塞来昔布抗胃癌作用机制及Fas、FasL在胃癌中表达意义的研究
|
摘要
研究背景胃癌是人类常见的恶性肿瘤之一,发病率和死亡率居我国各类恶性肿瘤的首位。临床早期胃癌大多无症状或症状不典型,早期诊断困难;临床就诊者大部分属于中、晚期,失去手术机会或术后易复发。因此,提高胃癌患者生活质量和无病生存期的化疗显得很重要。目前常用的化疗药物副作用大且疗效欠佳。因此寻找新的安全有效的非细胞毒化疗药物是目前胃癌等消化道肿瘤防治方面需要迫切解决的课题。
细胞增殖和凋亡是细胞生物学行为的两个重要方面,肿瘤的发生即为细胞恶性增殖和凋亡失控所致。近年来,Fas和FasL在消化道肿瘤中尤其在胃癌前病变、胃癌中的表达及其与细胞凋亡之间的关系已引起广泛关注。Fas是细胞表面重要的死亡受体,与其配体FasL结合活化并传导凋亡信号是诱导细胞凋亡的重要途径,Fas与FasL结合后,通过胞浆内Fas相关死亡域蛋白(FADD),再和门冬氨酸特异半胱氨酸蛋白酶(caspase-8)酶原发生相互作用,激活caspase-8酶原,进一步激活多种caspase联级反应,最终导致细胞凋亡。既往研究已证明胃癌前病变及胃癌组织表达FasL,不仅可以介导表达Fas的胃癌前病变及胃癌细胞凋亡,而且可能介导胃癌前病变及胃癌组织中表达Fas的肿瘤浸润淋巴细胞(TIL)发生凋亡,从而使胃癌细胞逃逸机体自身免疫清除,成为胃癌发生、发展的重要潜在生物学基础。深入研究胃癌及局部淋巴结组织Fas、FasL的表达,为进一步阐明Fas凋亡系统在胃癌发生、发展及免疫逃逸机制和防治方面提供实验依据。
NSAIDS降低胃肠道肿瘤发生的危险性,已成为肿瘤防治领域的研究热点。国外多项大规模的流行病学研究、动物实验和临床研究均发现,长期规律服用非甾体抗炎药(NSAIDS)能使结肠癌发病的危险性降低。我们前期研究发现吲哚美辛(IN)和塞来昔布具有抗结肠肿瘤细胞增殖效应。然而传统的NSAIDS如IN,在抑制COX-2的同时抑制了COX-1,长期服用对胃肠道及肾等脏器产生损害,限制了其在临床上的广泛和长期应用。新型NSAIDS,选择性抑制COX-2,则既有抑瘤作用,又避免了胃肠道副作用。
选择性COX-2抑制剂抑制胃癌细胞增殖,诱导细胞凋亡的研究,倍受肿瘤学专家们关注。国内外多个研究发现塞来昔布有抑制胃癌细胞增殖凋亡作用,对其作用的分子机理研究仅局限于对环氧化酶-2的活性抑制。一些研究表明COX-2抑制剂通过抑制环氧化酶-2的活性,减少前列腺素E2的释放,进而抑制细胞增殖,诱导细胞凋亡。但选择性COX-2抑制剂塞来昔布对细胞周期调控具有重要意义的细胞周期依赖性蛋白激酶抑制因子p16和p21表达的影响,及对细胞Fas、FasL凋亡途径中Fas、FasL蛋白表达和凋亡相关调控因子Bcl-2蛋白表达的影响,国内外尚未见相关文献报道。探讨选择性COX-2抑制剂塞来昔布对BGC-823胃癌细胞抑瘤作用,从细胞周期调控系统,Fas、FasL凋亡系统与凋亡信号转导通路调控等层面,“立体”和系统地研究胃肿瘤细胞增殖和凋亡调控网络,揭示选择性COX-2抑制剂塞来昔布抑制BGC-823胃癌细胞增殖和凋亡调控机理,将为包括塞来昔布在内的选择性COX-2抑制剂抗胃癌等肿瘤的临床应用提供实验依据,为发现新的分子靶标提供新的思路。
第一章塞来昔布抑制BGC-823胃癌细胞增殖及对p16和p21表达的影响
目的:研究塞来昔布对体外培养的BGC-823胃癌细胞增殖的影响及对细胞周期依赖性蛋白激酶抑制因子p16和p21表达的影响。方法:采用MTT比色法检测塞来昔布对BGC-823胃癌细胞增殖的抑制;通过流式细胞仪技术研究不同浓度的塞来昔布对BGC-823胃癌细胞周期的影响;通过RT-PCR技术检测塞来昔布对细胞周期依赖性蛋白激酶抑制因子p16 mRNA及p21 mRNA表达的影响。结果:①塞来昔布浓度为20,40,60,80,100,120μmol/L,24hr时抑制率(%)分别为:7.63±2.66,13.33±0.95,18.83±0.91,24.63±1.55,33.20±1.14,55.00±6.50;48hr时抑制率(%)分别为:10.72±3.20,25.16±2.70,37.22±1.60,42.42±2.41,46.79±4.57,91.64±4.14:72hr时抑制率(%)分别为:10.91±1.61,31.39±3.20,54.82±1.25,62.41±5.51,74.88±1.02,98.17±0.69。塞来昔布各浓度组均抑制胃癌细胞BGC-823的生长,并呈时间和浓度依赖性。②流式细胞仪检测结果显示:塞来昔布浓度为0,20,40,60,80,100μmol/L时,G_1期细胞数比例分别为0.603±0.016,0.643±0.006,0.671±0.005,0.708±0.008,0.750±0.007,0.787±0.006;S期细胞数比例分别为0.307±0.006,0.223±0.003,0.209±0.005,0.193±0.015,0.157±0.005,0.122±0.006。塞来昔布随浓度增加G_1期细胞数比例逐渐增加,S期细胞数比例逐渐减少。各浓度组间细胞数比例两两比较,具有显著性差异(P＜0.05)。③RT-PCR结果显示不同浓度塞来昔布作用于BGC-823胃癌细胞后,塞来昔布各浓度组p16 mRNA和p21 mRNA扩增产物均有表达。