發(fā)布時(shí)間：2018-06-18 10:15

  本文選題：喉癌 + 羅格列酮�。� 參考：《鄭州大學(xué)》2010年博士論文

【摘要】： 喉癌是耳鼻咽喉科原發(fā)于上皮的惡性腫瘤,占耳鼻咽喉科惡性腫瘤的11%-22%。盡管近幾十年來喉癌的治療方法取得了較大的進(jìn)展,但在生存率和患者生活質(zhì)量方面仍然需要提高。隨著新的化療藥物的不斷出現(xiàn),喉癌的治療也過渡到了手術(shù),放療和化療的綜合性治療,因此研究和探索喉癌更多的更有效的化療藥物有著深遠(yuǎn)的意義。 過氧化酶增殖體激活受體(peroxisome poliferator-activited receptor, PPAR)是一種細(xì)胞核轉(zhuǎn)錄因子,具有多種生物學(xué)效應(yīng)并參與多種機(jī)體生理反應(yīng),尤其是在脂肪的貯存和代謝中發(fā)揮重要的無可比擬的作用。目前的研究表明PPAR分為三種亞型(α,δ,γ),其中PPARy亞型與腫瘤關(guān)系最為密切,因此在腫瘤的功能研究的也得最為廣泛和深入。很多報(bào)道都顯示PPARy在多種腫瘤組織中表達(dá),當(dāng)應(yīng)用PPARy激動(dòng)劑作用后就可以引起腫瘤細(xì)胞增殖和侵襲能力的抑制、血管形成減少及誘導(dǎo)凋亡等腫瘤細(xì)胞的惡性生物學(xué)行為改變。因此,近年來以PPARy為靶點(diǎn)的藥物研究進(jìn)展迅速,已成為當(dāng)前抗腫瘤藥物研究開發(fā)的熱點(diǎn)之一 PPARy激動(dòng)劑可分為天然激動(dòng)劑和合成激動(dòng)劑兩大類。人工合成PPARy激動(dòng)劑則以噻唑烷二酮類(thiazolidinedione compounds, TZDs)最為代表,在臨床上應(yīng)用于糖尿病的治療。近幾年的大量研究表明TZDs可以有效地抑制多種腫瘤細(xì)胞的增殖,抑制腫瘤新生血管的形成,阻滯細(xì)胞周期的進(jìn)行,誘導(dǎo)凋亡,況且TZDs作為糖尿病主要治療藥物因其療效好,副作用少在臨床上廣泛應(yīng)用多年,所以TZDs對(duì)腫瘤的增殖抑制作用顯得更為有意義。研究表明TZDs的抑瘤機(jī)制十分復(fù)雜,甚至有學(xué)者提出TZDs有可通過激活PPARγ外的其它途徑來發(fā)揮抗腫瘤的作用,但是TZDs的抗腫瘤作用卻是毋庸質(zhì)疑的。 為了深入探討TZDs對(duì)喉癌Hep-2細(xì)胞的影響,本研究首先應(yīng)用TZDs代表藥物羅格列酮(Rosiglitazone, RGZ)和曲格列酮(Troglitazone, TRG)在體外作用于Hep-2細(xì)胞,采用MTT、流式細(xì)胞術(shù)、Real-time PCR、western和ELISA多種分子生物學(xué)技術(shù)體外觀察了TZDs對(duì)Hep-2細(xì)胞增殖、凋亡和缺氧誘導(dǎo)的HIF-1α和VEGF的影響并探討其發(fā)生機(jī)制；接著在體外實(shí)驗(yàn)的基礎(chǔ)上,我們研究觀察RGZ和TRG對(duì)人喉癌Hep-2細(xì)胞裸鼠皮下移植瘤影響及機(jī)制及RGZ和TRG在荷瘤裸鼠的毒性反應(yīng),為喉癌化學(xué)治療拓展新的思路和方法,為將來以PPARγ為靶點(diǎn)的喉癌防治提供理論基礎(chǔ)及實(shí)驗(yàn)依據(jù),為TZDs的開發(fā)、臨床應(yīng)用提供有價(jià)值的實(shí)驗(yàn)依據(jù)。本研究分為以下三章： 第一章RGZ和TRG對(duì)人喉癌Hep-2細(xì)胞增殖、凋亡的影響及機(jī)制研究方法 1.采用MTT比色法測(cè)定經(jīng)12.5、25、50、100μmol/L RGZ或TRG分別作用12、24、36、48、60、72h后的Hep-2細(xì)胞增殖活性的改變。 2.采用流式細(xì)胞術(shù)分別檢測(cè)經(jīng)50μmol/L RGZ或TRG作用0、24、48、72h后的Hep-2細(xì)胞凋亡率和細(xì)胞周期分布。 3.采用Real-time PCR和western方法分別檢測(cè)經(jīng)50μmol/L RGZ或TRG作用0、24、48、72h后Hep-2細(xì)胞中COX-2和p65 mRNA和蛋白及VEGFmRNA水平的變化。 4.采用ELISA方法分別檢測(cè)經(jīng)25、50、100μmol/L RGZ或TRG作用24h后Hep-2細(xì)胞培養(yǎng)上清液中VEGF蛋白水平的變化。 