發(fā)布時間：2018-05-18 17:47

  本文選題：垂體腺瘤 + 白細胞介素-6　； 參考：《山東大學》2016年博士論文

【摘要】：垂體是重要的內(nèi)分泌器官,通過分泌幾個重要的激素:催乳素(PRL),生長激素(GH),促腎上腺皮質(zhì)激素(ACTH),促甲狀腺激素(TSH)等,在機體中發(fā)揮著至關重要的作用。垂體前葉通過調(diào)節(jié)靶腺激素分泌,參與組織器官的正常發(fā)育和生長。垂體的異常嚴重擾亂機體的代謝平衡,不同的器官會有不同程度的異常表現(xiàn)。垂體腺瘤是一種生長在垂體前葉的特殊顱內(nèi)腫瘤,它不只具有一般腫瘤的特征還具有導致內(nèi)分泌紊亂的特點。垂體腺瘤大約占到腦腫瘤的10～20%,為多見的單克隆抗體起源腫瘤,在顱內(nèi)腫瘤中發(fā)病率接近腦膜瘤,排在膠質(zhì)瘤和腦膜瘤后面居第三位。大部分的垂體腺瘤為良性,只有小部分具有侵襲性,其中0.1～0.2%最終癌變,垂體腺癌的惡性程度與其預后密切相關。垂體腺瘤分為功能性腺瘤和非功能性腺瘤兩類,其臨床表現(xiàn)有包括占位效應和內(nèi)分泌損害兩方面。非功能性腺瘤多于功能性腺瘤,在功能性腺瘤當中,發(fā)病率最高為泌乳素腺瘤(PRL型),其下依次為生長激素腺瘤(GH型)、促腎上腺皮質(zhì)激素腺瘤(ACTH型)、促卵泡和黃體生成素腺瘤(FSHLH)。功能性腺瘤的臨床癥狀主要由激素分泌紊亂導致的。兩類腺瘤在生長增大到一定程度時均可引起相應的占位效應。垂體腺瘤由一系列的垂體關鍵基因突變引起,這些基因包括蛋白激酶C(PKC)、p16、GADD45γ等。由于垂體腺瘤臨床表現(xiàn)的變異性和腫瘤的生長不可預測性,引發(fā)了眾多研究者的的持續(xù)關注。以往的研究表明,垂體腺瘤可以從不同的角度對身體的發(fā)育和生長產(chǎn)生負面的影響。垂體腺瘤引起的過量激素分泌會產(chǎn)生一系列代謝紊亂及臟器損傷。另一方面,由于腫瘤的壓迫,引起其他激素分泌的降低,會導致靶腺功能的下降。目前,對垂體腺瘤的化療及手術治療的研究已經(jīng)有大量的報道。已有的分子生物學研究表明,某些調(diào)控因子的基因和蛋白表達在垂體腺瘤中起著至關重要的作用。研究發(fā)現(xiàn)p53對垂體腺瘤的發(fā)生有著抑制作用,這種抑制作用可以被多形性腺瘤基因(pleomorphic adenoma gene-like 1,PLAGL1)與 RPRM,P21及佛波醇12肉豆蔻酸13醋酸酯誘導蛋白(phorbol-12-myristate-13-acetate-induced Protein 1,PMAIP1)的聯(lián)合作用所破壞。眾所周知GADD45β的過度表達可以通過激活細胞凋亡抑制因子抑制腫瘤的生長,這表明Gadd45β可能對垂體腺瘤也有潛在的抑制作用。垂體腺瘤可導致多種基因表達水平的升高或下降,其中大部分的變化也顯示對腫瘤發(fā)生的調(diào)控作用。雖然一些研究報告涉及到了垂體腺瘤對潛在靶基因的影響,到目前為止仍沒有滿意的解決方法系統(tǒng)性的通過對高通量數(shù)據(jù)分析的方法,對基因表達庫進行研究以分析垂體腺瘤引起的基因和蛋白表達差異。本研究旨在通過基因表達譜分析將垂體腺瘤與正常垂體對照研究,以探討相關基因表達的類型和變化。之后,通過建立蛋白質(zhì)相互作用(PPI)的差異表達基因網(wǎng)絡(DEGs),分析了垂體腺瘤差異性表達基因的影響以及不同的差異性蛋白質(zhì)之間的相互作用。研究的目的是通過在正常垂體及垂體腺瘤篩選差異表達基因及其蛋白產(chǎn)物,分析它們之間的相互作用,以研究垂體腺瘤的發(fā)病機理。通過搜集公共功能基因組學數(shù)據(jù)存儲庫(public functional genomics data repository)的基因表達譜(gene expression profiling),篩選出正常垂體及垂體腺瘤之間的差異表達基因(differential expressed genes,DEGs)�；虮磉_譜數(shù)據(jù)集GSE26966下載于功能性基因組數(shù)據(jù)庫GEO。在納入研究的23個樣品中,9個樣本取自正常垂體及14個樣本取自垂體腺瘤。所有探針集的注釋信息由Afffymetrix 人類基因組 u133a2.0 陣列(Affmetrix Human Genome U133 Plus 2.0 Array)提供。在數(shù)據(jù)處理和差異表達分析時,把CEL文件中探針水平的數(shù)據(jù)通過affy包系統(tǒng)的穩(wěn)健多元陣列平均函數(shù)(robust multi-array average,RMA)轉(zhuǎn)換成探針表達式值矩陣,并通過該數(shù)據(jù)集的芯片平臺R/Bioconductor注解包將編碼轉(zhuǎn)變?yōu)榛蛎Q。由于一個基因有許多相應的探針,最終將所有探針的表達式值的平均值通過計算(歸一化)對應同一個基因的表達值。垂體腺瘤和正常垂體對比的差異表達基因(DEGs)通過R軟件limma包的貝葉斯線性模型識別,只有 log fold change(LFC)值1.5 和錯誤發(fā)現(xiàn)率(false discovery rate,FDR)為校正的P0.05的基因才被選擇為差異表達基因(DEGs)。為了確保篩選的差異表達基因(DEGs)可以很好的體現(xiàn)樣本特征,本研究對差異表達基因(DEGs)進行了聚類分析并且繪制了聚類圖。上調(diào)和下調(diào)的差異性表達基因功能則是通過對基因本體(gene ontology GO)的功能富集分析進行進一步的研究。之后,基因序列被映射到數(shù)據(jù)庫,構建成上調(diào)和下調(diào)的差異性表達基因的蛋白質(zhì)相互作用(protein-protein interactionPPI)網(wǎng)絡。研究發(fā)現(xiàn)下調(diào)差異表達基因(DEGs)的PPI網(wǎng)絡表現(xiàn)出相對集中的特點,網(wǎng)絡中一些節(jié)點蛋白如EGR1,STAT3,JUNB和FOS都是癌癥中常見的轉(zhuǎn)錄因子。相對的,上調(diào)差異表達基因(DEGs)的PPI網(wǎng)絡表現(xiàn)出稀疏的狀態(tài)。通過這兩個PPI網(wǎng)絡之間的比較,證明下調(diào)基因在垂體腺瘤中起著主要作用。最后,對下調(diào)的差異表達基因的蛋白質(zhì)相互作用(PPI)網(wǎng)絡的功能模塊進行分析。本研究在正常垂體和垂體腺瘤樣本間一共篩選出211個上調(diào)和413個下調(diào)差異表達基因。通過GO富集分析PPI網(wǎng)絡建立,發(fā)現(xiàn)下調(diào)的差異表達基因與免疫反應、激素調(diào)節(jié)和細胞增殖等功能相關。上調(diào)的差異性表達基因與陽離子轉(zhuǎn)運功能相關。從下調(diào)的差異表達基因的PPI網(wǎng)絡獲得五個模塊。其中四個具有明顯的生物學作用,其中的轉(zhuǎn)錄因子,如IL-6,STAT3,BCL6,EGR1,POU1F1,JunB和Fos是這些功能模塊的核心節(jié)點。本研究通過對正常垂體和垂體腺瘤基因表達譜和PPI網(wǎng)絡的篩選成功地找到差異表達基因及其相關的蛋白質(zhì)。