胶毒霉素对肿瘤相关成纤维细胞生物学效应的影响及其机制初探

发布时间：2018-07-08 15:34

  本文选题：胶毒霉素 + 肿瘤相关成纤维细胞　； 参考：《兰州大学》2015年硕士论文

【摘要】：研究背景及目的：肝细胞肝癌(hepatocellular carcinoma, HCC)是最常见的原发性肝肿瘤。许多国家HCC的发病率逐年上升,死亡率居高不下。研究认为,肝脏微环境的改变已经成为HCC的病理标志之一,80%以上的HCC是由慢性肝炎-肝纤维化-肝硬化“三部曲”演变而来,同时炎症反应和细胞外基质沉积很大程度上改变了肝脏微环境。近些年,高通量的基因组分析已经逐渐阐明了与HCC发生发展密切相关的基因网络以及信号转导通路,某些重要基因成为肿瘤治疗药物的靶点。但是,HCC的复发和转移仍然困扰着我们,其原因可能与肝癌微环境相关。因此,寻找靶向微环境的药物是我们面临的挑战。肿瘤相关成纤维细胞(tumor associated fibroblasts, TAFs)是肿瘤微环境的主要细胞组分之一,它是由肝星状细胞和肝成纤维细胞等基质细胞演变而来,参与维持肿瘤的标志性特征。同时,TAFs可以增强肿瘤细胞的耐药能力。既往研究发现,胶毒霉素(Gliotoxin)可通过诱导肝星状细胞(hepatic stellate cell, HSC)凋亡而显著减轻肝纤维化。低浓度的Gliotoxin (0.1 μM)即可诱导HSC凋亡,而对正常肝细胞无明显损伤,只有当浓度达到30-50 μM时方可引起正常肝细胞坏死。我们近期的实验结果证实低浓度Gliotoxin(IC50=143.1 nM)即可显著抑制TAFs增殖。既然Gliotoxin对肝星状细胞(TAFs的主要来源之一)有很强的杀伤效果,我们推测Gliotoxin可能通过作用于微环境从而对HCC有治疗作用。为了验证这一推论,本研究将从以下两方面展开：首先,分离培养并鉴定人HCC来源的TAFS,观察Gliotoxin对TAFs生物学特性的影响以及凋亡诱导作用；进一步检测Gliotoxin对TGF-β通路及其下游基因的作用；建立TAFs与肝癌细胞株的共培养体系,观察Gliotoxin对共培养细胞的作用其次,建立DEN诱导原发性肝癌模型,研究Gliotoxin对HCC的治疗作用。该研究将肿瘤微环境作为治疗HCC的靶点之一,可能为临床上HCC的治疗提供新的理论依据。实验方法：1.Gliotoxin对TAFs的作用：①分离并鉴定TAFs,将人HCC组织切成2 mm3大小,胶原酶Ⅳ消化、梯度离心后得到TAFs,进一步纯化成纤维细胞。细胞免疫荧光检测α-SMA、Vimentin、Desmin的表达。②Gliotoxin对TAFs生物学效应的影响,体外研究不同浓度Gliotoxin对TAF增殖及迁移的作用：将TAFs以3×103/孔的数量置于96孔板中,加入不同浓度的Gliotoxin培养6天,第6天单荧光素报告基因检测TAFs的增殖情况,计算IC50；选定Gliotoxin合适浓度(100nM)溶于含3%胎牛血清(FBS)的培养基中并加入24孔板,计数5×104的TAFs接种于Transwell小室,24小时后结晶紫固定、拍照,利用ImagePro软件计算TAFs的迁移情况。2.Gliotoxin对TAFs凋亡的诱导作用：①100nM的Gliotoxin处理TAFs后,利用Caspase3荧光试剂盒检测不同时间点TAFs由Caspase3的表达,通过计算Caspase3活性增高倍数评价Gliotoxin对TAFs凋亡的作用。②100nM的Gliotoxin处理TAFs,4小时后收集细胞。Annexin V与碘化吡啶(PI)标记TAFs,流式细胞仪检测凋亡情况,重点分析Gliotoxin对早期凋亡的影响。③不同浓度(0、30 nM、100n M、300 nM)的Gliotoxin处理TAFs,在不同时间点(15 min、30min、 60min、120min、180 min)检测ATP的表达量,分析Gliotoxin对ATP的消耗能力。3.Gliotoxin对TAFs作用机制的初步探讨：①TAFs培养基中加入100nM的Gliotoxin,48小时后提取细胞RNA,使用逆转录试剂盒将RNA逆转为cDNA, Real-time PCR检测TAFs相关标记物-SMA、Vimentin、Desmin、纤维细胞相关蛋白(FAP)以及TGF-β通路下游基因(C-myc、Smad5、AP-1、SP-1、Bcl-2)的表达。②TAFs培养基中分别加入0 nM、30nM、100 nM、300 nM的Gliotoxin,4小时后收集蛋白,定量后western-blot检测TGF-β通路Smad蛋白家族的活化情况；另一组TAFs于24小时后检测TGF-β通路报告基因3TP的荧光表达。4.Gliotoxin对TAFs-肝肿瘤细胞共培养系统的作用：①Gliotoxin处理TAFs后,收集细胞培养上清,同时获取正常培养基、成纤维细胞株(normal fibroblasts, NFs)、TAFs培养上清作为条件培养基。将Hep3B细胞(3x103/孔)分到96孔板,加入条件培养基,CCK-8法检测细胞增殖情况。②24孔板下层加入正常、NFs、TAFs、TAFs-Gliotoxin的条件培养基,transwell小室中加入SMMC-7721细胞(5×104),24小时后结晶紫染色,拍照、计数迁移细胞。5. Gliotoxin对DEN肝癌模型的治疗作用：①Gliotoxin治疗肝癌的效果评估,22周处死所有大鼠,大鼠肝脏给予门静脉生理盐水灌注,取出肝脏。观察肝脏外观的变化。取组织制作石蜡切片,切片后进行HE染色,评估Gliotoxin对肝癌的治疗效果。②Gliotoxin对肝脏纤维化的影响,利用Masson和天狼星红对肝脏组织进行染色,观察胶原的分布情况。图像扫描并计算胶原分布面积；免疫组织化学检测组织中a-SMA的表达。6.统计学处理：数据采用SPSS 16.0统计软件包进行分析,结果以X±SD表示。多组间采用One-Way ANOVA方差分析,P0.05为统计结果具有显著性差异。实验结果：Gliotoxin具有抑制TAFs的作用：①细胞免疫荧光检测发现TAFs表达α-SMA、Desmin与Vimentin,其中a-SMA与vimentin在所有TAFs中均表达。而Desmin只在部分TAFs中表达。②Gliotoxin浓度低于50 nM时对细胞无明显的杀伤效应。当Gliotoxin浓度在50-400 nM之间时,TAFs的存活率随着药物浓度的升高而迅速降低。根据药敏试验的曲线得到Gliotoxin对TAFs的IC50为147.1 nM.③ Gliotoxin可以抑制TAFs的迁移。30 nM的Gliotoxin即对TAFs的迁移具有一定的抑制作用。100 nM的Gliotoxin处理TAFs可以使TAFs的迁移数量降低至对照组的一半。当Gliotoxin浓度提升至300 nM后,迁移抑制率约为90%。④Gliotoxin促进TAFs凋亡。1)100nM的Gliotoxin处理TAFs后,Caspase3活性检测结果发现,15min开始Caspase3的活性已经开始增加,并且具有一定时间依赖性。180分钟是Caspase3活性最高,为对照组的25倍以上。2)100nM的Gliotoxin处理TAFs,4小时后利用流式细胞仪检测TAFs凋亡情况,结果显示早期凋亡由10.83%增加至16.23%,说明Gliotoxin可以促进TAFs的凋亡。3)ATP含量测试实验表明60分钟时,300nM Gliotoxin处理的TAFs开始消耗ATP,此时中低浓度组的ATP含量无明显变化。