本文選題：胰腺癌 + Hedgehog通路��； 參考：《第二軍醫(yī)大學(xué)》2015年博士論文

【摘要】：研究背景及目的胰腺導(dǎo)管腺癌(pancreatic ductal adenocarcinoma, PDAC)是消化系統(tǒng)常見惡性腫瘤之一,約占胰腺惡性腫瘤的90%以上。既往研究證實,諸如Hedgehog (HH)通路異�；罨�、炎癥和K-ras突變等因素均參與了PDAC的形成過程。HH信號通路參與了胰腺形態(tài)發(fā)生過程,而在大多數(shù)正常胰腺中該通路處于沉默狀態(tài)。但HH通路異�；罨赑DAC中十分常見,且在早期即有表現(xiàn)。HH通路活化機制可大致分為①配體過表達(dá)介導(dǎo)的經(jīng)典活化通路②以信號通路成員突變?yōu)橹鞯姆墙?jīng)典活化通路,其中前者較為常見。在人類,經(jīng)典活化過程由HH通路配體Sonic Hedgehog (Shh)引發(fā),最終導(dǎo)致HH通路核因子glioma-associated oncogene(Gli)家族蛋白入核,啟動對下游基因的調(diào)控。在Gli家族中,Gli1是最主要的活化因子,Gli1入核是HH通路活化的標(biāo)志。研究證實,炎癥和PDAC的發(fā)生密切相關(guān)。核因子-κB (nuclear factor-kappa B, NF-κB)是炎癥反應(yīng)的重要成員,它參與了PDAC的發(fā)生、發(fā)展過程。NF-κB入核,NF-κB通路活化,從而啟動對下游基因的調(diào)控。K-ras突變發(fā)生于PDAC早期。在PDAC中K-ras突變率頗高,可達(dá)75～95%。臨床中發(fā)現(xiàn),K-ras基因突變存在多個位點,但主要集中在第12、13密碼子。K-ras蛋白只有在和三磷酸鳥苷(guanosine triphosphate, GTP)結(jié)合后(K-ras-GTP)才能實現(xiàn)對細(xì)胞活性的調(diào)控。通常情況下K-ras-GTP蛋白會在GTP酶活化蛋白(GTPase-activating proteins, GAPs)的作用下迅速轉(zhuǎn)變成無活性的K-ras-GDP,使K-ras蛋白處于失活狀態(tài)。K-ras基因突變導(dǎo)致K-ras蛋白持續(xù)處于K-ras-GTP狀態(tài),使K-ras蛋白保持活化狀態(tài)。既往研究證實上述三條通路參與PDAC的發(fā)病過程,HH通路和NF-κB間存在相關(guān)性,且NF-κB可活化HH通路,K-ras突變可導(dǎo)致HH通路和NF-κB的活化,但三者間在胰腺癌發(fā)生中相互作用及其機制卻鮮見報道。探討三者之間的相互作用機制,對深入了解PDAC發(fā)病的分子機制,尋求特異、有效的個體化治療方法至關(guān)重要。據(jù)此,本課題開展了以下研究：第一部分PDAC組織和細(xì)胞株中HH與NF-κB通路主要成員表達(dá)和K-ras基因突變的檢測、及三者之間相關(guān)性分析實驗材料、方法：收集32例胰腺癌組織和3株P(guān)DAC細(xì)胞株,采用免疫組化、實時定量PC、western-blot和DNA測序技術(shù),分別檢測Shh蛋白和Gli1、NF-κB核蛋白的表達(dá),以及K-ras基因12和13密碼子突變情況。實驗結(jié)果：在PDAC組織中存在Shh、Gli1和NF-κB表達(dá)量之間的正相關(guān)性,同時這種正相關(guān)性在K-ras突變的狀態(tài)下顯著存在,表明在PDAC發(fā)病中HH和NF-κB通路活化具有顯著正相關(guān)性,并且這種相關(guān)性具有一定的K-ras突變依賴性；PDAC細(xì)胞中可能也存在HH通路和NF-κB通路活化的正相關(guān)性,并且這種相關(guān)性也可能具有一定的K-ras突變依賴性。第二部分PDAC細(xì)胞株中活化NF-κB通路對HH通路的調(diào)控作用觀察,并分析此調(diào)控作用對K-ras突變的依賴性實驗材料、方法：選取K-ras 基因野生(BxPC-3)和突變(Panc-1/12密碼子突變；SW1990/13密碼子突變)PDAC細(xì)胞進(jìn)行干預(yù),活化NF-κB通路的作用研究。對上述細(xì)胞株分別進(jìn)行①白介素-1p(interleukin-1β, IL-1β)②腫瘤壞死因子-α(tumor necrosis factor-a, TNF-a)刺激干預(yù)(以單純培養(yǎng)基處理組作為對照),采用q-PCR、Westernblot方法檢測干預(yù)后Shh, Glil和NF-kB的mRNA和蛋白質(zhì)表達(dá)變化,同時平行檢測干預(yù)后細(xì)胞增殖、凋亡等變化,觀察干預(yù)方法對NF-κB通路本身活化作用以及促進(jìn)HH通路活化的作用效果,并分析這種作用效果與K-ras突變的相關(guān)性。實驗結(jié)果：在K-ras突變的PDAC細(xì)胞株中,干預(yù)活化NF-κB通路后可促進(jìn)HH通路進(jìn)一步高度活化,并同時增強了PDAC細(xì)胞株的惡性細(xì)胞行為特征；但在K-ras野生的PDAC細(xì)胞株中,這種干預(yù)活化的作用效果不顯著。研究表明,在PDAC發(fā)病中NF-κB通路活化可Crosstalk(串話)促進(jìn)HH通路活化,并且此Crosstalk作用具有一定的K-ras突變依賴性。第三部分PDAC細(xì)胞株中活化-HH通路對NF-κB通路的調(diào)控作用觀察、并分析此調(diào)控作用對K-ras突變的依賴性實驗材料、方法：同第二部分研究,選取K-ras基因野生(BxPC-3)和突變(Panc-1/12密碼子突變；SW1990/13密碼子突變)的PDAC細(xì)胞株,分別進(jìn)行①Gli1 cDNA轉(zhuǎn)染過表達(dá)、②配體Shh刺激干預(yù)(以單純培養(yǎng)基處理組作為對照),采用q-PCR、 Westernblot方法檢測干預(yù)后Shh、Gli1和NF-κB的mRNA和蛋白質(zhì)表達(dá)變化,同時平行檢測干預(yù)后細(xì)胞增殖、凋亡等變化,觀察干預(yù)方法對HH通路本身的活化作用以及促進(jìn)NF-κB通路活化的作用效果,并分析這種作用效果與K-ras突變的關(guān)系。實驗結(jié)果：在K-ras突變的PDAC細(xì)胞株中,干預(yù)活化HH通路后可促進(jìn)NF-κB通路進(jìn)一步高度活化,并同時增強了PDAC細(xì)胞株的惡性細(xì)胞行為特征；但在K-ras野生的PDAC細(xì)胞株中,這種干預(yù)活化的作用效果不顯著。研究表明,在PDAC發(fā)病中HH通路活化可Crosstalk (串話)促進(jìn)NF-κB通路活化,并此Crosstalk作用具有一定的K-ras突變依賴性。