本文選題：垂體瘤 + 侵襲性　； 參考：《第三軍醫(yī)大學(xué)》2016年博士論文

【摘要】：研究背景和目的:垂體瘤占顱內(nèi)腫瘤約15%[1],其組織學(xué)為良性,但是有25-55%的垂體瘤朝周圍結(jié)構(gòu)浸潤,比如鞍隔的骨性組織,篩竇和/或海綿竇等,這些垂體瘤稱為侵襲性垂體瘤[2][3][4]。垂體瘤的侵襲性常與高Ki-67指數(shù),并與嚴(yán)重的癥狀、更差的預(yù)后、高復(fù)發(fā)率、以及藥物替代治療的低反應(yīng)性相關(guān)[5]�，F(xiàn)有的研究已表明,染色體、基因(如:11p/q, p53),粘附分子(如:E-cadherin),金屬基質(zhì)蛋白(如:MMP2, MMP8),炎癥因子(如:IL-6, IL-17)的異常變化與垂體瘤的進(jìn)展、侵襲相關(guān)[5][6][7][8][9][10][11]。但評估、解釋其侵襲性的特異性的組織學(xué)和分子生物學(xué)標(biāo)準(zhǔn)卻依然缺乏。不僅如此,現(xiàn)有的研究多從垂體瘤自身基因、轉(zhuǎn)錄、轉(zhuǎn)錄后修飾等幾個(gè)層面上的異常變化探索其侵襲性的來源,極少研究聚焦于外界環(huán)境如微生物感染等對垂體瘤發(fā)生發(fā)展的影響。15-20%的人類腫瘤都與促腫瘤病毒相關(guān)[12]。促腫瘤病毒促進(jìn)腫瘤發(fā)生發(fā)展的一重要機(jī)制是慢性感染常導(dǎo)致氧化應(yīng)激與炎癥,受感染的細(xì)胞分泌炎癥因子如IL-1β、IL-6及TNF-α,形成炎癥環(huán)境(inflammatory milieu),炎癥刺激、影響、激活NF-κB、STAT3及MAPKs等信號(hào)通路促進(jìn)腫瘤的發(fā)展[13]。近年的研究發(fā)現(xiàn),模式識(shí)別受體(PRRs)不僅表達(dá)在免疫細(xì)胞,還能在腫瘤細(xì)胞中有表達(dá)[14]。PRRs中最常見的是Toll樣受體(TLR)家族,其家族的多個(gè)成員如TLR2[15],TLR3[16],TLR4[15][17]等均已證實(shí)在某些腫瘤中表達(dá),且參與腫瘤的發(fā)生與發(fā)展,其中與病毒感染最為密切相關(guān)的是TLR3。各種來源雙鏈RNA(dsRNA),壞死細(xì)胞來源或相關(guān)的RNA和人工合成的Poly(I:C)[18][19]均是TLR3的配體。病毒雙向轉(zhuǎn)錄過程中形成的dsRNA可激活TLR3,這與病毒類型(DNA病毒、RNA病毒等)無關(guān)[20]。已有大量的研究表明,高危HPV16被發(fā)現(xiàn)與人類多種腫瘤發(fā)生相關(guān),包括宮頸癌[21]、口咽癌[22]、肛門癌[23]以及頭頸部癌[24]等。不僅如此,某些腫瘤中HPV16陽性的腫瘤細(xì)胞可更多朝周圍結(jié)構(gòu)侵襲,以及更遠(yuǎn)處的遷移[21]。HHV6是嗜B淋巴細(xì)胞病毒,與兒童淋巴瘤患者的預(yù)后密切相關(guān)[25]。而HSV1則與乳腺癌病人總體存活率相關(guān),并且與吸煙、飲酒、HPV感染等因素綜合決定頭頸部癌的發(fā)生[26][27]。在垂體瘤中,尚未有報(bào)道其發(fā)生發(fā)展與某種病毒感染有關(guān),因此,本研究擬檢測侵襲性與非侵襲性垂體瘤中前述三個(gè)促腫瘤病毒(HPV16,HSV1以及HHV6B)的感染情況,探討病毒感染與垂體瘤侵襲、增殖之間的關(guān)系。并且在體外垂體瘤細(xì)胞系中,探索病毒作用的分子機(jī)制,為臨床上預(yù)估、治療侵襲性垂體瘤提供新的思路。方法:1.利用免疫組織化學(xué)、巢式PCR等技術(shù),研究HPV16、HSV1、HHV6B DNA、病毒蛋白在垂體瘤病人病理標(biāo)本中的表達(dá)。2.利用qRT-PCR以及免疫組織化學(xué)的方法檢測垂體瘤病人病理標(biāo)本中TLR3 mRNA以及蛋白水平的表達(dá)。3.利用大鼠垂體瘤細(xì)胞系GH3細(xì)胞系在體外探究TLR3對細(xì)胞侵襲、增殖能力的影響以及分子機(jī)制探究。結(jié)果:1. HPV16和HHV6B在侵襲性垂體瘤標(biāo)本中感染率更高60例垂體瘤標(biāo)本中,HPV16在侵襲性垂體瘤陽性檢測率為70%,非侵襲性垂體瘤陽性檢測率為26.67%,侵襲性垂體瘤組中HPV 16的陽性檢測率顯著高于非侵襲性組(P0.01); HHV6B在侵襲性垂體瘤中的陽性檢測率為55.33%,在非侵襲性垂體瘤中陽性檢測率為23.33%,兩者之間差異顯著(P0.05); HSV1在侵襲性垂體瘤的檢出率為50%,非侵襲性垂體瘤檢出率為30%,差異無統(tǒng)計(jì)學(xué)意義(P0.05)。因此,HPV16、HHV6B感染與垂體瘤的侵襲性正相關(guān),而HSV1的感染與垂體瘤侵襲性無關(guān)。2. TLR3的mRNA與蛋白在侵襲組中表達(dá)均顯著高于非侵襲性PA組,且與HPV16、HHV6B感染率正相關(guān)。在mRNA水平上,我們檢測了侵襲性垂體瘤組與非侵襲性垂體瘤組中與病毒感染相關(guān)的TLRs中的TLR3、4、7、8、9的表達(dá),我們的結(jié)果發(fā)現(xiàn),僅TLR3在侵襲性與非侵襲性組之間有差異(P0.01)。在侵襲組中,TLR3在mRNA水平上表達(dá)增加。緊接著,我們又用免疫組化的方法檢測了 TLR3蛋白水平的表達(dá)。TLR3的蛋白在每一例垂體瘤患者標(biāo)本中均檢測出有表達(dá),且TLR3表達(dá)在胞漿。通過對TLR3蛋白表達(dá)的定量統(tǒng)計(jì),我們發(fā)現(xiàn)TLR3蛋白水平在侵襲性組顯著高于非侵襲性組(P0.01)。通過統(tǒng)計(jì)學(xué)方法分析TLR3表達(dá)量與HPV16、HHV6B感染率之間的關(guān)系,我們發(fā)現(xiàn)病毒感染率與TLR3表達(dá)之間呈正相關(guān)。3. TLR3的激活可促進(jìn)垂體瘤細(xì)胞系GH3的增殖我們在8個(gè)時(shí)間點(diǎn)上檢測了 200 μg/ml Poly (I:C)對GH3細(xì)胞系的影響。