120分钟后,100nM Gliotoxin处理TAFs的ATP含量开始下降,而300nM浓度Gliotoxin处理组ATP含量降低幅度已经超过50%。4小时后中、高浓度组的ATP持续维持在低水平。⑤Gliotoxin抑制TAFs中TGF-P通路的活化不同浓度Gliotoxin处理TAFs,4小时后收集蛋白检测TGF-β通路活化情况,我们发现Smad2与Smad3表达无明显差别,但是Smad2/3磷酸化水平显著下降。另外,我们利用TGF-β通路报告基因检测该通路的活化情况,发现Gliotoxin可以抑制TGF-β通路报告基因荧光素酶的含量。利用Real-time PCR检测TGF-β通路下游基因表达,发现Gliotoxin处理后通路下游基因C-myc、Bcl-2以及AP-1表达下调。同时TAFs标记物α-SMA、Desmin、 Vimentin与FAP表达下调。⑥Gliotoxin对TAFs-肝肿瘤细胞共培养系统的作用。1)我们利用NFs、TAFs、TAFs-Gliotoxin的细胞培养上清处理Hep3B细胞,在不同时间点检测肿瘤细胞的数量,结果发现NFs、TAFs均可促进肿瘤细胞株的增殖,但是TAFs的促增殖能力更强,如果TAFs经Gliotoxin处理,它的促增殖能力有所下降,与NFs水平相近。2)NFs促进肿瘤细胞株SMMC-7721迁移的能力较弱,TAFs则显著增强7721细胞的迁移。Gliotoxin可以部分抑制TAFs的促迁移作用。Gliotoxin对DEN肝癌模型的治疗作用：①Gliotoxin治疗肝癌的效果评估。22周处死所有大鼠,取出肝脏。大体观察各处理组肝脏的变化。发现模型组和溶剂对照组肝脏已经出现多发的肝癌结节,或表面出现肿瘤肿块,同时肝硬化程度较重。Gliotoxin治疗组大鼠未见肿瘤肿块。HE染色后评估Gliotoxin对肝癌的治疗效果。结果显示：模型组有6只大鼠被诊断为肝细胞癌,两只大鼠为重度不典型增生；DMSO组5只大鼠被诊断为肝细胞癌,其余为不典型增生。肝细胞癌多数为中高分化,两组中各有一只为低分化肿瘤；Gliotoxin治疗组(0.5mg/kg与1.5mg/kg)各有1只大鼠被诊断为高分化癌,其余均为不典型增生和肝硬化。②Gliotoxin对肝脏纤维化的影响。利用Masson和天狼星红对肝脏组织进行染色,观察胶原的分布情况。结果显示模型组及DMSO组胶原的表达未见明显差异,Gliotoxin治疗组特殊染色面积显著下降。免疫组织化学检测检测α-SMA的表达,发现α-SMA在模型组与治疗组的表达出现显著差异,Gliotoxin治疗组α-SMA表达范围局限于汇管区,而模型组α-SMA表达范围较大,已经延伸至肝细胞所在区域。结论：1. Gliotoxin抑制TAFs的增殖、迁移,促进TAFs的凋亡。2. Gliotoxin对TAFs的抑制作用与TGF-β通路有关。3. Gliotoxin抑制实验性肝癌的进展。
[Abstract]:Research background and objective: hepatocellular carcinoma (HCC) is the most common primary liver tumor. The incidence of HCC is rising year by year in many countries, and the mortality rate is high. It is considered that the change of liver microenvironment has become one of the pathological signs of HCC, and more than 80% of HCC is from chronic hepatitis liver fibrosis liver cirrhosis " The trilogy evolved, and the inflammatory response and extracellular matrix deposition greatly changed the liver microenvironment. In recent years, high throughput genome analysis has gradually elucidated the genetic network and signal transduction pathway closely related to the development of HCC, and some important genes have become the target of cancer therapy. But, HCC The recurrence and metastasis still perplex us, which may be related to the microenvironment of liver cancer. Therefore, the challenge to find the targeted microenvironment is the challenge we face. The tumor associated fibroblasts (TAFs) is one of the main cell components of the tumor microenvironment, which is composed of hepatic stellate cells and hepatic fibroblasts. The stromal cells evolve and participate in the maintenance of tumor markers. At the same time, TAFs can enhance the drug resistance of tumor cells. Previous studies have found that Gliotoxin can significantly reduce liver fibrosis by inducing apoptosis of hepatic stellate cell (HSC). Low concentration of Gliotoxin (0.1 u M) can induce HSC apoptosis. There is no obvious damage to normal hepatocytes. Only when the concentration reaches 30-50 M can cause normal hepatocyte necrosis. Our recent experimental results confirm that low concentration of Gliotoxin (IC50=143.1 nM) can significantly inhibit TAFs proliferation. Since Gliotoxin has a strong killing effect on hepatic stellate cells (one of the main sources of TAFs), we speculate Gl Iotoxin may have a therapeutic effect on HCC by acting on microenvironment. In order to verify this inference, this study will