發(fā)布時間：2018-05-08 06:19

  本文選題：原發(fā)性肝癌 + DEN��； 參考：《山東大學(xué)》2017年博士論文

【摘要】：研究背景及目的:原發(fā)性肝癌是最常見的惡性腫瘤之一,是全球癌癥死亡的主要原因。其發(fā)病率高,預(yù)后差,僅2012年,全球就約有782500例新的原發(fā)性肝癌病例發(fā)生,同時約有745500例肝癌死亡病例發(fā)生。肝細(xì)胞癌(hepatocellular carcinoma,HCC)占原發(fā)性肝癌患者的多數(shù)。由于原發(fā)性肝細(xì)胞癌具有高轉(zhuǎn)移率和高復(fù)發(fā)率,盡管近年的診斷和治療方法取得了相當(dāng)大的的進(jìn)步,但死亡率仍然很高。目前用于預(yù)防肝癌藥物的數(shù)量是很有限的,而且很多的藥物仍然僅處于臨床試驗階段,所以當(dāng)務(wù)之急是研究和發(fā)現(xiàn)新的肝癌藥物和方法,希望我們的研究能為肝癌預(yù)防和治療提供新的思路。目前親水性膽汁酸的抗癌作用日益得到人們的關(guān)注。熊去氧膽酸(ursodeoxycholic acid,UDCA)屬于親水性膽汁酸,很多證據(jù)表明它可以抑制體外培養(yǎng)的肝癌細(xì)胞株增殖,降低大鼠肝癌模型的肝癌發(fā)生率,它還可以降低丙型肝炎患者罹患肝癌的風(fēng)險,并改善原發(fā)性膽汁性肝硬化病人的預(yù)后。鵝去氧膽酸(chenodeoxycholic acid,CDCA)是知的最豐富的初級膽汁酸,它可以減少膳食膽固醇吸收,并使膽固醇結(jié)石溶解,其衍生物HS-1200是親水性膽汁酸的新成員�，F(xiàn)已報道鵝去氧膽酸衍生物HS-1200 {N-[(3 α,5 β,7 α)-3,7-二羥基-24-氧代膽留烷-24-基)β-丙氨酸芐酯}在數(shù)種人類癌癥中顯示其抗癌活性,HS-1200可以在人前列腺癌細(xì)胞、骨肉瘤細(xì)胞、乳腺癌細(xì)胞中誘導(dǎo)癌細(xì)胞凋亡并抑制癌細(xì)胞增殖,而且可以誘導(dǎo)人肝癌細(xì)胞株BEL7402、HepG2凋亡。然而,HS-1200對生物體內(nèi)肝癌是否有潛在的抗癌作用尚未闡明。為此,我們建立了兩種動物肝癌模型,分別通過口服和腹腔注射兩種給藥途徑來驗證HS-1200對生物體內(nèi)肝癌的作用。第一部分鵝去氧膽酸衍生物HS-1200抑制二乙基亞硝胺誘導(dǎo)的大鼠原發(fā)性肝癌的實(shí)驗研究研究目的:雖然肝癌發(fā)展的分子機(jī)制仍然未全部為人所知,但DNA氧化損傷被認(rèn)為是參與人類肝癌發(fā)生和進(jìn)展的重要原因。氧化應(yīng)激由于過度生產(chǎn)活性氧(reactive oxygen species,ROS)等自由基被認(rèn)為引起遺傳不穩(wěn)定性,從而導(dǎo)致致癌作用。8-羥基脫氧鳥苷(8-OHdG)是一種被人們廣泛接受的R0S觸發(fā)氧化損傷DNA的損傷標(biāo)記物,同時也被確定為慢性丙型肝炎病毒感染者進(jìn)一步發(fā)展為肝細(xì)胞癌的危險因素。MTH1(mutT homologl)基因是肝細(xì)胞DNA修復(fù)基因,編碼的MTH1蛋白通過抑制8-OHdG錯并入DNA鏈而有利于氧化誘導(dǎo)的DNA損傷的修復(fù)。腫瘤組織中MTH1的上調(diào)表達(dá)可以消除腫瘤細(xì)胞中過量的8-OHdG,從而參與DNA損傷修復(fù)過程,使得腫瘤細(xì)胞繼續(xù)分裂與增殖,維持腫瘤細(xì)胞的生存�，F(xiàn)在已經(jīng)有報道在一些人類癌癥如腎癌、乳腺癌、結(jié)腸直腸癌中MTH1的表達(dá)增加。另外,也有報道證實(shí)與相鄰的非癌組織相比,MTH1在肝癌組織中明顯增加。然而,其在肝癌發(fā)生中的確切作用還不是很清楚。我們試圖研究HS-1200抑制肝癌發(fā)生的潛在能力,并探討MTH1參與肝癌發(fā)生的作用。鑒于此,我們建立了通過腹腔注射二乙基亞硝胺(diethylnitrosamine,DEN)誘導(dǎo)產(chǎn)生大鼠原發(fā)性肝癌的動物模型,我們以不同劑量的HS-1200干預(yù)此模型,來觀察HS-1200對于模型大鼠肝功能和肝癌發(fā)生的作用,并研究大鼠肝組織MTH1mRNA的水平,從而探討HS-1200的抗腫瘤活性。研究方法:實(shí)驗共需145只雄性Wistar鼠,其中50只大鼠用于確定HS-1200潛在的肝毒性和腎毒性,20只用于通過腹腔內(nèi)注射DEN進(jìn)行DEN誘導(dǎo)的原發(fā)性肝癌的實(shí)驗性造模。在進(jìn)行了 HS-1200的安全性無毒評估和大鼠肝癌模型成功建模之后,其它75只大鼠進(jìn)行如下實(shí)驗:大鼠隨機(jī)分為5組:對照組(N = 15),HS-1200組(N = 15),HCC(肝細(xì)胞癌)組(N = 15),HCC+低劑量 HS-1200 組(N = 15)和 HCC+高劑量HS-1200(N = 15)組。后三組按照實(shí)驗造模條件腹腔內(nèi)注射DEN建立大鼠肝癌模型,同時后四組通過每日口服灌胃法對大鼠進(jìn)行不同劑量HS-1200的藥物干預(yù)。20周后,處死大鼠,稱大鼠體重,取其肝臟稱重,計算肝重/體重比(肝系數(shù))及結(jié)節(jié)計數(shù),并進(jìn)行病理學(xué)檢驗。大鼠心臟采血用ELISA法檢測血清中AFP、ALT、AST的水平。取各組大鼠的肝組織,分別提取RNA,應(yīng)用實(shí)時熒光定量RT-PCR法檢測各組大鼠肝組織中MTH1mRNA的表達(dá)情況。結(jié)果:1.20周末時HCC組、HCC+低劑量HS-1200組和HCC+高劑量HS-1200組均成功建立大鼠原發(fā)性肝癌模型,各組的成瘤率分別為93%(14/15)、73%(11/15)、53%(8/15)。對照組和HS-1200組大鼠的體重、肝重及肝臟系數(shù)無明顯差異,HCC組、HCC+低劑量HS-1200組和HCC+高劑量HS-1200組大鼠的體重均明顯低于對照組(P0.05);但與HCC組相比,動物接受低劑量或高劑量HS-1200治療后顯示其體重增加,肝臟重量和肝系數(shù)降低了(P0.05);且HCC+高劑量HS-1200組大鼠的體重較HCC+低劑量HS-1200組明顯升高,肝重和肝臟系數(shù)明顯降低(P0.05)。2.對照組和HS-1200組的大鼠肝臟均正常未見結(jié)節(jié)。HE肝臟病理形態(tài)學(xué)觀察顯示對照組和HS-1200組肝小葉結(jié)構(gòu)正常,無變性和壞死現(xiàn)象;HCC組正常肝小葉組織結(jié)構(gòu)消失,假小葉形成,肝細(xì)胞索排列紊亂,可見癌巢,腫瘤細(xì)胞異型性明顯,可見大片狀壞死;在應(yīng)用HS-1200干預(yù)之后,癌巢形成和出血壞死減少了,肝臟病理有了明顯改善,HCC+低劑量HS-1200組正常肝小葉結(jié)構(gòu)消失,可見假小葉結(jié)構(gòu),偶見癌巢及出血壞死;HCC+高劑量HS-1200組肝臟病理改善更顯著,僅偶見假小葉,無明顯癌巢,出血壞死少見。