生長曲線結(jié)果顯示,在分析的時(shí)間點(diǎn)內(nèi),Poly (I:C)可以促進(jìn)GH3細(xì)胞的增殖。4. TLR3的激活可影響GH3細(xì)胞系的凋亡與細(xì)胞周期Poly (I:C)處理組與對照組對比可以發(fā)現(xiàn),處理組中更少的凋亡細(xì)胞,更多的細(xì)胞處于細(xì)胞周期的S期�？沟蛲龅腂cl-2在Poly (I:C)處理組中表達(dá)增加,促凋亡剪切活化的Caspase 3在添加Poly (I:C)組中的表達(dá)更少。而促進(jìn)凋亡的Bax蛋白在幾個(gè)處理組之間差異無統(tǒng)計(jì)學(xué)意義。與此同時(shí),我們檢測了促進(jìn)細(xì)胞從G1/G0期進(jìn)入S期的蛋白CyclinD1,我們發(fā)現(xiàn),CyclinD1的表達(dá)在Poly(I:C)處理組中增多。5. TLR3的激活可促進(jìn)GH3細(xì)胞的侵襲在預(yù)先TLR3-siRNA預(yù)處理或未處理的Transwell上室中,加入Poly(I:C)。48小時(shí)后,侵襲的細(xì)胞被染色和計(jì)數(shù)。統(tǒng)計(jì)分析顯示,Poly(I:C)處理組穿過上室的細(xì)胞更多。6. TLR3下游的NF-κB被激活我們運(yùn)用免疫熒光的方法檢測了 Poly (I:C)刺激后NF-κB p65亞基的亞細(xì)胞定位。不僅如此,我們還分別檢測了 p65分別在細(xì)胞漿、核中的表達(dá)水平。在Poly (I:C)刺激24小時(shí)后,更多的p65轉(zhuǎn)移到了細(xì)胞核內(nèi),同時(shí)p65蛋白的表達(dá)水平在核內(nèi)也是高于胞漿。7. Poly (I:C)刺激GH3后,下游腫瘤侵襲相關(guān)蛋白與炎癥因子的分泌增加。我們發(fā)現(xiàn),GH3在Poly(I:C)刺激后MMP9表達(dá)的增加,與體外研究一致,我們發(fā)現(xiàn)在人侵襲性PA病理標(biāo)本中MMP9的表達(dá)水平高于非侵襲性組。NF-κB的激活可導(dǎo)致某些炎癥因子的分泌。Poly(I:C)刺激GH3細(xì)胞后,可導(dǎo)致下游NF-κB的激活。因此我們檢測了 NF-κB轉(zhuǎn)錄調(diào)控的炎癥因子IL-6, IL-1β與TNFα,三者在Poly (I:C)干擾組中分泌均上調(diào)。結(jié)論:1.HPV16, HHV6B的感染率與垂體瘤的侵襲、增殖正相關(guān)。2. TLR3在侵襲性垂體瘤中表達(dá)更高。3.在垂體瘤標(biāo)本中,TLR3的表達(dá)與HPV16, HHV6B的感染率呈正相關(guān)。4.通過病毒類似物Poly (I:C)激活TLR3信號(hào)通路可促進(jìn)大鼠垂體瘤細(xì)胞系GH3的增殖與侵襲。5. NF-κB的激活及其下游調(diào)控的炎癥因子IL-6、IL-1β、TNF-α與MMP9亦參與促進(jìn)GH3細(xì)胞系的增殖和侵襲。
[Abstract]:Background and purpose: pituitary adenomas account for about 15%[1] of intracranial tumors, and their histology is benign, but 25-55% pituitary tumors are infiltrated around the surrounding structures, such as the osseous tissue of the sellar septum, ethmoid sinus and / or cavernous sinus, which are known as invasive pituitary tumor [2][3][4]. pituitary tumor invasiveness and high Ki-67 index, and with severe symptoms, more Poor prognosis, high recurrence rate, and low responsiveness related [5]. studies in drug replacement therapy have shown that chromosomes, genes (such as 11p/q, p53), adhesion molecules (such as: E-cadherin), metal matrix proteins (such as MMP2, MMP8), abnormal changes in inflammatory factors (such as IL-6, IL-17), and the progression of pituitary adenomas, and the invasion of [5][6][7][8][9][10][11]. However, the assessment of its invasive specific histology and molecular biological standards is still lacking. Not only that, the existing studies have explored the invasiveness of the pituitary tumor at several levels, such as its own genes, transcriptional, posttranscriptional modifications, and so on, and rarely study the pituitary tumor focusing on the external environment, such as microbiological infection. Human tumors that affect the development of.15-20% are an important mechanism for the tumor - related [12]. - promoting oncology promoting the development of tumors. Chronic