結果表明,激素和免疫相關基因的低表達促進垂體腺瘤的發(fā)生。低表達的IL6和STAT3在垂體腺瘤的免疫異常中扮演了關鍵的角色。同時,POU1F1低表達導致垂體激素分泌的減少,是垂體腺瘤的重要誘因。垂體腺瘤理想治療目標為調(diào)整患者激素水平至正常范圍,消除瘤體對周圍組織的壓迫,緩解瘤體在顱內(nèi)誘發(fā)的不良癥狀及體征等。目前臨床上垂體腺瘤常用的治療方案為手術切除和放射治療,但二者在實際臨床應用中均存在一定的局限性。手術切除作為垂體腺瘤臨床治療的首選方案,雖然能有效緩解瘤體對周圍組織的壓迫,下調(diào)患者激素水平,但若瘤體切除不完全或腫瘤已出現(xiàn)周圍組織侵犯,可導致手術的風險性增加,誘發(fā)諸多并發(fā)癥并易發(fā)生術后復發(fā)。放射治療主要用于術后復發(fā)、殘留及不耐受或拒絕手術患者,作為垂體腺瘤治療的二線方案,放射治療可抑制腫瘤的生長,恢復患者激素分泌水平,但治療周期較長,且有研究顯示放射治療可誘發(fā)垂體功能減退,損傷顱內(nèi)神經(jīng)細胞,嚴重時還可導致惡性腫瘤的發(fā)生。因此結合患者的臨床病理特征,權衡利弊選擇合理的治療方案對垂體腺瘤患者預后改善有著重要意義。研究證實腫瘤的發(fā)生發(fā)展是一個復雜、多步驟的連續(xù)過程,免疫逃逸作為腫瘤惡化進展的關鍵,目前普遍認為其與腫瘤周圍微環(huán)境的改變有關[1]。正常狀態(tài)下,免疫系統(tǒng)的淋巴細胞可通過抗原識別完成對惡變細胞和自體細胞的有效區(qū)分,但在腫瘤細胞中,它一方面可通過降低或沉默自身免疫原性來躲避免疫系統(tǒng)的抗原識別;另一方面它可激活免疫抑制細胞如調(diào)節(jié)性T細胞(Treg)和調(diào)節(jié)性B細胞(Breg),誘導分泌免疫抑制細胞因子如TGF-β和IL-10[2],在腫瘤病灶組織周圍形成免疫抑制網(wǎng)絡最終實現(xiàn)免疫逃逸。對Treg細胞在腫瘤發(fā)生發(fā)展中的作用國內(nèi)外學者已展開的大量的研究,Breg細胞作為另一大類具有特殊免疫抑制功能細胞,以往研究多集中在自身免疫性疾病、移植免疫耐受、感染與炎癥反應等方面,但伴隨研究深入,發(fā)現(xiàn)Breg細胞也參與促腫瘤的生長及轉(zhuǎn)移[3,4]。包括皮膚良性腫瘤的發(fā)生、抑制T淋巴細胞的抗腫瘤效應、抑制肝癌細胞的凋亡、增強肝癌細胞的增殖和遷移活性。臨床研究也證實在卵巢癌、胃癌、肺癌、胰腺癌、乳腺癌等惡性實體瘤中可見Bregs細胞的浸潤并與腫瘤微環(huán)境的免疫抑制及腫瘤的惡性侵襲密切相關。鑒于Bregs在腫瘤進展中的重要作用,針對Bregs的靶向藥物研究成為目前的關注熱點,尤其是腫瘤局部浸潤Bregs,通過直接干預Bregs活化數(shù)量消除其負性調(diào)控,或間接抑制Bregs分泌的細胞因子恢復免疫監(jiān)視功能發(fā)揮抗腫瘤效應,成為目前腫瘤治療研究的新型靶向。B10細胞作為Bregs的亞型,研究顯示這一類含量稀少表型特殊的B細胞在腫瘤逃逸過程中有著重要作用,包括參與CLL免疫抑制調(diào)控[11]、胰腺癌的進展過程[12]。研究證實放射治療過程中腫瘤細胞的凋亡可導致腫瘤抗原的釋放進而激活機體的先天免疫信號[13],并伴隨腫瘤微環(huán)境免疫抑制的減弱[14]。這也提示我們在垂體腺瘤反射治療過程中,是否同樣存在B10細胞的變化,因此圍繞垂體腺瘤放療患者組織內(nèi)B10細胞變化我們展開了相關研究,收集復發(fā)垂體腺瘤患者48例,23例術前接受放射治療,25例未接受治療,患者經(jīng)手術摘除垂體腺瘤后,通過檢測垂體腺瘤患者組織CD19+CD1d+CD5+和B10細胞亞群比例,測定垂體腺瘤患者組織miR-98和HDAC1 mRNA表達,明確放射治療過程中垂體腺瘤患者組織B10細胞變化特點。研究發(fā)現(xiàn)放射治療可下調(diào)垂體腺瘤患者組織中B10細胞及其亞群CD19+CD1d+CD5+和CD19+CD24+CD38+數(shù)量及分布頻率;放射治療垂體腺瘤患者組織中miR-98 mRNA表達顯著上調(diào),提示放射治療可促進miR-98表達,miR-98表達上調(diào)可抑制IL-10轉(zhuǎn)錄,進而影響B(tài)10細胞免疫抑制功能。
[Abstract]:The pituitary gland is an important endocrine organ, which plays a vital role in the body by secreting a few important hormones, such as PRL, GH, ACTH, and TSH. The anterior pituitary is involved in the normal development and growth of the tissues and organs by regulating the secretion of the target gland hormone. The pituitary adenoma is a special intracranial tumor that grows in the anterior pituitary. It is not only characteristic of the general tumor, but also has the characteristics of endocrine disorder. The pituitary adenoma accounts for about 10 to 20% of the brain tumor, which is a common monoclonal antibody. The incidence of tumor origin is close to meningioma in intracranial tumors and third in glioma and meningioma. Most pituitary adenomas are benign, only a small part is invasive, of which 0.1 to 0.2% are eventually cancerous, and the malignancy of pituitary adenocarcinoma is closely related to the prognosis. Pituitary adenomas are divided into functional adenomas and nonfunctional glands. There are two types of tumor, including two aspects of space occupying effect and endocrine damage. Nonfunctional adenomas are more than functional adenomas. Among functional adenomas, the highest incidence is prolactin adenoma (type PRL), which