3.與對照組相比,HCC組大鼠血清中ALT、AST和AFP的含量明顯升高(P0.05與對照組比較),這意味著肝功能的惡化;而HS-1200干預(yù)之后,各項指標(biāo)的升高得到了不同程度的逆轉(zhuǎn),較HCC組均有所降低(P0.05與HCC組比較);且HS-1200高劑量組各項指標(biāo)的降低更明顯。4.以正常對照組大鼠肝臟MTH1mRNA的表達(dá)水平1為參照,HCC組的相對表達(dá)量為16.23±0.74(P0.05)。應(yīng)用HS-1200治療顯著逆轉(zhuǎn)MTH1 mRNA的上調(diào)表達(dá),高劑量HS-1200似乎在這方面有更高的功效(HCC+低劑量HS-1200組,9.48±0.46;HCC+高劑量 HS-1200 組,6.13±0.33;P0.05 與 HCC 組比較)。結(jié)論:1.HS-1200無明顯肝、腎毒性,保證了此藥物的安全性。DEN腹腔注射可以成功建立大鼠原發(fā)性肝癌模型。2.HS-1200可降低DEN誘導(dǎo)的大鼠肝臟瘤變率,并降低大鼠血清中AFP含量,說明HS-1200對大鼠原發(fā)性肝癌的發(fā)生具有抑制作用。3.HS-1200可降低大鼠血清中AST、ALT的水平,可降低大鼠肝臟中MTH1mRNA的表達(dá),說明HS-1200對大鼠原發(fā)性肝癌發(fā)生的抑制作用與其改善大鼠肝功能抑制炎癥、抑制氧化應(yīng)激有關(guān)。第二部分鵝去氧膽酸衍生物HS-1200抑制HepG2裸鼠肝癌移植瘤的實(shí)驗研究研究目的:為了進(jìn)一步研究HS-1200對肝癌腫瘤血管生成及轉(zhuǎn)移性肝癌的作用,我們通過瘤體接種BALB/C裸鼠,復(fù)制了人肝癌細(xì)胞株HepG2裸鼠皮下移植瘤模型,觀察HS-1200干預(yù)對移植瘤組織結(jié)構(gòu)、超微結(jié)構(gòu)及新生血管生成的影響。以發(fā)現(xiàn)HS-1200對于肝癌腫瘤血管生成因子VEGF、bFGF表達(dá)及血管生成的作用,從而為HS-1200應(yīng)用于臨床肝癌及轉(zhuǎn)移的治療進(jìn)一步積累實(shí)驗依據(jù)。研究方法:人肝癌細(xì)胞株HepG2調(diào)整細(xì)胞密度為1.5×107/ml,將細(xì)胞懸液接種于裸鼠腋窩皮下。皮下成瘤至長徑約10mm時,剝離瘤體,取離體瘤組織以每個大小2×2×2mm3接種于60余只裸鼠左側(cè)腋窩皮下。待接種瘤體長至長徑約10mm,將荷瘤裸鼠隨機(jī)分對照組(N=20)、20mg/kg低劑量HS-1200組(N=20)、60 mg/kg高劑量HS-1200組(N=20)。后兩組分別腹腔注射相對應(yīng)的劑量的HS-1200,每天一次,對照組裸鼠以相同方式給予等量滅菌注射用水處理,共2周。之后處死裸鼠并剝離移植瘤,測量并稱重移植瘤,計算瘤體積,計算低、高劑量HS-1200治療組瘤重的抑瘤率。光鏡和電鏡觀察各組移植瘤組織結(jié)構(gòu)和超微結(jié)構(gòu),免疫組織化學(xué)法檢測各組移植瘤VEGF、bFGF表達(dá)。結(jié)果:1.低、高劑量HS-1200組移植瘤體積、重量均明顯小于對照組,抑瘤率分別為38.23%、47.05%。2.光鏡觀察,對照組見血管增生活躍,瘤細(xì)胞內(nèi)癌巢分布,細(xì)胞呈明顯異型性。HS-1200干預(yù)組移植瘤見血管數(shù)量稀少或缺如,癌巢明顯減少,HS-1200高劑量組更明顯。3.透射電鏡觀察,對照組呈現(xiàn)細(xì)胞形態(tài)怪異,核大畸形等惡性腫瘤特有的超微結(jié)構(gòu)特點(diǎn);低、高劑量HS-1200組移植瘤組織見不同時期凋亡細(xì)胞,凋亡小體存在,壞死瘤細(xì)胞及細(xì)胞崩解碎片可見,且HS-1200高劑量組更明顯。4.免疫組化結(jié)果表明,低、高劑量HS-1200組移植瘤中VEGF、bFGF陽性表達(dá)比對照組明顯下調(diào)(p0.05),且HS-1200高劑量組更明顯。結(jié)論:1.HS-1200可抑制人肝癌細(xì)胞株HepG2裸鼠皮下移植瘤生長。2.HS-1200干預(yù)使移植瘤血供明顯減少,提示HS-1200可抑制移植瘤新生血管生成。3.對比移植瘤超微結(jié)構(gòu)特點(diǎn),證明HS-1200干預(yù)可誘導(dǎo)移植瘤細(xì)胞凋亡。4.根據(jù)免疫組化結(jié)果,推測HS-1200下調(diào)VEGF、bFGF表達(dá),進(jìn)而抑制移植瘤新生血管生成,表現(xiàn)抗肝癌及轉(zhuǎn)移性肝癌的作用。
[Abstract]:Background and purpose: primary liver cancer is one of the most common malignant tumors and is the main cause of global cancer death. Its incidence is high and the prognosis is poor. Only in 2012, there are about 782500 new cases of primary liver cancer in the world, and about 745500 cases of hepatocellular carcinoma (hepatocellular carcinoma, HCC). The majority of patients with HCC. Due to the high metastasis rate and high recurrence rate of primary hepatocellular carcinoma (HCC), although considerable progress has been made in diagnosis and treatment in recent years, the mortality rate is still high. The number of drugs used to prevent liver cancer is limited and many drugs are still in clinical trial stage, so many drugs are still in the clinical trial stage, so The urgent task is to study and discover new liver cancer drugs and methods, and hope our research can provide new ideas for the prevention and treatment of liver