腫瘤的增長。在前期工作中我們發(fā)現(xiàn),膠質瘤組織endocan高表達,其表達水平與膠質瘤病理級別呈正相關。由此派生如下問題:在腫瘤組織中高表達的HCMV和endocan是否存在相互作用進而促進膠質瘤進展?其中的分子機制是什么?為此,本研究利用HCMV AD169株,通過感染體外培養(yǎng)的膠質瘤細胞U87,探究HCMV感染對STAT3以及endocan表達的影響以及三者之間可能的調控關系。在此基礎上,通過免疫組化的方法,檢測了79例腦膠質瘤標本(腫瘤組織)及8例正常腦組織標本中p STAT3的表達水平及其與膠質瘤病理級別的相關性。本研究主要實驗結果和結論如下:(1)HCMV感染上調U87細胞endocan和p STAT3的表達:利用HCMV感染U87細胞,感染后第1、2和4天收集細胞樣本,qPCR檢測endocan m RNA表達水平,發(fā)現(xiàn)endocan m RNA分別上升25%、270%和400%,與對照相比具有顯著差別(p0.05和p0.01)。與此相一致,endocan蛋白水平的表達在感染后第1天變化不顯著,第2天達峰值,為對照的1.6倍(p0.01),第4天仍維持在較高水平,為對照的1.3倍(p0.05)。提示HCMV感染可促進endocan的表達。同時,利用Western blot檢測HCMV感染U87細胞中p STAT3的表達變化,結果顯示,感染第1天p STAT3表達水平即升高至對照的1.7倍,差別顯著(p0.01),且明顯早于endocan表達上調的時間;感染后第2、4天p STAT3表達水平仍維持在較高的水平,和對照相比分別上調1.5倍和1.3倍。提示HCMV感染可促進p STAT3的表達。(2)STAT3下調和更昔洛韋處理可阻斷HCMV介導的STAT3磷酸化和endocan表達增加利用RNAi技術建立U87-STAT3下調細胞株,命名為U87-STAT3-down,并實施HCMV感染實驗,結果顯示感染后第2天,細胞中endocan和p STAT3蛋白水平分別降低至對照組的80%和43%(p0.05),提示STAT3下調可能抑制HCMV感染引起endocan的上調表達,換言之HCMV可能通過STAT3調控endocan的表達。在HCMV感染U87細胞2h后,加入抗病毒藥物更昔洛韋(GCV),抑制HCMV復制。于感染后1、2、4天收集細胞樣本,檢測STAT3和endocan的m RNA以及蛋白的表達。與HCMV感染組相比,GCV處理組的STAT3以及endocan的m RNA和蛋白均表達下調,提示抑制HCMV復制同樣抑制了HCMV感染引起的U87細胞中endocan和STAT3的上調,進一步提示HCMV通過STAT3調控endocan的表達。(3)p STAT3蛋白在膠質瘤腦組織中的表達:本實驗利用免疫組織化學法,對79例膠質瘤石蠟標本中的p STAT3表達情況進行了檢測。結果顯示,在膠質瘤標本中p STAT3的表達水平明顯增加,而在對照腦組織中僅有微量表達。結合膠質瘤組織中HCMVpp65蛋白高表達,在體實驗結果進一步支持“HCMV通過STAT3調控endocan的表達,進而參與膠質瘤進展”的推論�？傊�,本部分研究通過體外和體內實驗證明HCMV感染能夠通過激活STAT3上調膠質瘤細胞endocan表達,為深入揭示HCMV參與膠質瘤發(fā)生機制提供了資料,同時為臨床上治療膠質瘤提供了新思路�？共《局委熀投喟悬c的抗血管生成或許能成為膠質瘤的重要的輔助治療手段。二.HHV-6與膠質瘤的相關性研究HHV-6是皰疹病毒家族的成員,屬于玫瑰疹病毒屬,1986年首次分離于艾滋病(AIDS)晚期患者。HHV-6與HCMV同屬于β皰疹病毒亞科,兩病毒具有相似的生物學特性包括包膜糖蛋白以及核衣殼結構等。病毒基因的轉錄和翻譯與HCMV相似,分為三個階段:即刻早期基因、早期基因和晚期基因。成熟的病毒顆粒采用殺死宿主細胞的方式進行釋放。HHV6對星形膠質細胞具有親嗜性,感染早期會引發(fā)特異性的炎癥反應,病毒通過調節(jié)多種前炎性因子和趨化因子的活性,逃避免疫系統(tǒng)的攻擊。HHV-6與膠質瘤的關系的研究剛剛起步。近年來,陸續(xù)有研究小組報道在膠質瘤組織中檢出HHV-6病毒抗原和核酸。例如,Crawford JR小組通過PCR和ISH的方法檢測到88例小兒膠質瘤,發(fā)現(xiàn)HHV-6 U57基因的陽性表達。與HCMV相似,也有與上述相反的研究結論,例如Chan PK小組應用巢式PCR技術檢測98例石蠟包埋膠質瘤組織中HHV-6的DNA,結果顯示僅有8例HHV-6陽性�？梢奌HV-6與膠質瘤的關系尚需深入研究。為進一步明確HHV-6與膠質瘤的關系,本部分實驗通過免疫組化的方法檢測GBM中HHV-6的表達情況。主要研究結果如下:(1)病人一般情況:從首都醫(yī)科大學附屬三博腦科醫(yī)院收集70例膠質母細胞瘤(GBM)標本和6例對照腦組織(取自腦外傷手術病人)。其中GBM患者男女比例接近1:1,平均年齡52.3歲(6-73歲)。對照腦組織取自腦外傷病人,無糖尿病、高血壓等心腦血管疾病和感染性疾病。(2)HHV-6抗原在腦組織的分布:利用免疫細胞化學方法檢測腦組織(石蠟切片)中HHV-6抗原的表達。結果顯示,在GBM組織中HHV-6的陽性率為36%(25/70),在25例陽性組織中,呈弱陽性率為88%(22/25)、陽性率4%(1/25)、強陽性率8%(2/25),而對照組(外傷)腦組織中未檢出HHV-6的表達。HHV-6在胞質和細胞核中均有表達。本研究僅僅檢測了HHV-6在高級別膠質瘤組織中的表達,其陽性率遠遠高于對照組,提示HHV-6可能與膠質瘤的發(fā)生存在一定的關聯(lián)。尚需擴大樣本量、結合臨床隨訪進行進一步研究HHV-6表達率以及陽性強度與臨床指征、病人預后的相關性。病毒感染與膠質瘤的關系尚存爭議。本研究首先通過實驗證明HCMV感染通過激活STAT3上調膠質瘤細胞endocan表達,為深入闡明HCMV參與膠質瘤進展的機制提供新的線索,抗HCMV和endcoan治療可能會成為膠質瘤治療的重要輔助手段。再次,我們發(fā)現(xiàn)中國漢族膠質母細胞瘤患者中HHV-6抗原表達明顯升高,HHV-6感染可能與膠質瘤的發(fā)生存在一定的關聯(lián),但具體機制有待于擴大樣本量、結合臨床進一步闡明。
[Abstract]:Glioblastoma is the most common intracranial tumor originating from glial cells, accounting for more than 80% of malignant brain tumors. According to the pathological types of gliomas, the WHO classifies them into four grades: grade I and II are low grade gliomas, and grade III and IV are high grade gliomas. GBM is the most aggressive primary tumor of the central nervous system, accounting for 46.1% of the primary malignant brain tumors. The 5-year survival rate of the patients is only 5.1%. At present, it is mainly treated by radiotherapy, chemotherapy and surgical resection, but the effect is not satisfactory. Therefore, it is an important problem to find new treatment methods in the field of neuroscience. The etiology of gliomas is unknown. Many factors, including genetic factors, ionizing radiation and