結(jié)果 1.RGZ或TRG作用后導(dǎo)致細(xì)胞的增殖活性明顯受到抑制,其抑制率呈濃度依賴性和時(shí)間依賴性增加(P0.05)。 2.流式細(xì)胞術(shù)結(jié)果顯示50μmol/L RGZ或TRG作用24、48、72h后,G0/G1期細(xì)胞比例呈時(shí)間依賴性逐漸升高(P0.01),S期細(xì)胞比例逐漸降低(P0.01),而G2/M期細(xì)胞比例也呈逐漸降低趨勢(shì)(P0.01)；隨著RGZ或TRG作用時(shí)間延長(zhǎng),細(xì)胞凋亡率呈時(shí)間依賴性逐漸增加,不同時(shí)間組間存在顯著性差異(P0.01)。 3. Real-time PCR和western結(jié)果顯示經(jīng)50μmol/L RGZ或TRG作用24、48、72h后Hep-2細(xì)胞中COX-2和p65 mRNA和蛋白及VEGF mRNA表達(dá)水平呈時(shí)間依賴性的下降,不同時(shí)間組間有顯著性差異(P0.01)。 4. ELISA結(jié)果顯示經(jīng)25、50、100μmol/L RGZ或TRG作用24h后Hep-2細(xì)胞培養(yǎng)上清液中VEGF蛋白水平呈時(shí)間依賴性的下降,不同時(shí)間組間有顯著性差異(P0.01)。 第二章RGZ和TRG對(duì)缺氧誘導(dǎo)的Hep-2細(xì)胞HIF-1α和VEGF表達(dá)的影響研究 方法 1采用MTT法檢測(cè)缺氧環(huán)境下經(jīng)12.5、25、50、100μmol/LRGZ或TRG分別作用12、24、36、48、60、72h后Hep-2細(xì)胞增殖活性的改變。 2.缺氧環(huán)境下經(jīng)25、50、100μmol/L RGZ或TRG作用Hep-2細(xì)胞24h后,采用Real-time PCR和ELISA法分別檢測(cè)細(xì)胞中VEGF mRNA和培養(yǎng)上清液蛋白水平的變化。 3.采用Real-time PCR和western檢測(cè)RGZ或TRG作用Hep-2細(xì)胞16h后Hep-2細(xì)胞中HIF-1αmRNA和蛋白水平的變化。 4.采用western方法檢測(cè)缺氧環(huán)境下經(jīng)25、50、100μmol/L RGZ或TRG作用6h后Hep-2細(xì)胞中p-AKT/AKT, p-ERK1/2/ERK1/2, p-STAT3/STAT3蛋白水平的變化。 5.采用transwell小室侵襲實(shí)驗(yàn)檢測(cè)50μmol/LRGZ或TRG在缺氧和常氧環(huán)境下對(duì)Hep-2細(xì)胞侵襲能力的影響。 6.采用明膠酶譜法分析50μmol/LRGZ或TRG在缺氧和常氧環(huán)境下對(duì)Hep-2細(xì)胞MMP-2活性的影響。 結(jié)果 1.MTT結(jié)果表明缺氧環(huán)境下RGZ和TRG作用Hep-2細(xì)胞后細(xì)胞的增殖活性受到明顯抑制,且比常氧環(huán)境下對(duì)細(xì)胞的抑制作用更為明顯,細(xì)胞抑制率具有時(shí)間依賴性和劑量依賴性(P0.01)。 2. Real-time PCR和ELISA結(jié)果顯示RGZ和TRG呈濃度依賴性抑制缺氧誘導(dǎo)的培養(yǎng)上清液中VEGF蛋白和細(xì)胞內(nèi)mRNA的水平,各組間差異有統(tǒng)計(jì)學(xué)意義(P0.01)。而HIF-1αmRNA表達(dá)水平在各濃度組均無明顯改變(P0.05)。 3. western結(jié)果表明RGZ和TRG呈濃度依賴性抑制缺氧誘導(dǎo)的Hep-2細(xì)胞HIF-1α、p-AKT、p-ERK1/2和p-STAT3蛋白的表達(dá),各組間差異有統(tǒng)計(jì)學(xué)意義(P0.01)；而AKT、ERK1/2和STAT3蛋白表達(dá)水平在各濃度組均無明顯改變,各組間差異無統(tǒng)計(jì)學(xué)意義(P0.05)。 4. Transwell小室侵襲實(shí)驗(yàn)結(jié)果表明缺氧和常氧環(huán)境下RGZ和TRG都可以明顯的抑制Hep-2細(xì)胞的侵襲,各組間差異有統(tǒng)計(jì)學(xué)意義(P0.01)。 5.明膠酶譜法分析結(jié)果表明缺氧和常氧環(huán)境下RGZ和TRG均可以抑制Hep-2細(xì)胞MMP-2活性,各組間差異有統(tǒng)計(jì)學(xué)意義(P0.01)。 