cancer. The current anticancer effect of hydrophilic bile acids is getting more and more attention. Ursodeoxycholic acid (ursodeoxycholic acid, UDCA) belongs to hydrophilic bile acid, a lot of evidence suggests that it can inhibit in vitro Chenodeoxycholic acid (CDCA) is the most abundant primary bile acid known to reduce the risk of HCC in patients with hepatitis C and improve the prognosis of patients with primary biliary cirrhosis. It can reduce the dietary cholesterol absorption. HS-1200 is a new member of the hydrophilic bile acid. It has been reported that the HS-1200 {N-[(3, 5 beta, 7 alpha) -3,7- two hydroxy -24- oxycholestyl benzyl benzyl benzyl} of the oxydeoxycholic acid derivatives shows its anticancer activity in several human cancers, and HS-1200 can be used in human prostate cancer cells and bone meat. Tumor cells, breast cancer cells induce cancer cells to apoptosis and inhibit the proliferation of cancer cells, and can induce human hepatoma cell line BEL7402, HepG2 apoptosis. However, HS-1200 has no potential anti-cancer effect on liver cancer in vivo. Therefore, two animal models of liver cancer were established by oral and intraperitoneal injection of two kinds, respectively. Drug pathway to verify the effect of HS-1200 on liver cancer in vivo. Part 1 Experimental Study on the inhibition of two ethyl nitrosamine induced primary liver cancer by HS-1200 derivative of goose deoxycholic acid derivative: Although the molecular mechanism of the development of liver cancer is still unknown, DNA oxygenation injury is considered to be involved in human liver cancer and the occurrence of HCC. The important cause of progress. Oxidative stress, due to excessive production of active oxygen (reactive oxygen species, ROS) and other free radicals, is considered to cause genetic instability, resulting in the carcinogenic effect of.8- hydroxy deoxy guanosine (8-OHdG) as a widely accepted marker of R0S triggered oxidative damage DNA, and also identified as chronic C type C The.MTH1 (mutT homologl) gene, a risk factor for hepatitis virus infection, is the DNA repair gene of liver cells. The encoded MTH1 protein is beneficial to the repair of DNA damage induced by the incorporation of 8-OHdG into the DNA chain. The up regulation of MTH1 in the tumor tissue can eliminate the excess 8-OHdG in the tumor cells. It is now reported that the expression of MTH1 in some human cancers, such as kidney cancer, breast cancer, and colorectal cancer, has increased. In addition, it has also been reported that MTH1 is significantly increased in liver cancer tissue compared with adjacent non cancer tissue. However, MTH1 has been significantly increased. The exact role of HS-1200 in the development of liver cancer is not clear. We have tried to study the potential ability of HS-1200 to inhibit the occurrence of liver cancer and explore the role of MTH1 in the occurrence of liver cancer. In view of this, we established animal models of primary liver cancer induced by intraperitoneal injection of two ethyl nitrosamines (DEN). Different doses of HS-1200 were used to observe the effect of HS-1200 on liver function and liver cancer in model rats, and to study the level of MTH1mRNA in rat liver tissue, and to explore the anti tumor activity of HS-1200. Methods: 145 male Wistar rats were needed in the experiment, of which 50 rats were used to determine the potential hepatotoxicity and renal toxicity of HS-1200. 