occupational chemical exposure, may play an important role in the development of gliomas. Hepatocellular carcinoma, cervical carcinoma and nasopharyngeal carcinoma are closely related. In recent years, there have been reports of human cytomegalovirus (HCMV), EBV, human herpesvirus 6 (HHV-6), simian vacuole virus 40 (SV40) and simian sarcoma virus (WMSV) in glioma tissues, but most of them are western research data. It is necessary to accumulate the data on the relationship between herpes virus and the occurrence of gliomas in China. Preliminary results of HHV antigen detection in 79 gliomas showed that the positive rate of herpes simplex virus 1,2 in gliomas was higher than that in controls. There was no significant difference in brain tissue, EBV positive rate was low, no varicella-zoster virus and HHV-8 were detected, but the detection rate of HCMV and HHV-6 was significantly higher than that of the control group. Therefore, this study focused on the detection rate of HCMV and HHV-6 in glioma tissues and its possible correlation with the occurrence of glioma. 1. HCMV in the occurrence of glioma may be. HCMV is the largest genome in the human herpesvirus family, belonging to the beta subfamily of the Herpesviridae family. The genome is a double-stranded DNA, about 180-240 kb in length. The HCMV genome expresses in a certain time sequence. It can be divided into immediate early (IE), early (E) and late (L) genes, encoding 227 viral proteins, including the structural protein pp65 in the early and late stages of infection. HCMV infection rate in the population is as high as 60-90%, and once the infection carries. HCMV infection has a latent-reactivation characteristics, can cause a variety of clinical symptoms. In 2002, Cobbs et al. first found in glioma tissue HCMV IE1 antigen expression rate as high as 99%. HCMV infection and glioma closely related. Over the next decade, different research groups have detected HCMV antigens and nucleic acids in glioma tissues, including pp65, g B, pp28, pp71, p52/76kD, US28, UL55, UL123 and so on, further supporting Cobbs'experimental results and conclusions. At present, it is believed that the causes of the above different results may include different preparation methods of tissue specimens, different detection indicators and methods, and different research groups. In the past, we found that the positive rates of HCMV pp65 protein and DNA expression in 79 glioma tissues were 65.8% (52/79) and 54.4% (43/79) respectively. Therefore, combined with previous reports, we believe that HCMV plays an important role in the occurrence and development of glioma, but the mechanism of HCMV involved in the progression of glioma remains to be further clarified. Angiogenesis is known to be a necessary condition for tumor growth and metastasis, HCM. STAT3 is an important member of the signal transducer and activator of transcription (STAT) family. STAT3 is slightly expressed in normal tissues and cells and is phosphorus-bound. Activation after acidification to form dimers is an important regulatory factor in embryonic development and differentiation, especially in the development of neural stem cells and astrocytes. Abnormally high expression of STAT3 in tumor tissues and cells may participate in malignant invasion and metastasis of tumor cells. Gliomas are highly vascularized tumors. Abundant neovascularization is an important pathological basis for the growth, invasion and metastasis of gliomas. This process is regulated by a variety of angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietin (Ang) and endocan. Among them, endocan is a molecular weight. 