is followed by growth hormone adenoma (type GH), adrenocorticotropic hormone adenoma (ACTH type), follicle promoting and luteinizing adenoma (FSH LH. The clinical symptoms of functional adenomas are mainly caused by hormonal disorder. The two types of adenomas may cause the corresponding occupying effect when the growth is increased to a certain extent. Pituitary adenomas are caused by a series of mutations in the key pituitary genes, including protein kinase C (PKC), p16, GADD45 gamma, and so on. The unpredictability of the growth of the heterosexual and tumor growth has led to the continuous attention of many researchers. Previous studies have shown that pituitary adenomas can have a negative impact on the development and growth of the body from different angles. The excessive hormone secretion caused by pituitary adenomas may produce a series of metabolic disorders and organ damage. On the other hand, the swelling is due to swelling. The pressure of the tumor, causing the decrease of other hormone secretion, will lead to the decline of the function of the target gland. At present, there have been a lot of reports on the chemotherapy and surgical treatment of pituitary adenomas. Molecular biology studies have shown that the gene and protein expression of some regulatory factors play a vital role in pituitary adenomas. Research has found that p53 It has an inhibitory effect on the occurrence of pituitary adenomas, which can be destroyed by the combination of the pleomorphic adenoma gene-like 1, PLAGL1 and RPRM, P21 and the 12 myristic acid 13 acetate induced protein (phorbol-12-myristate-13-acetate-induced Protein 1, PMAIP1). Overexpression can inhibit tumor growth by activating the inhibitory factor of apoptosis, which suggests that Gadd45 beta may also have a potential inhibitory effect on pituitary adenomas. Pituitary adenomas may lead to a rise or decline in a variety of gene expression levels, and most of the changes also indicate the regulatory role of the tumor. The effect of pituitary adenoma on potential target genes has not been satisfactorily solved so far. The gene and protein expression differences caused by pituitary adenomas are analyzed by the method of high throughput data analysis to analyze the difference in gene and protein expression caused by pituitary adenomas. Normal pituitary control study to explore the types and changes of related gene expression. After that, the differential expression gene network (DEGs) of protein interaction (PPI) was established to analyze the influence of differentially expressed genes in pituitary adenomas and the interaction between different differential proteins. The purpose of this study was to pass through the normal pituitary and drooping. Body adenoma screening differentially expressed genes and their protein products to analyze the interaction between them in order to study the pathogenesis of pituitary adenomas. By collecting the gene expression profiles (gene expression profiling) of the public functional genomics data repository (gene expression profiling), the normal pituitary gland and the pituitary gland were screened. The differential expression gene (differential expressed genes, DEGs). The gene expression profile data set GSE26966 was downloaded from the functional genomic database GEO. in the 23 samples taken into the study. 