20 experimental models of primary liver cancer induced by intraperitoneal injection of DEN for DEN induced primary liver cancer. After the safety non-toxic evaluation of HS-1200 and the successful modeling of the rat model of liver cancer, the following 75 rats were divided into 5 groups randomly: the control group (N = 15), the HS-1200 group (N = 15), the HCC (N = 15), HC, HC C+ low dose HS-1200 group (N = 15) and HCC+ high dose HS-1200 (N = 15) group. The latter three groups were injected intraperitoneally with DEN to establish rat liver cancer model. At the same time, the four groups of rats were treated with different doses of HS-1200 by oral administration of the stomach daily for.20 weeks, and the rats were killed and weighed, and the weight of the rats was weighed, and the weight of the liver was calculated. The weight of the rats was calculated and the weight of the liver was calculated. Calculation of the weight of the liver was taken and calculated. The weight of the rat was calculated. The weight of the rat was weighed and the liver was weighed and calculated. Liver weight / weight ratio (liver coefficient) and nodule count and pathological examination. The level of AFP, ALT and AST in serum was detected by ELISA method in rat heart. RNA was extracted from liver tissues of rats in each group, and the expression of MTH1mRNA in liver tissues of each group was detected by real-time quantitative fluorescence quantitative RT-PCR. Results: HCC group at 1.20 weekend, HCC+ low The rat primary liver cancer model was successfully established in the dose HS-1200 group and the high dose HCC+ HS-1200 group. The tumor formation rate of each group was 93% (14/15), 73% (11/15), and 53% (8/15). There was no significant difference between the weight of the control group and the HS-1200 group, the liver weight and the liver coefficient, and the weight of the HCC group, the HCC+ low dose HS-1200 group and the HCC+ high dose HS-1200 group were all obvious. Lower than the control group (P0.05), but compared with the HCC group, the body weight and liver coefficient decreased (P0.05) after the animals received low or high dose HS-1200, and the weight of the HCC+ high dose HS-1200 group was significantly higher than that of the low HCC+ dose HS-1200 group, and the liver weight and liver coefficient decreased significantly (P0.05).2. control group and HS-1200 group. The liver pathomorphology of normal liver.HE showed normal liver lobular structure in control group and HS-1200 group, without degeneration and necrosis. In group HCC, normal hepatic lobule structure disappeared, false lobule formed, liver cell cord arranged disorder, cancer nests