第三章RGZ和TRG對(duì)人喉癌Hep-2細(xì)胞裸鼠移植瘤的影響研究方法 1.建立人喉癌裸鼠移植瘤模型后隨機(jī)分為對(duì)照組、RGZ實(shí)驗(yàn)組和TRG實(shí)驗(yàn)組,每組6只,治療組瘤內(nèi)注射50μmoL/L的RGZ和TRG,每3天注射一次；瘤內(nèi)注射0.5%二甲基亞砜。共治療4周。 2.每d觀察裸鼠的飲食、活動(dòng)等生理狀況。每周測(cè)量瘤體大小及裸鼠體質(zhì)量,繪制腫瘤生長(zhǎng)變化曲線。待4周后治療結(jié)束時(shí)處死小鼠,剝瘤稱重,計(jì)算質(zhì)量抑瘤率。HE染色后光學(xué)顯微鏡下觀察腦、心、肝、肺、脾和腎等重要臟器變化。 3.采用免疫組化技術(shù)檢測(cè)各組裸鼠移植瘤CD34抗原表達(dá)情況,并對(duì)染色結(jié)果進(jìn)行統(tǒng)計(jì)分析計(jì)算MVD值。 4.采用Real-time PCR和western技術(shù)檢測(cè)各組移植瘤COX-2、p65、HIF-1α和VEGF mRNA及蛋白表達(dá)情況。 結(jié)果 1.與對(duì)照組相比,RGZ和TRG能明顯抑制裸鼠移植瘤的生長(zhǎng),對(duì)照組和實(shí)驗(yàn)組裸鼠瘤體積、瘤質(zhì)量組間比較差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。 2.治療過程中,裸鼠未見明顯不良反應(yīng)。治療結(jié)束時(shí)各組心、肝、肺、脾、腎等重要臟器無明顯器質(zhì)性改變。 3.與對(duì)照組相比,實(shí)驗(yàn)組腫瘤組織中MVD值明顯減少,三組間MVD值相比差異具有統(tǒng)計(jì)學(xué)意義(P0.01)。 4. Real-time PCR和western結(jié)果表明RGZ和TRG能抑制裸鼠移植瘤COX-2、p65和VEGF mRNA和蛋白及HIF-1α蛋白的表達(dá),組間比較差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。 結(jié)論 1.RGZ和TRG對(duì)Hep-2細(xì)胞具有濃度和時(shí)間依賴性增殖抑制作用,阻滯Hep-2細(xì)胞于G0/G1期,誘導(dǎo)細(xì)胞凋亡,其機(jī)制與抑制COX-2和p65蛋白和mRNA及VEGF mRNA的表達(dá),下調(diào)VEGF蛋白的分泌有關(guān)。 2.缺氧環(huán)境下RGZ或TRG依然對(duì)Hep-2細(xì)胞增殖有明顯的抑制作用,能抑制VEGFmRNA的表達(dá)和培養(yǎng)上清液VEGF蛋白的分泌,下調(diào)缺氧誘導(dǎo)的HIF-1α蛋白水平；其機(jī)制與抑制AKT、ERK1/2和STAT3蛋白磷酸化及通過蛋白酶體通路促進(jìn)HIF-1α蛋白的降解密切相關(guān)；能抑制常氧和缺氧環(huán)境下Hep-2細(xì)胞的侵襲,其機(jī)制與降低MMP-2活性密切相關(guān)。 3.RGZ和TRG能抑制喉癌裸鼠移植瘤生長(zhǎng),降低腫瘤組織MVD值,下調(diào)喉癌裸鼠移植瘤COX-2、p65、HIF-1α和VEGF表達(dá)。且對(duì)機(jī)體無明顯毒、副作用。
[Abstract]:Cancer of the larynx is an epithelia in the Department of Otolaryngology, which is a malignant tumor. 11%-22%., which accounts for the malignant tumor of the otorhinolaryngology, has made great progress in the treatment of laryngology in recent decades, but it still needs to be improved in terms of survival and quality of life. With the continuous emergence of new chemotherapeutic drugs, the treatment of larynx cancer has also been transferred to the hand. The comprehensive treatment of surgery, radiotherapy and chemotherapy, therefore, it is of great significance to research and explore more and more effective chemotherapeutic drugs for laryngeal cancer.