第四部分PDAC中HH通路和NF-κB通路之間Crosstalk的K-ras突變依賴性的分子機制研究實驗材料、方法：在上述第二和三部分的細(xì)胞干預(yù)實驗基礎(chǔ)上,進(jìn)一步檢測細(xì)胞中K-ras蛋白及活性表達(dá)變化,檢鋇K-ras基因下游基因p-/t-ERK1/2,和p-/t-AKTl的表達(dá)變化,并利用Ras活性檢測試劑盒檢測Ras活性變化,綜合判斷K-ras通路的活化水平變化；同時分別采用RNA干擾技術(shù)(si-Kras)阻斷PDAC細(xì)胞內(nèi)K-ras基因的表達(dá),和采用G12D突變型K-ras基因cDNA質(zhì)粒轉(zhuǎn)染野生型細(xì)胞,觀察這些阻斷和補救的反向措施對K-ras本身活性的干預(yù)成功性,及對Crosstalk相互促進(jìn)活化的影響,進(jìn)一步確定HH和NF-κB通路之間相互促進(jìn)活化的Crosstalk的K-ras突變依賴性的分子機制。實驗結(jié)果：K-ras活性改變是HH和NF-κB通路活化及二者間Corsstalk對K-ras突變依賴的主要分子機制。第五部分PDAC中HH通路和NF-κB通路之間Crosstalk的K-ras突變依賴性的動物研究實驗材料、方法：在細(xì)胞學(xué)研究基礎(chǔ)上,我們進(jìn)行動物實驗,以深入探討HH通路和NF-κB通路之間Crosstalk的K-ras突變依賴性。我們利用①Glil cDNA穩(wěn)轉(zhuǎn)的SW1990細(xì)胞和普通SW1990細(xì)胞種植于胸腺缺失的裸鼠,檢測Gli1和NF-κB核蛋白表達(dá),觀察Gli1過表達(dá),HH通路活化對NF-κB通路的影響；同時平行檢測腫瘤大小,驗證HH通路活化對腫瘤生長的影響；②分別以K-ras基因野生(BxPC-3)和突變(Panc-1/12密碼子突變；SW1990/13密碼子突變)的PDAC細(xì)胞種植于胸腺缺失的裸鼠,成瘤后分別以PBS(對照)、Shh、IL-1β和TNF-a刺激裸鼠,檢測Shh蛋白表達(dá)以及Gli1和NF-κB核蛋白表達(dá),觀察不同K-ras表型細(xì)胞對HH通路和NF-κB通路活化,以及二者間的crosstalk;同時平行檢測腫瘤大小,驗證HH通路和NF-κB通路活化對腫瘤生長的影響。實驗結(jié)果：①K-ras突變的PDAC細(xì)胞中,Gli1過表達(dá)、HH通路活化可促進(jìn)NF-κB通路活化,并促進(jìn)腫瘤生長；②K-ras突變的PDAC細(xì)胞中,存在HH通路和NF-κB通路的crosstalk。研究提示,動物體中,也存在HH通路和NF-κB通路的Crosstalk的K-ras突變依賴性。全文結(jié)論1、PDAC中,K-ras基因12、13密碼子突變在PDAC組織中發(fā)生率高(81.25%)；HH通路和NF-κB通路活化間的顯著正相關(guān)關(guān)系存在K-ras突變依賴性；2、PDAC中,NF-κB通路活化,以及其對HH通路的活化作用存在K-ras突變依賴性；3、PDAC中,HH經(jīng)典活化通路,以及其對NF-κB通路的活化作用存在K-ras突變依賴性；4. PDAC中,K-ras活性改變是PDAC中HH通路和NF-κB活化及二者間相互活化作用K-ras突變依賴性的主要機制；5、動物實驗證實HH經(jīng)典活化通路,NF-κB通路活化,以及二者間相互活化作用的K-ras依賴性。
[Abstract]:Background and objective pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors of the digestive system, accounting for more than 90% of the malignant tumors of the pancreas. Previous studies have confirmed that such as the abnormal activation of the Hedgehog (HH) pathway and the involvement of the.HH signaling pathway in the formation of PDAC, such as inflammation and K-ras mutations, are involved in the process. The process of pancreatic morphogenesis is in silence in most normal pancreas. However, the abnormal activation of HH pathway is very common in PDAC, and in the early stage, the activation mechanism of.HH pathway may be roughly divided into the classical activation pathways mediated by ligand overexpression, the non classical activation pathway, which is the main signal transduction pathway. The former is more common in the former. In humans, the classical activation process is triggered by the HH pathway ligand Sonic Hedgehog (Shh), which eventually leads to the nuclear factor glioma-associated oncogene (Gli) family protein of the HH pathway and the regulation of the downstream genes. In the Gli family, Gli1 is the most important activating factor. Gli1 nucleation is the sign of the activation of the HH pathway. In fact, inflammation is closely related to the occurrence of PDAC. Nuclear factor kappa B (nuclear factor-kappa B, NF- kappa B) is an important member of the inflammatory response. It participates in the occurrence of PDAC. The development process of.NF- kappa B enters the nucleus and NF- kappa B pathway is activated, thus starting to regulate the downstream