50 kDa dermatin sulfate proteoglycan is mainly secreted by vascular endothelial cells. Under physiological conditions, endocan is very low in the blood. Its function is related to cell adhesion and inflammatory reaction. Some inflammatory factors and VEGF can stimulate endocan secretion by endothelial cells. It has been found that endocan is in tumor tissue and blood of tumor patients. In a nude mice tumor-bearing model, ectopic expression of endocan promotes tumor growth. In our previous work, we found that the expression of endocan in glioma tissue was high, and the expression level was positively correlated with the pathological grade of glioma. In this study, we investigated the effect of HCMV infection on the expression of STAT3 and endocan and the possible relationship between them by infecting glioma cell U87 in vitro with HCMV AD169 strain. The main results and conclusions of this study are as follows: (1) HCMV infection up-regulates the expression of endocan and pSTAT3 in U87 cells: U87 cells were infected with HCMV, and cell samples were collected on the 1st, 2nd and 4th day after infection, and endocan was detected by qPCR. The expression level of endocan m RNA increased by 25%, 270% and 400% respectively, which was significantly different from that of the control (p0.05 and p0.01). Similarly, the expression of endocan protein did not change significantly on the first day after infection, reached a peak value on the second day, which was 1.6 times as high as that of the control (p0.01), and remained at a high level on the fourth day, 1.3 times as high as that of the control (p0.05). At the same time, Western blot was used to detect the expression of P STAT3 in U87 cells infected with HCMV. The results showed that the expression of P STAT3 in U87 cells infected with HCMV increased to 1.7 times of the control on the first day of infection, and the difference was significant (p0.01), and the expression of P STAT3 was significantly earlier than that of endocan. At a higher level, the expression of P STAT3 was up-regulated by 1.5 and 1.3 times, respectively, compared with the control group. (2) STAT3 down-regulation and ganciclovir treatment could block HCMV-mediated STAT3 phosphorylation and endocan expression. U87-STAT3 down-regulated cell line was established by RNAi technique, named U87-STAT3-down, and HCMV infection experiment was carried out. The results showed that the levels of endocan and P STAT3 decreased to 80% and 43% respectively (p0.05) on the 2nd day after infection, suggesting that STAT3 down-regulation may inhibit the up-regulation of endocan expression induced by HCMV infection. In other words, HCMV may regulate the expression of endocan through STAT3. HCMV replication was made. Cell samples were collected 1,2,4 days after infection to detect the expression of STAT3 and endocan m RNA and protein. Compared with HCMV infection group, the expression of STAT3 and endocan m RNA and protein in GCV treatment group were down-regulated, suggesting that inhibiting HCMV replication also inhibited the up-regulation of endocan and STAT3 in U87 cells induced by HCMV infection. The results showed that HCMV regulated the expression of endocan by STAT3. (3) The expression of P STAT3 protein in brain tissues of glioma: The expression of P STAT3 in paraffin-embedded samples of 79 glioma specimens was detected by immunohistochemistry. The results showed that the