were visible, tumor cells had obvious heteromorphosis and visible necrosis; HS-12 00 after intervention, the formation of cancer nests and hemorrhagic necrosis were reduced, the pathological changes of liver were obviously improved. The structure of normal lobule in HCC+ low dose HS-1200 group disappeared, the structure of false lobule, tumor nest and hemorrhagic necrosis were seen, and the pathological improvement of liver in HCC+ high dose HS-1200 group was more significant, only false lobules, no obvious cancer nests, and hemorrhagic necrosis were rare.3. and pairs. The levels of ALT, AST and AFP in the serum of HCC rats increased significantly (compared with those of the control group), which meant the deterioration of liver function. After HS-1200 intervention, the increase of various indexes was reversed in varying degrees, compared with those in the HCC group (compared with the P0.05 and HCC group), and the decrease of each index in the HS-1200 high dose group was more obvious. The expression level of MTH1mRNA in the liver of normal control group was 1 as reference, and the relative expression of HCC group was 16.23 + 0.74 (P0.05). HS-1200 treatment significantly reversed the up expression of MTH1 mRNA. High dose HS-1200 seemed to have higher efficacy in this area (HCC+ low dose HS-1200 group, 9.48 + 0.46; HCC+ high dose HS-1200 group, 6.13 + 0.33; 6.13 + 0.33; Compared with group HCC) conclusion: 1.HS-1200 has no obvious liver, renal toxicity, and ensures the safety of this drug,.DEN intraperitoneal injection can successfully establish rat primary liver cancer model.2.HS-1200 can reduce the rate of liver cancer induced by DEN, and reduce the content of AFP in the rat serum, indicating that HS-1200 has an inhibitory effect on the occurrence of primary liver cancer in rats. .3.HS-1200 can reduce the level of AST and ALT in rat serum and reduce the expression of MTH1mRNA in the liver of rats, indicating that the inhibitory effect of HS-1200 on the occurrence of primary liver cancer in rats is related to the improvement of rat liver function inhibition inflammation and inhibition of oxidative stress. The second part of the goose deoxycholic acid derivative HS-1200 inhibits the transplanted tumor of the liver cancer of HepG2 nude mice. Objective: in order to further study the effect of HS-1200 on the angiogenesis and metastatic liver cancer of liver cancer, we inoculated BALB/C nude mice through the tumor and replicated the subcutaneous transplantation tumor model of human hepatoma cell line HepG2 in nude mice. The effects of HS-1200 intervention on the tissue structure, ultrastructure and angiogenesis of the transplanted tumor were observed. The effect of HS-1200 on the angiogenic factor VEGF, bFGF expression and angiogenesis of hepatocellular carcinoma, thus further accumulating the experimental basis for the treatment of HS-1200 in the treatment of liver cancer and metastasis. The study method: the cell density of human hepatocellular carcinoma cell line HepG2 is 1.5 * 107/ml, and the cell suspension