genes in the early stage. The mutation rate is quite high, up to 75~95 It is found that there are several loci in the K-ras gene mutation, but it is mainly concentrated in the 12,13 codon.K-ras protein only after combining with guanosine triphosphate (GTP) (K-ras-GTP) to realize the regulation of cell activity. In general, K-ras-GTP egg white will be in GTP enzyme activated protein (GTPase-activating proteins, GA). Ps changed rapidly into inactive K-ras-GDP, which made the K-ras protein in the inactivation state of.K-ras gene mutation leading to the continuous K-ras-GTP state of the K-ras protein and the active state of the K-ras protein. The previous study confirmed that the above three pathways were involved in the pathogenesis of PDAC, and there was a correlation between HH path and NF- kappa B, and NF- kappa was activated. K-ras mutation can lead to the activation of HH pathway and NF- kappa B, but the interaction between the three and the pathogenesis of pancreatic cancer is rarely reported. It is very important to explore the mechanism of the interaction between the three and to find out the molecular mechanism of the pathogenesis of PDAC, and to seek specific and effective individualized treatment methods. The first part was the detection of the main members of HH and NF- kappa B pathway in PDAC tissue and cell lines, and the detection of K-ras gene mutation, and the correlation analysis between the three experimental materials. Methods: 32 cases of pancreatic cancer and 3 PDAC cell lines were collected. Immunohistochemistry, real-time quantitative PC, Western-blot and DNA sequencing techniques were used to detect Shh protein and Gli, respectively. 1, NF- kappa B nucleoprotein expression, and mutation of K-ras gene 12 and 13 codon. Experimental results: there is a positive correlation between Shh, Gli1 and NF- kappa B expression in PDAC tissue, and this positive correlation exists in the state of K-ras mutation, indicating that HH and NF- kappa pathway activation has a significant positive correlation in the pathogenesis of PDAC, and This correlation has a certain K-ras mutation dependence, and there may be a positive correlation between the activation of the HH pathway and the NF- kappa B pathway in the PDAC cells, and this correlation may also have a certain K-ras mutation dependence. The regulation of the NF- kappa B pathway in the second part of the PDAC cell line is observed and the regulatory role is analyzed for K. -ras mutation dependent experimental materials, methods: select the K-ras gene wild (BxPC-3) and mutation (Panc-1/12 codon mutation, SW1990/13 codon mutation) PDAC cells to intervene and activate the NF- kappa B pathway. Rosis factor-A, TNF-a) stimulation intervention (with simple culture medium treatment group as control), q-PCR and Westernblot methods were used to detect the changes of mRNA and protein expression in Shh, Glil and NF-kB, parallel detection of cell proliferation, apoptosis and other changes after intervention. The activation of NF- kappa B pathway and the promotion of HH pathway