Peroxisome poliferator-activited receptor (PPAR) is a nuclear transcription factor. It has a variety of biological effects and participates in a variety of physiological responses, especially in the storage and metabolism of fat. The present study shows that PPAR is divided into three subtypes (alpha, delta). The PPARy subtype is most closely related to tumor, so it is also the most extensive and in-depth study of tumor function. Many reports show that PPARy is expressed in a variety of tumor tissues. When PPARy agonists are used, the proliferation and invasion of tumor cells can be inhibited, angiogenesis and apoptosis can be induced. The malignant biological behavior of the tumor cells is changed. Therefore, recent advances in the study of PPARy as the target of drugs have become one of the hotspots in the research and development of antitumor drugs.
PPARy agonists can be divided into two major categories: natural agonists and synthetic agonists. Synthetic PPARy agonists are the most representative of the thiazolidane two ketone (thiazolidinedione compounds, TZDs), and are clinically applied to the treatment of diabetes. In recent years, a large number of studies have shown that TZDs can inhibit the proliferation of many tumor cells and inhibit the tumor. The formation of neovascularization, block cell cycle and induce apoptosis, and TZDs as the main therapeutic drug for diabetes is widely used for many years because of its good curative effect and less side effects. Therefore, the inhibitory effect of TZDs on tumor proliferation is more meaningful. The research shows that the mechanism of TZDs is very complex, and even some scholars have proposed TZDs. It is possible to play an anti-tumor role by activating other pathways outside PPAR gamma, but the anti-tumor effect of TZDs is beyond doubt.