be carried out in the following two aspects: first, to isolate and identify the TAFS of human HCC origin, to observe the effect of Gliotoxin on the biological characteristics of TAFs and to induce apoptosis, and to further detect the Gliotoxin to TGF- beta pathway and its lower level. A co culture system of TAFs and hepatoma cells was established to observe the effect of Gliotoxin on co cultured cells, to establish a DEN induced primary liver cancer model and to study the therapeutic effect of Gliotoxin on HCC. This study could serve as one of the targets for the treatment of HCC, which may provide a new theory for the treatment of HCC in clinical practice. According to the experimental method: the effect of 1.Gliotoxin on TAFs: (1) separate and identify TAFs, cut the human HCC tissue into 2 mm3 size, digest collagenase IV, obtain TAFs after gradient centrifugation, and further purify the fibroblasts. Cell immunofluorescence detection of the expression of alpha -SMA, Vimentin, Desmin. (2) the effect of Gliotoxin on TAFs biological effect, in vitro studies are not The effect of the same concentration of Gliotoxin on the proliferation and migration of TAF: placing TAFs in 96 Kong Banzhong with the number of 3 x 103/ holes, adding different concentrations of Gliotoxin for 6 days, sixth days single fluorescein report gene detection of TAFs proliferation, IC50, selected Gliotoxin suitable concentration (100nM) in medium containing 3% fetal bovine serum (FBS) and adding 24 The hole plate, count 5 * 104 TAFs inoculated in the Transwell compartment, 24 hours later crystal violet fixed, photographed, using ImagePro software to calculate the TAFs migration of.2.Gliotoxin on the induction of TAFs apoptosis: (1) 100nM Gliotoxin treated TAFs, using Caspase3 fluorescent kit to detect the same time TAFs by Caspase3 expression, through calculation Se3 activity was increased to evaluate the effect of Gliotoxin on TAFs apoptosis. (2) 100nM Gliotoxin treated TAFs,.Annexin V and pyridine (PI) labeled TAFs were collected 4 hours later, and apoptosis was detected by flow cytometry, and the effect of Gliotoxin on early apoptosis was analyzed. At the same time point (15 min, 30min, 60min, 120min, 180 min), the expression of ATP was detected. A preliminary discussion on the action mechanism of Gliotoxin on ATP was discussed. Markers -SMA, Vimentin, Desmin, fibrous cell related protein (FAP) and the expression of downstream genes of TGF- beta pathway (C-myc, Smad5, AP-1, SP-1, Bcl-2). (2) TAFs medium added 0 nM, 100, 300, 4 hours later to collect protein and determine the activation of protein family in beta pathway; Group TAFs was tested after 24 hours to detect the effect of TGF- beta pathway reporter gene 3TP on the co culture system of TAFs- liver tumor cells: (1) after Gliotoxin treatment TAFs, collecting cell culture supernatant, obtaining normal medium, fibroblast cell line (normal fibroblasts, NFs), TAFs culture supernatant as the conditioned medium. B cells (3x103/ hole) were divided into 96 orifice plates, adding conditioned medium and CCK-8 method to detect cell proliferation. (2) the lower layer of 24 orifice was added to normal, NFs, TAFs, TAFs-Gliotoxin conditioned medium, SMMC-7721 cells (5 * 104) were