9 samples were taken from the normal pituitary and 14 samples were taken from the pituitary adenoma. The annotation information of all the probe sets was derived from the Afffymetrix human genome u133a2. The.0 array (Affmetrix Human Genome U133 Plus 2 Array) is provided. In data processing and differential expression analysis, the probe level data in the CEL file is converted to the probe expression value matrix through the robust multivariate array average function of the Affy packet system (robust multi-array average,) and through the chip platform of the data set The uctor annotated packet transforms the encoding into a gene name. As a gene has a number of corresponding probes, the average value of the expression value of all probes is finally calculated (normalized) to correspond to the expression value of the same gene. The differential expression gene (DEGs) of the pituitary adenoma and the normal pituitary (DEGs) is used by the Bayesian linear model of the R software package. Identification, only the log fold change (LFC) value 1.5 and the error discovery rate (false discovery rate, FDR) are selected as the differentially expressed genes (DEGs). In order to ensure that the selected differentially expressed genes (DEGs) can well reflect the sample characteristics, the differentially expressed genes (DEGs) are cluster analysis and plotted in this study. The function of differentially expressed genes between up and down is further studied by the functional enrichment analysis of gene ontology GO. After that, the gene sequence is mapped to the database to construct the protein interaction (protein-protein interactionPPI) network of up and down differentially expressed genes (protein-protein interactionPPI). The study found that the PPI network that down regulated differentially expressed genes (DEGs) showed a relatively concentrated characteristic. Some of the nodes in the network, such as EGR1, STAT3, JUNB and FOS, were common transcription factors in cancer. Relative, the PPI network up regulating the differential expression gene (DEGs) showed a sparse state. By comparison of these two PPI networks Down regulated genes play a major role in pituitary adenomas. Finally, the functional modules of the protein interaction (PPI) network of down regulated differentially expressed genes were analyzed. In this study, 211 up-regulated and 413 down regulated differentially expressed genes were screened in normal pituitary and pituitary adenoma samples. The PPI network was established by GO enrichment analysis. The down regulated differentially expressed genes were related to the functions of the immune response, hormone regulation and cell proliferation. The up-regulated differentially expressed genes were related to the cation transport function. Five modules were obtained from the PPI network of down regulated differentially expressed genes. Four of them had obvious biological use, such as the transcription