塞来昔布浓度为0,20,40,60,80,100μmol/L时,p16 mRNA表达的相对丰度分别为:0.223±0.006,0.296±0.012,0.381±0.008,0.438±0.017,0.494±0.002,0.663±0.068;p21 mRNA表达的相对丰度分别为:0.435±0.045,0.642±0.098,0.730±0.014,0.813±0.069,0.907±0.058,1.030±0.051,p16 mRNA和p21 mRNA表达的相对丰度随塞来昔布浓度增加而增加。各浓度组间相对丰度两两比较,具有显著性差异(P＜0.05)。结论:①塞来昔布抑制BGC-823胃癌细胞增殖,呈时间和浓度依赖性。②塞来昔布干预BGC-823胃癌细胞增殖,使G_1期细胞数增多,S期细胞数减少,阻滞胃癌细胞周期于G_1期。③塞来昔布通过上调细胞周期依赖性蛋白激酶抑制因子p21mRNA和p16 mRNA表达,抑制BGC-823胃癌细胞周期进展。
第二章塞来昔布诱导BGC-823胃癌细胞凋亡及对Fas、FasL及Bd-2表达的影响
目的:研究塞来昔布诱导BGC-823胃癌细胞凋亡及对凋亡相关蛋白Fas、FasL及Bcl-2表达的影响。方法:通过流式细胞仪技术观察不同浓度的塞来昔布对BGC-823胃癌细胞凋亡的影响;通过WesternBlotting技术检测塞来昔布对凋亡相关蛋白Fas、FasL和Bcl-2表达的影响。结果:①流式细胞仪检测发现:塞来昔布浓度在0,20,40,60,80,100μmol/L时,凋亡细胞比率(%)分别为:0.503±0.018,5.870±0.325,11.396±0.267,17.567±0.376,24.439±0.326,52.933±2.575;随塞来昔布浓度增加凋亡细胞比率增加。各浓度组间凋亡细胞比率两两比较,具有显著性差异(P＜0.05)。②WesternBlotting结果显示:塞来昔布浓度为0,20,40,60,80,100μmol/L时,作用BGC-823胃癌细胞48h后,Fas蛋白相对含量分别是0.1113±0.0037,0.1017±0.0065,0.1975±0.0100,0.3297±0.0053,0.4595±0.0045,0.5204±0.0148;FasL蛋白相对含量分别是0.8070±0.0268,0.7311±0.0780,0.6254±0.0501,0.5465±0.0180,0.4378±0.0081,0.3760±0.0034;Bcl-2蛋白相对含量分别是0.5448±0.0049,0.5213±0.0326,0.4256±0.0421,0.3934±0.0305,0.2659±0.0121,0.2294±0.0081。在0～100μmol/L浓度范围内Fas蛋白表达上调和FasL、Bcl-2蛋白表达下调,均呈浓度依赖性。各浓度组间蛋白相对含量两两比较,具有显著性差异(P＜0.05)。结论:①塞来昔布诱导BGC-823胃癌细胞凋亡,在一定范围内呈浓度依赖性。②塞来昔布在一定浓度范围内,Fas蛋白表达呈浓度依赖性上调,FasL、Bcl-2蛋白表达呈浓度依赖性下调。③塞来昔布诱导胃癌细胞凋亡可能与Fas蛋白上调,FasL、Bcl-2蛋白下调有关。
第三章Fas、FasL在胃癌及局部淋巴结组织中表达意义
目的:探讨胃癌及局部淋巴结组织中Fas、FasL蛋白的表达与胃癌发生发展及转移的关系。方法:通过免疫组化方法研究64例胃癌及局部淋巴结组织和20例正常胃组织Fas和FasL蛋白的表达,并分析其与年龄、性别、病理亚型和有无淋巴结转移的关系。结果:①正常胃组织Fas蛋白阳性表达率高,在胃癌组织中Fas蛋白阳性表达率低;正常胃组织FasL蛋白阳性表达率低,在胃癌组织中FasL蛋白阳性表达率高。二者间阳性表达均有显著性差异(P＜0.001)。②Fas蛋白在有侵犯组淋巴结组织中阳性表达率高,在无侵犯组淋巴结组织中阳性表达率低,二者间阳性表达有显著性差异(P=0.003)。FasL在两组淋巴结组织中阳性表达无差异(P=0.593)。③Fas蛋白在高中分化组胃癌组织中阳性表达率高,在低分化组胃癌组织中阳性表达低,二组间阳性表达有显著性差异(P=0.015)。反之,FasL蛋白在高中分化组胃癌组织中阳性表达率低,在低分化组胃癌组织中阳性表达率高,二组间阳性表达有显著性差异(P=0.021)。④胃癌组织中Fas、FasL蛋白阳性表达率与年龄、性别及是否有淋巴结转移无明显关系。⑤胃癌组织中Fas和FasL两者间阳性表达率,两两比较有显著性差异(P＜0.001);两者表达无直线相关性(r_s=-0.425,P=0.575)。结论:①胃癌组织中Fas蛋白表达下调,FasL蛋白表达上调。②有侵犯淋巴结组织中Fas蛋白表达上调,无侵犯淋巴结组织中表达下调。③高分化胃癌组织中Fas蛋白阳性表达高于低分化胃癌组织;高分化胃癌组织中FasL蛋白阳性表达低于低分化胃癌组织。