added to Transwell compartment, the color of crystal violet staining after 24 hours, and counting the.5. Gliotoxin of the migratory cells to the DEN hepatoma model The effect of treatment: (1) the evaluation of the effect of Gliotoxin on liver cancer. All rats were killed 22 weeks. The liver was given to the rat liver. The liver was perfused with the portal vein. The liver was taken out. The changes of liver appearance were observed. Tissue paraffin section was made, and then HE staining was made to evaluate the effect of Gliotoxin on liver cancer. (2) the effect of Gliotoxin on liver fibrosis, and the effect of Gliotoxin on liver fibrosis The liver tissue was stained with Masson and Sirius red. The distribution of collagen was observed. The images were scanned and the area of collagen distribution was calculated. The expression of a-SMA in the immunohistochemical staining tissue was treated with.6. statistics. The data were analyzed with SPSS 16 software package, and the results were expressed in X SD. One-Way ANOVA variance scores were used among the groups. Analysis, P0.05 has significant difference for statistical results. Experimental results: Gliotoxin has the effect of inhibiting TAFs: (1) cell immunofluorescence detection found that TAFs expressed alpha -SMA, Desmin and Vimentin, in which a-SMA and vimentin were expressed in all TAFs, while Desmin was expressed only in partial TAFs. When the concentration of Gliotoxin is between 50-400 nM, the survival rate of TAFs rapidly decreases with the increase of drug concentration. According to the curve of the drug sensitivity test, the IC50 of the TAFs is 147.1 nM., and Gliotoxin can inhibit the TAFs migration.30 nM, which has a certain inhibitory effect on the migration of the.30. Toxin processing TAFs can reduce the number of migration of TAFs to half of the control group. When the Gliotoxin concentration is raised to 300 nM, the migration inhibition rate is approximately 90%. 4 Gliotoxin to promote TAFs apoptosis.1) 100nM Gliotoxin processing TAFs. Caspase3 activity was the highest in dependent.180 minutes, TAFs was treated with Gliotoxin of 100nM in the control group of more than 25 times.2). The apoptosis of TAFs was detected by flow cytometry after 4 hours. The results showed that the early apoptosis was increased from 10.83% to 16.23%, indicating that Gliotoxin could promote TAFs apoptosis.3) ATP content test experiment indicated 60 minutes. The TAFs of N treatment began to consume ATP, and at this time, the ATP content in the middle and low concentration group had no obvious change for.120 minutes, and the ATP content of TAFs in 100nM Gliotoxin treatment began to decline, while the ATP content reduction of 300nM concentration Gliotoxin treatment group was more than after the hour, and the persistence of the high concentration group remained at the low level. The activation of the pathway with different concentrations of Gliotoxin treatment TAFs, after 4 hours to collect protein to detect the activation of TGF- beta pathway, we found that there was no significant difference in the expression of Smad2 and Smad3, but the level of Smad2/3 phosphorylation was significantly decreased. Furthermore, we used TGF- beta pathway to report the activation