is inoculated subcutaneously in the armpit of nude mice. When the diameter of the tumor was about 10mm, the tumor tissue was stripped and the tumor tissue was inoculated subcutaneously in the left armpit of more than 60 nude mice with each size of 2 x 2 x 2mm3. After the tumor was inoculated to a long diameter of about 10mm, the tumor bearing nude mice were randomly divided into the control group (N=20), the 20mg/kg low dose HS-1200 group (N=20) and the 60 mg/kg high dose HS-1200 group (N=20). The latter two groups were injected with the corresponding dose of the corresponding dose. HS-1200, once a day, the control group of nude mice was treated with the same amount of Sterile Water for Injection for 2 weeks. Then the nude mice were killed and the transplanted tumor was stripped and measured and weighed. The tumor volume was calculated. The tumor weight inhibition rate of the low, high dose HS-1200 treatment group was calculated. The tissue structure and ultrastructure of the transplanted tumor were observed by light and electron microscopy, and the ultrastructure and ultrastructure were observed by light microscope and electron microscope. VEGF and bFGF expression were detected by the immunohistochemical method. Results: 1. low, high dose HS-1200 group was significantly smaller than the control group, the tumor suppressor rate was 38.23%, the 47.05%.2. light microscope was observed respectively. The control group found the vascular proliferation active, the tumor cell nests distributed in the tumor cells, and the cells showed the number of blood vessels in the obvious heteromorphic.HS-1200 intervention group. HS-1200 high dose group was more obvious.3. transmission electron microscopy, and the control group showed peculiar ultrastructural characteristics of malignant tumor such as cell morphology and nuclear large malformation. Low, high dose HS-1200 group saw apoptotic cells in different period, apoptotic bodies, necrotic tumor cells and cell disintegration fragments. The results showed that the.4. immunohistochemical results of high dose HS-1200 group showed that the positive expression of VEGF in the transplanted tumor of HS-1200 group was lower than that of the control group (P0.05), and the HS-1200 high dose group was more obvious. Conclusion: 1.HS-1200 could inhibit the growth of the transplanted tumor of human liver cancer cell line, the growth.2.HS-1200 intervention to make the transplanted tumor blood supply. The results suggest that HS-1200 can inhibit the ultrastructural characteristics of the neovascularization of the transplanted tumor, and that the HS-1200 intervention can induce the apoptosis of the transplanted tumor cell.4.. According to the immunohistochemical results, it is suggested that HS-1200 can down regulate the VEGF, bFGF expression, and then inhibit the neovascularization of the transplanted tumor, and show the role of anti hepatoma and metastatic liver cancer.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R735.7

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