Background Gastric carcinoma is the most common human malignancies,morbidity and mortality in our country home of the first types of tumors.Clinically,most of the early gastric cancer has no symptoms or no typical symptoms,which has brought difficulty to early diagnosis;on the clinical the majority of doctors' offices visiting of patients belong to advanced gastric cancer,which lose the opportunity to surgery or relapse easily after operation.As a result,improving the quality of life of patients with gastric cancer and disease-free survival of the chemotherapy appears to be very important.At present,common chemotherapeutics have more drug side effects,and the efficacy below the mark.Therefore,it is an urgent need to resolve the issue that the gastrointestinal cancer prevention and treatment need research and develop the new of safe and effective chemotherapy drugs.
Cell proliferation and apoptosis in cell biology are two important aspects of behavior.The incidence of tumor cell proliferation and apoptosis is caused by out of control.In recent years,it has attracted great attention about the expression of Fas and FasL in the digestive tract tumors,especially in precancerous lesions of gastric and gastric cancer, and its relationship with cell apoptosis.Fas as important death receptor of cell surface,binding FasL and activation of apoptosis signal transduction is an important way of induced apoptosis.FasL and Fas bind through intracytoplasmic Fas-associated death domain protein(FADD),that interact to activate caspase-8 zymogen to further caspase activation together a variety of class reaction,eventually leading to apoptosis.Past research has proved the expression of FasL in gastric cancer and gastric precancerous lesions,which can mediate gastric cancer and gastric precancerous lesions cell with expression of Fas apoptosis and mediate TIL cells expression of Fas apoptosis in gastric precancerous lesions and gastric cancer tissue,which make the gastric cancer cells escape the body's own immune clearance and become a potential biological basis of genesis and survival and development of gastric cancer.To depth study expression of Fas and FasL in gastric cancer and local lymph node tissues is of great significance to further clarify the Fas system in apoptosis of gastric cancer,development and immune escape mechanisms and provide experimental evidence for prevention and treatment.