In order to investigate the effect of TZDs on laryngeal cancer Hep-2 cells, this study first used TZDs to represent Rosiglitazone (RGZ) and Zugle (Troglitazone, TRG) in Hep-2 cells in vitro. MTT, flow cytometry, Real-time PCR, Western and various molecular biology techniques were observed in vitro. The effect of cell proliferation, apoptosis and hypoxia induced HIF-1 alpha and VEGF and its mechanism are discussed. On the basis of in vitro experiments, we observe and observe the effects of RGZ and TRG on the subcutaneous transplanted tumor of human larynx Hep-2 cells in nude mice and the toxic reaction of RGZ and TRG in nude mice bearing tumor, and develop new ideas and methods for the chemotherapy of larynx cancer. In the future, it provides the theoretical basis and experimental basis for the prevention and control of laryngeal cancer with PPAR gamma as a target. It provides valuable experimental basis for the development of TZDs and clinical application. This study is divided into the following three chapters:
Chapter one: the effects of RGZ and TRG on the proliferation and apoptosis of human laryngeal carcinoma Hep-2 cells and its mechanism.
1. MTT colorimetric assay was used to detect the change of Hep-2 cell proliferation activity after 12,24,36,48,60,72h treated by 12.5,25,50100 mol/L RGZ or TRG.
2. flow cytometry was used to detect the apoptosis rate and cell cycle distribution of Hep-2 cells after 0,24,48,72h treated with 50 mol/L RGZ or TRG.
3. Real-time PCR and Western methods were used to detect the changes in COX-2 and p65 mRNA and protein and VEGFmRNA levels in Hep-2 cells after the action of 50 mol/L RGZ or TRG on 0,24,48,72h.
4. ELISA method was used to detect the change of VEGF protein level in Hep-2 cell culture supernatant after 25,50100 24h mol/L or RGZ treatment.
Result
The proliferation activity of cells was significantly inhibited after 1.RGZ or TRG treatment, and the inhibition rate increased in a concentration dependent and time-dependent manner (P0.05).
The results of 2. flow cytometry showed that after the action of 50 mol/L RGZ or TRG, the proportion of cells in G0/G1 phase increased gradually (P0.01), the proportion of cells in S phase decreased gradually (P0.01), and the proportion of G2/M phase cells decreased gradually (P0.01). As RGZ or TRG work extended, the apoptosis rate was gradually increased in time dependent. There were significant differences between different time groups (P0.01).
The results of 3. Real-time PCR and Western showed that the COX-2 and p65 mRNA and protein and VEGF expressions in Hep-2 cells after the action of 50 mol/L RGZ or TRG were time dependent, and there was a significant difference between the different time groups.
The results of 4. ELISA showed that the level of VEGF protein in the supernatant of Hep-2 cells cultured by 25,50100 mol/L RGZ or TRG was time dependent, and there was a significant difference between different time groups (P0.01).
The second chapter is about the effect of RGZ and TRG on the expression of HIF-1 and VEGF in hypoxia induced Hep-2 cells.
Method
1 MTT method was used to detect the change of Hep-2 cell proliferation activity after 12,24,36,48,60,72h treatment by 12.5,25,50100 or mol/LRGZ or TRG in hypoxia environment.
The changes of VEGF mRNA in cells and protein levels in culture supernatant were detected by Real-time PCR and ELISA method in 2. mol/L RGZ or TRG Hep-2 cells 24h under anoxic environment.
3. Real-time PCR and Western were used to detect the changes of HIF-1 mRNA mRNA and protein levels in Hep-2 cells after RGZ or TRG acted on 16h cells.
4. the changes in the level of p-AKT/AKT, p-ERK1/2/ERK1/2, p-STAT3/STAT3 protein in Hep-2 cells after 25,50100 micron mol/L RGZ or TRG were detected by western method.
5. Transwell cell invasion assay was used to detect the effect of 50 mol/LRGZ or TRG on the invasion of Hep-2 cells under hypoxia and normoxic environment.
6. gelatin zymography was used to analyze the effects of 50 mol/LRGZ or TRG on MMP-2 activity in Hep-2 cells under hypoxia and normoxic environment.
Result
1.MTT results showed that the proliferation activity of RGZ and TRG cells in Hep-2 cells under anoxic environment was significantly inhibited, and the inhibitory effect on cells was more obvious than that under the normal oxygen environment. The cell inhibition rate was time dependent and dose dependent (P0.01).