infections often lead to oxidative stress and inflammation, and the infected cells secrete inflammatory factors such as IL-1 beta, IL-6 and TNF- a, and form the inflammatory environment (inflammatory milieu), inflammatory stimuli, and effects. The activation of NF- kappa B, STAT3 and MAPKs signaling pathway promotes tumor development in recent years. It has been found that the pattern recognition receptor (PRRs) is not only expressed in immune cells, but also the most common [14].PRRs in the tumor cells is the Toll like receptor (TLR) family, and a number of members of the family such as TLR2[15], TLR3[16], TLR4[15][17] and so on have been confirmed. It is expressed in some tumors and participates in the occurrence and development of the tumor. The most closely related to the virus infection is TLR3. RNA (dsRNA). The source of the necrotic cells or the associated RNA and the synthesized Poly (I:C) [18][19] are the ligands of TLR3. The dsRNA activable TLR3 formed during the bi-directional transformation of the virus is the type of the virus. A large number of studies (DNA virus, RNA virus, etc.) not related to [20]. have shown that high risk HPV16 has been found to be associated with a variety of human tumors, including cervical cancer [21], oropharyngeal cancer [22], anal cancer [23], and head and neck cancer [24] and so on. Not only so, the HPV16 positive tumor cells in some tumors can be more invasive to the surrounding structures, as well as more distant migration. [21].HHV6 is a B lymphocytic virus, which is closely related to the prognosis of patients with children's lymphoma, while HSV1 is associated with the overall survival of patients with breast cancer, and it is associated with smoking, drinking, HPV infection and other factors that determine the occurrence of [26][27]. in the pituitary tumor, which has not been reported to be associated with a certain viral infection. This study is intended to detect the infection of three HPV16, HSV1, and HHV6B in invasive and non invasive pituitary adenomas and to explore the relationship between viral infection and the invasion and proliferation of pituitary adenomas. In vitro, the molecular mechanism of the action of the virus is explored to provide a clinical prediction for the treatment of invasive pituitary tumors. New ideas. Methods: 1. using immunohistochemistry, nested PCR and other techniques, the expression of HPV16, HSV1, HHV6B DNA, the expression of viral protein in the pathological specimens of pituitary tumor patients,.2. using qRT-PCR and immunohistochemical method to detect the expression of TLR3 mRNA and protein level in the pathological specimens of pituitary tumor patients,.3. using rat pituitary tumor cells. The GH3 cell line was used to