NSAIDS can reduce the gastrointestinal cancer risk,which has become another hot spot in recent years in the field of prevention and treatment tumor.Abroad,a number of large-scale epidemiological studies, animal experiments and clinical studies have found that long-term use of the law of non-steroidal anti-inflammatory drugs(NSAIDS) can reduce the risk of the incidence of colon cancer.Our preliminary studies found that indomethacin(IN) and celecoxib have anti-colon tumor cell proliferation effect.Traditional NSAIDs,such as IN,can inhibit COX-2 at the same time COX-1,and thus the gastrointestinal tract and kidneys organ damage because of long-term use will have to limit its wide range and long-term of clinical applications.New NSAIDs,selectively inhibiting COX-2,are both anti-tumor effect and avoiding the side effects.
Oncology experts pay much attention to whether selective COX-2 inhibitors inhibit gastric cancer cell proliferation and induce apoptosis or not.Some study at home and abroad found that celecoxib has inhibited apoptosis and proliferation in gastric cancer cell,its role is limited to the molecular mechanism of celecoxib inhibition the activity of cyclooxygenase-2.Some studies show that COX-2 inhibitors can inhibit the activity of cyclooxygenase -2 and reduce the release of prostaglandin E2,thereby inhibiting cell proliferation and induced apoptosis.However, selective COX-2 inhibitors on gastric cancer cell proliferation and related regulatory genes p16 and p21 expression,and apoptosis-related proteins Fas,FasL and Bcl-2 protein expression in small studies.We explore the selective COX-2 inhibitor celecoxib on gastric cancer cells BGC-823 anti-tumor effect from the cell cycle regulation and control system,Fas, FasL system and the apoptosis signaling pathway level,and so on, "Stereo" and systematically research stomach tumor cell proliferation and apoptosis regulation and control network,revealed a selective COX-2 inhibitor celecoxib inhibited gastric cancer cell proliferation and apoptosis regulation and control mechanism,provided the experimental basis for clinical applications a selective COX-2 inhibitor anti-gastric tumors including celecoxib,as well as to provide new ideas for detecting new molecular targets.
ChapterⅠEffects of Celeeoxib on cell proliferation in human gastric cancer cell line BGC-823 and expression of p16 and p21
Objectives:To explore the effects of Celecoxib on cell proliferation of human gastric cancer cell line BGC-823 and expression of cell cycle regulation -related factor p16 and p21.Methods:MTT assay were used to quantify the influence of Celecoxib on the proliferation of gastric cancer cell line BGC-823.Flow cytometry(FCM) were used to measure the influence of Celecoxib on cell cycle of difference concentration celecoxib on BGC-823 cell.The expressions of p16 and p21 mRNA with difference concentration celecoxib on BGC-823 cell were observed by RT-PCR analysis.Results:①Celecoxib concentration 20,40,60,80,100,120μmol/L respectively,cultivating for 24hr the inhibition rate(%) were 7.63±2.66,13.33±0.95,18.83±9.10,24.63±1.55,33.20±1.14,55.00±6.50; 48hr when the inhibition rate(%),respectively:10.72±3.20,25.16±2.70,37.22±1.60,42.42±2.41,46.79±4.57,91.64±4.14;72hr when the inhibition rate(%),respectively:10.91±1.61,31.39±3.20,54.82±1.25,62.41±5.51,74.88±1.02,98.17±0.69Difference concentration celecoxib inhibited the cell growth rates of gastric cancer cell line BGC-823 in a time -dependent and concentration -dependent manner.②FCM showed:Celecoxib concentration 20,40,60,80,100,120μmol/L respectively,the proportion of G1 phase cells were 0.603±0.016,0.643±0.006,0.671±0.005,0.708±0.008,0.750±0.007,0.787±0.006;S phase cell ratio were 0.307±0.006,0.223±0.003,0.209±0.005,0.193±0.015,0.157±0.005,0.122±0.006;Celecoxib increased the proportion of cells in G_1 phase,whereas decreased the proportion of cells in the S phase in a concentration-dependent manner from 0 to 100μmol/L in BGC-823 cells.The proportion of cells between various concentration celecoxib groups has significant differences,(P＜0.05).③RT-PCR results showed that there were expressions of p16 and p21 amplified product by different concentrations of celecoxib on BGC-823 cells, relative abundance of expressions of p16 and p21 amplified product increased with celecoxib concentration.Celecoxib concentration 20,40,60,80,100,120μmol/L respectively,p16 PCR products relative abundance,respectively:0.223±0.006,0.296±0.012,0.381±0.008, 0.438±0.017,0.494±0.002,0.663±0.068:p21 PCR products relative abundance,respectively:0.435±0.045,0.642±0.098,0.730±0.014, 0.813±0.069,0.907±0.058,1.030±0.051.The relative abundance of p16 and p21 between various concentration celecoxib groups has significant differences,(P＜0.05).