activation were observed. The effect of this effect was analyzed and the correlation between the effect and the K-ras mutation was analyzed. Experimental results: in the PDAC cell line of the K-ras mutation, the intervention of the activation of the NF- kappa B pathway could promote the further activation of the HH pathway and enhance the behavior of the malignant cells of the PDAC cell line, but in the PDAC cell line of the wild K-ras, this intervention The effect of activation was not significant. The study showed that the activation of the NF- kappa B pathway in the pathogenesis of PDAC could promote the activation of the HH pathway, and the action of the Crosstalk had a certain K-ras mutation dependence. The regulation of the -HH pathway in the third part of the PDAC cell line was observed and the regulation of this regulation on K-ras mutation was analyzed. Dependent experimental materials, methods: the same second part of the study, select the K-ras gene wild (BxPC-3) and mutation (Panc-1/12 codon mutation; SW1990/13 codon mutation) PDAC cell lines, respectively, Gli1 cDNA transfection, and ligand Shh stimulation intervention (single pure culture group as the control), q-PCR, Westernblot prescription The changes of mRNA and protein expression of Shh, Gli1 and NF- kappa B were detected after the intervention, and the changes of cell proliferation and apoptosis after intervention were detected parallel. The effect of intervention on the activation of HH pathway itself and the effect of promoting the activation of NF- kappa B pathway were observed, and the relationship between the effect fruit and K-ras mutation was analyzed. The experimental results were in K-ras mutation. In the PDAC cell line, the activation of the activation of the HH pathway promoted the further activation of the NF- kappa B pathway and enhanced the behavioral characteristics of the malignant cells of the PDAC cell line, but the effect of this intervention was not significant in the PDAC cell line of the K-ras wild. The study showed that the HH pathway activation of Crosstalk (crosstalk) promoted NF in the pathogenesis of PDAC. Activation of the kappa B pathway, and this Crosstalk action has a certain K-ras mutation dependence. Fourth part PDAC HH pathway and NF- kappa B pathway in the K-ras mutation dependence of the molecular mechanism of molecular mechanisms to study the experimental materials. Methods: on the basis of the second and third part of the cell intervention experiments, further detection of the cell K-ras protein and activity in the cell The expression changes, the changes in the expression of the downstream gene p-/t-ERK1/2, and p-/t-AKTl of the barium K-ras gene were detected, and the changes in the activity of Ras were detected by the Ras activity detection kit and the activation level of the K-ras pathway was judged, and the RNA interference technique (si-Kras) was used to block the expression of the K-ras gene in the PDAC cell, and the G12D mutant K-ras gene was used. The cDNA plasmid transfected wild type cells, observed the