factors, such as IL-6, STAT3, BCL6, E. GR1, POU1F1, JunB and Fos are the core nodes of these functional modules. This study successfully found differentially expressed genes and related proteins by screening gene expression profiles and PPI networks of normal pituitary and pituitary adenomas. The results showed that the low expression of hormone and immune related genes promoted the occurrence of pituitary adenomas. Low expression of IL6 and STAT. 3 plays a key role in the immune abnormality of pituitary adenoma. At the same time, the low expression of POU1F1 leads to the decrease of pituitary hormone secretion. It is an important cause of pituitary adenoma. The ideal treatment of pituitary adenoma is to adjust the level of the hormone to the normal range, eliminate the oppression of the tumor body to the surrounding tissue and alleviate the adverse symptoms induced by the tumor in the intracranial. At present, surgical resection and radiotherapy are commonly used in the clinical treatment of pituitary adenomas, but there are some limitations in the actual clinical application of the two. Surgical excision is the first choice for clinical treatment of pituitary adenomas, although it can effectively alleviate the compression of the surrounding tissue and reduce the level of the hormone in the patient, but if the tumor is tumor An incomplete resection of the body or an invasion of the surrounding tissue may lead to an increase in the risk of surgery, a number of complications and postoperative recurrence. Radiation therapy is mainly used for postoperative recurrence, residual and intolerance or rejection of the operation, as a second line of pituitary adenoma treatment. Radiation therapy can inhibit the growth of the tumor and restore the patient. The level of hormone secretion is long, but the treatment cycle is longer, and there are studies showing that radiation therapy can induce hypophysis dysfunction and injury of intracranial nerve cells, and it can also lead to malignant tumor. Therefore, combining the clinicopathological features of the patients, choosing a reasonable treatment scheme to weigh the advantages and disadvantages is important to improve the prognosis of pituitary adenoma patients. Research confirms that the development of tumor is a complex, multi step process. Immune escape is the key to the progression of cancer. It is generally believed that it is related to the change of the microenvironment around the tumor, which is related to the normal state of [1].. The lymphocyte of the immune system can be used to complete the effective cells and autologous cells through the antigen recognition. But in tumor cells, it can avoid the antigen recognition of the immune system by reducing or silent autoimmunity, on the other hand, it activates the immunosuppressive cells such as regulatory T cells (Treg) and regulatory B cells (Breg), inducing secretory cytokines such as TGF- beta and IL-10[2], around the tumor tissue. The formation of immunosuppressive networks finally realizes immune escape. The role of Treg cells in the development of tumors has been extensively studied by domestic and