of the pathway, and found that Gliotoxin could inhibit the TGF- beta passage. The content of luciferase in the road was reported. The downstream gene expression of TGF- beta pathway was detected by Real-time PCR. The downstream gene C-myc, Bcl-2, and AP-1 expression were down regulated after Gliotoxin treatment. Meanwhile, TAFs marker alpha -SMA, Desmin, Vimentin and FAP expression downregulated. The cell culture of NFs, TAFs and TAFs-Gliotoxin cells was used to treat Hep3B cells, and the number of tumor cells was detected at different time points. The results showed that NFs and TAFs could promote the proliferation of tumor cell lines, but TAFs was more capable of promoting proliferation. If TAFs was treated with Gliotoxin, its ability to promote proliferation was decreased, and NFs level was similar.2) NFs promoted. The migration ability of tumor cell line SMMC-7721 was weak, and TAFs enhanced 7721 cell migration.Gliotoxin significantly. The effect of.Gliotoxin on DEN liver cancer model was partly inhibited by.Gliotoxin. (1) the effect of Gliotoxin on the liver cancer was evaluated by.22 weeks to kill all rats and remove the liver. The changes of liver in each treatment group were observed in general. It was found that the liver cancer nodules were found in the liver of the model group and the solvent control group, or the tumor was found on the surface of the liver. At the same time, there was no tumor mass in the heavy.Gliotoxin group of the liver cirrhosis to evaluate the therapeutic effect of Gliotoxin on the liver cancer. The results showed that 6 rats in the model group were diagnosed as hepatocellular carcinoma and two rats were diagnosed as hepatocellular carcinoma. For the severe atypical hyperplasia, 5 rats in group DMSO were diagnosed as hepatocellular carcinoma and the rest were atypical hyperplasia. Most of the hepatocellular carcinoma were medium and high differentiated, one in each of the two groups was low differentiated tumor, and 1 rats in the Gliotoxin group (0.5mg/kg and 1.5mg/kg) were diagnosed as highly differentiated carcinoma and the others were atypical hyperplasia and cirrhosis. (2) Glioto The effect of Xin on liver fibrosis. Using Masson and Sirius red to stain the liver tissue, the distribution of collagen was observed. The results showed that the expression of collagen in the model group and the DMSO group was not significantly different. The special staining area in the Gliotoxin group decreased significantly. The expression of alpha -SMA was detected by the immunohistochemical test, and the alpha -SMA was found in the model group. The expression of Gliotoxin in the treatment group was significantly different. The expression range of alpha -SMA in the Gliotoxin treatment group was limited to the sink area, and the expression of alpha -SMA in the model group was larger and extended to the region of the liver cells. Conclusion: 1. Gliotoxin inhibits the proliferation and migration of TAFs, and promotes the inhibitory effect of TAFs apoptosis.2. Gliotoxin on TGF- beta pathway related.3. Gli. Otoxin inhibits the progress of experimental liver cancer.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R735.7

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