explore in vitro the effect of TLR3 on cell invasion, proliferation and molecular mechanisms. Results: 1. HPV16 and HHV6B had higher infection rates in invasive pituitary tumor specimens, the positive detection rate of HPV16 in invasive pituitary tumor was 70%, the positive detection rate of non invasive pituitary tumor was 26.67%, invasive hypophysis. The positive detection rate of HPV 16 in the tumor group was significantly higher than that in the non invasive group (P0.01), the positive detection rate of HHV6B in invasive pituitary tumor was 55.33%, the positive detection rate in non invasive pituitary tumor was 23.33%, the difference was significant (P0.05), the detection rate of HSV1 in invasive pituitary tumor was 50%, and the detection rate of non-invasive pituitary tumor was 30%, the difference was 30%. There was no statistical significance (P0.05). Therefore, HPV16, HHV6B infection was positively related to the invasiveness of pituitary adenomas, while HSV1 infection and pituitary tumor invasiveness were not related to the.2. TLR3 mRNA and protein expression in the invasive group significantly higher than that in the non invasive PA group, and was positively related to the HPV16, HHV6B infection rate. In mRNA level, we detected invasive pituitary tumor groups and in the group of invasive pituitary adenomas. The expression of TLR3,4,7,8,9 in TLRs associated with virus infection in the non invasive pituitary tumor group, our results showed that only TLR3 was different between the invasive and non invasive groups (P0.01). In the invasive group, the expression of TLR3 was increased at the level of mRNA. Then, we also detected the expression of.TLR3 in the TLR3 protein level by immunohistochemical method. The protein was detected in every patient with pituitary adenoma, and TLR3 was expressed in the cytoplasm. By quantitative analysis of the expression of TLR3 protein, we found that the level of TLR3 protein was significantly higher in the invasive group than in the non invasive group (P0.01). The relationship between the expression of TLR3 and the rate of HPV16 and HHV6B infection was analyzed by statistical method, and we found that the relationship between the expression of TLR3 and the rate of HHV6B infection was analyzed. The positive correlation between the virus infection rate and the expression of TLR3.3. TLR3 activates the proliferation of the pituitary tumor cell line GH3. We detected the effect of 200 mu g/ml Poly (I:C) on the GH3 cell line at 8 time points. The growth curve shows that in the time point of analysis, Poly (I:C) can promote the activation of GH3 cell proliferation.4.. The apoptosis of the GH3 cell line and the cell cycle Poly (I:C) treatment group and the control group were found to