Conclusions:①Celecoxib inhibited BGC-823 gastric cancer cell proliferation,showing time and dose-dependent manner.②Celecoxib inhibited BGC-823 gastric cancer cell proliferation;G1 phase cells increased and S phase cells decrease in celecoxib on BGC-823gastric cancer cell,which block cell cycle in G1 phase.③Celecoxib inhibited cell cycle progress of BGC-823 gastric cancer cell,which may be associated with up-regulation of the expression of cell cycle dependent protein kinase p16 and p21,and alteration cell cycle progression.
ChapterⅡEffects of Celecoxib on cell apoptosis in human gastric cancer cell line BGC-823 and expression of Fas,FasL and Bcl-2
Objectives:To explore the effect of Celecoxib on cell apoptosis of human gastric cancer cell line BGC-823 and expression of Fas,FasL and Bcl-2.Methods:Flow cytometry was used to quantify the influence of Celecoxib on the apoptosis of gastric cancer cell line BGC-823.The expressions of Fas,FasL,bcl-2 proteins were observed by Western blot analysis.Results:①Flow cytometry found that the ratio of apoptotic cells increased with the concentration of celecoxib increased;Celecoxib concentration at 0,20,40,60,80100μmol / L,ratio of apoptotic cells(%) were:0.503±0.018,5.870±0.325,11.396±0.267,17.567±0.376, 24.439±0.326,52.933±2.575.The apoptotic rates of cells between various concentration celecoxib groups has significant differences,(P＜0.05).②Western blotting analysis showed:Celecoxib concentration at 0,20,40,60,80,100μmol / L,cultivating for 48h on BGC-823 gastric cancer cells,Relative content of Fas protein were 0.1113±0.0037,0.1017±0.0065,0.1975±0.0100,0.3297±0.0053,0.4595±0.0045,0.5204±0.0148;Relative content of FasL protein were 0.8070±0.0268,0.7311±0.0780,0.6254±0.0501,0.5465±0.0180,0.4378±0.0081,0.3760±0.0034;Relative content of Bcl-2 protein were 0.5448±0.0049,0.5213±0.0326,0.4256±0.0421,0.3934±0.0305,0.2659±0.0121,0.2294±0.0081.The expression of Fas was up-regulated,whereas the expressions of FasL and bcl-2 proteins were down-regulated in a concentration-dependent manner from 0 to 100μmol/L in gastric cancer cell line BGC-823.The expressions of Fas,FasL and Bcl-2 proteins between various concentration celecoxib groups have significant differences(P＜0.05,respsctively).Conclusions:①Celecoxib-induced gastric cancer BGC-823 cell apoptosis,to a certain range of dose-dependent manner.②At a certain celecoxib concentration scope, Fas protein increased and FasL,Bcl-2 protein reduced were dose-dependent manner.③Celecoxib induced cell apoptosis in gastric cancer cell line BGC-823,which may be associated with up-regulation of the expressions of Fas protein and down-regulated of the expressions of FasL and bcl-2 protein.
ChapterⅢExpression significance of Fas and FasL in gastric cancer tissues and local lymph nodes tissues
Objective:To investigate the relationship between the expression of Fas and FasL protein with genesis,development and transfer of gastric cancer.Methods:FasL and Fas expression of 64 cases gastric cancer and 20 cases normal gastric tissue were studied by immunohistochemistry, and analysis the relationship between their age,gender,pathological subtype and lymph node metastasis with FasL and Fas expression.