2. Real-time PCR and ELISA results showed that RGZ and TRG showed a concentration dependent inhibition of the level of VEGF protein and intracellular mRNA in the culture supernatant induced by hypoxia (P0.01), but the expression level of HIF-1 alpha mRNA was not significantly changed in the concentration groups (P0.05).
The results of 3. Western showed that RGZ and TRG showed a concentration dependent inhibition of the expression of HIF-1 alpha, p-AKT, p-ERK1/2 and p-STAT3 protein in Hep-2 cells induced by hypoxia (P0.01), but there was no significant change in the expression of AKT, ERK1/2 and STAT3 protein in each group. There was no significant difference between the groups.
The results of 4. Transwell cell invasion test showed that both RGZ and TRG could significantly inhibit the invasion of Hep-2 cells in hypoxia and normoxic environment, and there were significant differences between each group (P0.01).
5. the results of gelatin zymography showed that RGZ and TRG could inhibit MMP-2 activity in Hep-2 cells under hypoxia and normoxic environment, and the difference was statistically significant among all groups (P0.01).
The third chapter is about the influence of RGZ and TRG on human laryngeal carcinoma Hep-2 cell xenografts in nude mice.
1. the nude mice model of human larynx cancer was randomly divided into control group, RGZ experimental group and TRG experimental group, 6 rats in each group. The treatment group was injected with 50 mu moL/L RGZ and TRG, once every 3 days, and 0.5% two methyl sulfoxide was injected into the tumor for 4 weeks.
2. every d observed the diet, activity and other physiological conditions of nude mice. The tumor size and mass of nude mice were measured weekly and the tumor growth curve was plotted. After 4 weeks of treatment, the mice were killed and the tumor was weighed and the tumor suppressor rate was calculated by.HE staining. The changes of the brain, heart, liver, lung, spleen and kidney were observed under the optical microscope.
3. immunohistochemical staining was used to detect the expression of CD34 antigen in nude mice xenografts, and the MVD values were analyzed by statistical analysis.
4. Real-time PCR and Western were used to detect the expression of COX-2, p65, HIF-1 alpha and VEGF mRNA and protein in each group.
Result
1. compared with the control group, RGZ and TRG could obviously inhibit the growth of xenografts in nude mice, and there was a significant difference between the tumor volume and the mass group of the control group and the experimental group (P0.05).
2. during treatment, no obvious adverse reactions were observed in nude mice. No significant organic changes were found in heart, liver, lung, spleen, kidney and other important organs at the end of treatment.
3. compared with the control group, the MVD value in the tumor tissue of the experimental group was significantly reduced, and the difference of MVD between the three groups was statistically significant (P0.01).
The results of 4. Real-time PCR and Western showed that RGZ and TRG could inhibit the expression of COX-2, p65 and VEGF mRNA and protein and HIF-1 alpha protein in nude mice, and there was a statistically significant difference between groups (P0.05).
conclusion
1.RGZ and TRG have inhibitory effect on Hep-2 cells in concentration and time dependent proliferation, blocking Hep-2 cells in G0/G1 stage and inducing apoptosis. The mechanism is related to the inhibition of COX-2 and p65 protein and the expression of mRNA and VEGF mRNA, and down regulation of the secretion of VEGF protein.
In 2. anoxic environment, RGZ or TRG still inhibited the proliferation of Hep-2 cells, inhibited the expression of VEGFmRNA and the secretion of VEGF protein in the culture supernatant, and lowered the level of HIF-1 alpha protein induced by hypoxia; its mechanism was closely related to the inhibition of the phosphorylation of AKT, ERK1/2 and STAT3 protein and the degradation of HIF-1 alpha protein through the egg white enzyme pathway. It can inhibit the invasion of Hep-2 cells in normoxic and hypoxic environment, and its mechanism is closely related to the reduction of MMP-2 activity.
3.RGZ and TRG can inhibit the growth of transplanted tumor in nude mice, reduce the MVD value of tumor tissue, and down regulate the expression of COX-2, p65, HIF-1 A and VEGF in the transplanted tumor of the larynx, and have no toxic and side effects on the body.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R739.65

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