be less apoptotic cells in the treatment group and more cells in the S phase of the cell cycle. The expression of anti apoptotic Bcl-2 in the Poly (I:C) treatment group increased, and the expression of Caspase 3 promoting apoptotic shear activation was less in the addition of Poly (I:C) group. There was no statistical difference between the apoptotic Bax protein in several treatment groups. At the same time, we detected the protein CyclinD1 that promoted the cell to enter S phase from the G1/G0 phase. We found that the expression of CyclinD1 in the Poly (I:C) treatment group was increased by the activation of.5. TLR3, which could promote the invasion of GH3 cells in pre TLR3-siRNA preconditioning or untreated Tra. In the upper chamber of nswell, the cells that were attacked were stained and counted after the addition of Poly (I:C).48 hours. Statistical analysis showed that the NF- kappa B of the Poly (I:C) treatment group passing through the cells of the upper chamber more downstream of.6. TLR3 was activated and we detected the subcellular localization of the Poly (I:C) stimulation by the immunofluorescence method. The expression level of p65 in the cytoplasm and nucleus was detected. After 24 hours of Poly (I:C) stimulation, more p65 was transferred into the nucleus, and the expression level of p65 protein was also higher than that of.7. Poly (I:C) stimulated GH3 in the nucleus, and the secretion of the downstream tumor invasion related proteins and inflammatory factors increased. We found that GH3 was in Poly (I:C). The increase of MMP9 expression after excitation is consistent with the in vitro study. We found that the expression level of MMP9 in human invasive PA pathological specimens is higher than the activation of.NF- kappa B in the non invasive group, which leads to the secretion of.Poly (I:C) stimulated GH3 cells by some inflammatory factors, which can lead to the activation of the downstream NF- kappa B. Therefore, we detected the inflammatory factors of NF- kappa B transcriptional regulation. IL-6, IL-1 beta and TNF alpha, three in the Poly (I:C) interference group all up regulation. Conclusion: 1.HPV16, the infection rate of HHV6B and the invasion of pituitary tumor, the proliferation of.2. TLR3 in invasive pituitary tumor is higher.3. in the pituitary tumor specimens, TLR3 expression is positively correlated with the infection rate of HPV16, TLR3 signaling pathway can promote the proliferation of rat pituitary tumor cell line GH3 and the activation of.5. NF- kappa B and its downstream regulation of the inflammatory factor IL-6. IL-1 beta, TNF- A and MMP9 also participate in promoting the proliferation and invasion of the GH3 cell line.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R736.4