foreign scholars. Breg cells have special immunosuppressive functions as another major class. Previous studies focused on autoimmune diseases, transplantation immune tolerance, infection and inflammation, and so on. However, with the further study, it is found that Breg cells also participate in the growth of tumor and the metastasis of [3,4]. including benign tumor of the skin, inhibit the anti-tumor effect of T lymphocyte, inhibit the apoptosis of hepatoma cells, enhance the proliferation and migration activity of the hepatoma cells. The clinical study also confirmed that the malignant tumor, gastric cancer, lung cancer, pancreatic cancer, and breast cancer are malignant. The infiltration of Bregs cells in solid tumors is closely related to the immunosuppression of the tumor microenvironment and the malignant invasion of the tumor. In view of the important role of Bregs in the progression of the tumor, the research on targeted drugs for Bregs has become the focus of attention, especially the local infiltration of Bregs in the tumor, and to eliminate the negative effects of the number of Bregs activated by direct intervention in the number of Bregs. The regulation, or the indirect inhibition of the cytokines secreted by Bregs to restore the immune surveillance function to play an antitumor effect, has become a new target.B10 cell for cancer therapy as a subtype of Bregs. The study shows that this kind of rare B cells with rare phenotypes have an important role in the process of tumor escape, including participation in the CLL immune suppression. [11], the progress of pancreatic cancer [12]. research confirms that the apoptosis of tumor cells in the course of radiation therapy can lead to the release of tumor antigen and then activate the organism's innate immune signal [13], and with the decrease of [14]. in the tumor microenvironment immunity inhibition, it also suggests that we also have B10 cells in the process of pituitary adenoma counter shoot treatment. The changes of B10 cells in the tissue of patients with pituitary adenoma were studied, 48 cases of recurrent pituitary adenomas were collected, 23 patients received radiotherapy before operation, 25 cases were untreated. After surgical removal of pituitary adenomas, the proportion of CD19+CD1d+CD5+ and B10 cell subgroups in the pituitary adenoma was detected by detecting the pituitary adenoma. The expression of miR-98 and HDAC1 mRNA in the tissue of pituitary adenoma was determined and the characteristics of B10 cell changes in the tissue of pituitary adenoma patients were determined. The study found that radiation therapy could reduce the number and frequency of B10 cells and their subgroups CD19+CD1d+CD5+ and CD19+CD24+CD38+ in the tissues of pituitary adenomas; radiation therapy for pituitary adenoma patients group. The expression of miR-98 mRNA was significantly up-regulated, suggesting that radiotherapy can promote the expression of miR-98. Up regulation of miR-98 can inhibit the transcription of IL-10 and further affect B10.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R736.4

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