expression of P STAT3 in glioma specimens was significantly increased, but only in control brain tissues. Combining with the high expression of HCMVpp65 protein in glioma tissues, in vivo experimental results further support the hypothesis that HCMV regulates endocan expression through STAT3 and then participates in glioma progression. It provides information for further revealing the mechanism of HCMV involvement in gliomas and provides new ideas for clinical treatment of gliomas. Antiviral therapy and multi-target anti-angiogenesis may be important adjuvant therapy for gliomas. 2. Correlation between HHV-6 and gliomas. HHV-6 is a member of herpes virus family and belongs to Mei. Rosea virus, first isolated from advanced AIDS patients in 1986. HHV-6 and HCMV belong to the same subfamily of beta-herpesvirus. The two viruses have similar biological characteristics, including envelope glycoprotein and nucleocapsid structure. Because mature virus particles are released by killing host cells, HHV6 is a cytophilic agent to astrocytes and can induce specific inflammation in the early stage of infection. The virus escapes the attack of the epidemic system by regulating the activity of various pro-inflammatory and chemokines. In recent years, a number of research groups have reported detection of HHV-6 virus antigens and nucleic acids in gliomas. For example, the Crawford JR team detected 88 cases of childhood gliomas by PCR and ISH, and found positive expression of HHV-6 U57 gene. Similar to HCMV, there are also contrary research findings, such as the Chan PK team using nested PCR technology. In order to further clarify the relationship between HHV-6 and glioma, immunohistochemical method was used to detect the expression of HHV-6 in GBM. The main results were as follows: (1) Patients in general Situation: Seventy specimens of glioblastoma (GBM) and six control brain tissues were collected from Sanbo Brain Hospital Affiliated to Capital Medical University. The male-female ratio of GBM patients was close to 1:1, with an average age of 52.3 years (6-73 years). The control brain tissues were taken from brain trauma patients without diabetes, hypertension and other cardiovascular and cerebrovascular diseases and infections. Disease. (2) Distribution of HHV-6 antigen in brain tissues: Immunocytochemical method was used to detect the expression of HHV-6 antigen in brain tissues (paraffin section). The results showed that the positive rate of HHV-6 in GBM tissues was 36% (25/70). In 25 positive tissues, the weak positive rate was 88% (22/25), the positive rate was 4% (1/25), and the strong positive rate was 8% (2/25) compared with the control group (trauma). HHV-6 expression was not detected in brain tissues. HHV-6 was expressed in both cytoplasm and nucleus. The positive rate of HHV-6 expression in high grade glioma tissues was much higher than that in control group, suggesting that HHV-6 may be associated with the occurrence of glioma. The relationship between HCMV infection and glioma remains controversial. This study first demonstrated that HCMV infection up-regulates endocan expression in glioma cells by activating STAT3, providing new clues to further elucidate the mechanism of HCMV involvement in glioma progression and anti-HCMV and E. Ndcoan therapy may be an important adjuvant therapy for glioma. thirdly, we found HHV-6 in Chinese Han glioblastoma patients
【學位授予單位】：首都醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R739.41

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