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5 邢月明;趙新萍;宋翔;吳偉;黃柏;;伽瑪?shù)逗喜⑩?60治療垂體瘤的研究[A];山西省抗癌協(xié)會(huì)第六屆腫瘤學(xué)術(shù)交流會(huì)論文匯編[C];2003年

6 錢偉;黃潤生;房景玉;;伽瑪?shù)吨委煿δ苄源贵w瘤初步報(bào)告[A];2006年浙江省神經(jīng)外科學(xué)術(shù)會(huì)議論文匯編[C];2006年

7 郎黎薇;;應(yīng)用健康咨詢理論輔導(dǎo)垂體瘤術(shù)后的病人[A];全國第三屆重癥監(jiān)護(hù)護(hù)理學(xué)術(shù)交流暨專題講座會(huì)議論文匯編[C];2006年

8 張新文;金心;劉漢江;吳曄;賀軍華;;影響垂體瘤質(zhì)地的相關(guān)因素分析[A];2011年浙江省神經(jīng)外科學(xué)學(xué)術(shù)年會(huì)論文匯編[C];2011年

9 陳曉媛;張秀娟;;垂體瘤并發(fā)糖尿病酮癥酸中毒1例[A];中華醫(yī)學(xué)會(huì)第十一次全國內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2012年

10 谷衛(wèi);;垂體瘤術(shù)前診斷與術(shù)后治療[A];浙江省醫(yī)學(xué)會(huì)神經(jīng)外科學(xué)習(xí)班論文集[C];2012年

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5 劉偉國;巧用內(nèi)窺鏡 摘取垂體瘤[N];健康報(bào);2006年

6 張?zhí)戾a;治療垂體瘤應(yīng)盡早開刀[N];家庭醫(yī)生報(bào);2008年

7 北京三博復(fù)興腦科醫(yī)院　張宏偉;男性垂體瘤莫耽誤治療[N];光明日報(bào);2006年

8 健康時(shí)報(bào)記者　 白軼南;垂體瘤癥狀容易被忽視[N];健康時(shí)報(bào);2006年

9 健康時(shí)報(bào)特約專家 李文良 王鵬;早期垂體瘤治療易延誤[N];健康時(shí)報(bào);2006年

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3 張靖;NEDD4-1、PTEN在垂體瘤中的表達(dá)及作用的研究[D];山東大學(xué);2014年

4 胡吉;垂體瘤組織基因表達(dá)譜及發(fā)病機(jī)制研究[D];復(fù)旦大學(xué);2005年

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2 敖京生;生長抑素受體亞型在垂體瘤中的表達(dá)[D];北京協(xié)和醫(yī)學(xué)院;2011年

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4 劉春生;垂體瘤質(zhì)地的術(shù)前評估和多因素分析[D];山西醫(yī)科大學(xué);2011年

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6 安娟姬;多巴胺D2受體在垂體瘤細(xì)胞凋亡中的作用[D];延邊大學(xué);2002年

7 沈圓圓;鞍區(qū)非垂體瘤病變的鑒別診斷[D];浙江大學(xué);2011年

8 張春泳;垂體瘤中VEGF和NFKBp65的表達(dá)及腫瘤分子生物學(xué)相關(guān)的免疫組織學(xué)研究[D];青島大學(xué);2005年

9 李旭;胰島素樣生長因子-1（IGF-1）在不同類型腦腫瘤患者血清中表達(dá)水平的研究[D];天津醫(yī)科大學(xué);2012年

10 云云;Toll樣受體3介導(dǎo)呼吸道合胞病毒感染的炎癥反應(yīng)[D];安徽醫(yī)科大學(xué);2007年

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