success of the intervention of these blocking and remedial actions on the intervention of K-ras's own activity, and the effect on the mutual promotion of Crosstalk, and further determined the molecular mechanism of K-ras mutation dependence between the HH and the NF- kappa B pathway, which promoted the activation of Crosstalk. The experimental results: K-ras activity change is H. H and NF- kappa B pathway activation and the main molecular mechanism of Corsstalk dependence on K-ras mutation between the two. Fifth the K-ras mutation dependence of Crosstalk between the HH pathway and NF- kappa B pathway in PDAC. Methods: on the basis of cytology, we carried out animal tests to explore the relationship between the HH pathway and the nuclear kappa pathway. Crosstalk K-ras mutation dependence. We use Glil cDNA stable SW1990 cells and common SW1990 cells to grow the nude mice with thymus deletion, detect the expression of Gli1 and NF- kappa B nuclear protein, observe the effect of Gli1 overexpression, HH pathway activation on the NF- kappa pathway, simultaneously detect the size of the tumor and verify the effect of the activation of the pathway on the growth of the tumor. (2) the PDAC cells of K-ras gene wild (BxPC-3) and mutation (Panc-1/12 codon mutation; SW1990/13 codon mutation) were planted in the nude mice of the thymus deletion, and the expression of Shh protein was detected by PBS (control), Shh, IL-1 beta and TNF-a respectively. The expression of Shh protein and the expression of Gli1 and NF- kappa nuclear proteins were detected and the different phenotype cells were observed. The activation of H pathway and NF- kappa B pathway, as well as the crosstalk between the two, simultaneously detected the tumor size, and verified the effect of the activation of the HH pathway and NF- kappa B pathway on the growth of the tumor. In the cell, the crosstalk. study of the HH pathway and the NF- kappa B pathway suggests that there is also a K-ras mutation dependence of Crosstalk in the HH pathway and the NF- kappa B pathway in the animal body. Conclusion 1, PDAC, K-ras gene 12,13 codon mutation occurs in a high rate (81.25%), and there is a significant positive correlation between the activation and the activation of the pathway. Ras mutation dependence; 2, PDAC, the activation of NF- kappa B pathway, and the K-ras mutation dependence on the activation of HH pathway; 3, PDAC, HH classical activation pathway, and the existence of K-ras mutation dependence on the activation of NF- kappa B pathway; in 4. PDAC, the activity change is the activation and the mutual activation of the two. The main mechanisms of K-ras mutation dependence; 5, animal experiments confirmed that the HH classical activation pathway, the activation of the NF- kappa B pathway, and the K-ras dependence of the mutual activation among the two.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R735.9

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10 袁小剛;Hedgehog信號通路在胃癌發(fā)生發(fā)展中的作用及機制探討[D];南昌大學(xué);2011年

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