Results:①Expression of Fas protein in normal gastric tissue is high, expression of Fas protein in gastric cancer tissue is low.Expression of FasL protein in normal gastric tissue is low;expression of FasL protein in gastric cancer tissue is high.The positive expressions between the two groups have significant differences,(P<0.001).②Expression of Fas in infringement lymph node tissue is high;Expression of Fas in non-infringement lymph node tissues is low.Fas positive expressions between the two groups have significant differences,(P=0.003).FasL positive expression between the two groups lymph tissues have no difference,(P=0.593).③Expression of Fas protein in highly and moderately differentiated gastric cancer tissue is high;Expression of Fas protein in poorly differentiated gastric cancer tissue is low.Expression of FasL protein in highly and moderately differentiated gastric cancer tissue is low;Expression of FasL protein in poorly differentiated gastric cancer tissue is high.The positive expressions between the two groups have significant differences,(P=0.015 and P=0.021,respectively).④There is no significant relationship between age,sex and whether or not lymph node metastases with expression of Fas and FasL in gastric cancer.⑤There was a significant difference between Fas and FasL positive expression rate in gastric cancer(P＜0.001);both the expression of non-linear correlation(rs=-0.425,P=0.575).Conclusions:①Fas expression in gastric cancer down-regulation,FasL expression in gastric cancer up-regulation.②Fas expression in infringement lymph node tissue up-regulation,in non-infringement lymph node tissues down-regulation.③Fas expressions in the well-differentiated gastric cancer were higher than it in poorly differentiated gastric cancer;FasL expressions in the well-differentiated gastric cancer tissues were lower than it in poorly differentiated gastric cancer.
细胞增殖和凋亡是细胞生物学行为的两个重要方面,肿瘤的发生即为细胞恶性增殖和凋亡失控所致。近年来,Fas和FasL在消化道肿瘤中尤其在胃癌前病变、胃癌中的表达及其与细胞凋亡之间的关系已引起广泛关注。Fas是细胞表面重要的死亡受体,与其配体FasL结合活化并传导凋亡信号是诱导细胞凋亡的重要途径,Fas与FasL结合后,通过胞浆内Fas相关死亡域蛋白(FADD),再和门冬氨酸特异半胱氨酸蛋白酶(caspase-8)酶原发生相互作用,激活caspase-8酶原,进一步激活多种caspase联级反应,最终导致细胞凋亡。既往研究已证明胃癌前病变及胃癌组织表达FasL,不仅可以介导表达Fas的胃癌前病变及胃癌细胞凋亡,而且可能介导胃癌前病变及胃癌组织中表达Fas的肿瘤浸润淋巴细胞(TIL)发生凋亡,从而使胃癌细胞逃逸机体自身免疫清除,成为胃癌发生、发展的重要潜在生物学基础。深入研究胃癌及局部淋巴结组织Fas、FasL的表达,为进一步阐明Fas凋亡系统在胃癌发生、发展及免疫逃逸机制和防治方面提供实验依据。
NSAIDS降低胃肠道肿瘤发生的危险性,已成为肿瘤防治领域的研究热点。国外多项大规模的流行病学研究、动物实验和临床研究均发现,长期规律服用非甾体抗炎药(NSAIDS)能使结肠癌发病的危险性降低。我们前期研究发现吲哚美辛(IN)和塞来昔布具有抗结肠肿瘤细胞增殖效应。然而传统的NSAIDS如IN,在抑制COX-2的同时抑制了COX-1,长期服用对胃肠道及肾等脏器产生损害,限制了其在临床上的广泛和长期应用。新型NSAIDS,选择性抑制COX-2,则既有抑瘤作用,又避免了胃肠道副作用。
选择性COX-2抑制剂抑制胃癌细胞增殖,诱导细胞凋亡的研究,倍受肿瘤学专家们关注。国内外多个研究发现塞来昔布有抑制胃癌细胞增殖凋亡作用,对其作用的分子机理研究仅局限于对环氧化酶-2的活性抑制。一些研究表明COX-2抑制剂通过抑制环氧化酶-2的活性,减少前列腺素E2的释放,进而抑制细胞增殖,诱导细胞凋亡。但选择性COX-2抑制剂塞来昔布对细胞周期调控具有重要意义的细胞周期依赖性蛋白激酶抑制因子p16和p21表达的影响,及对细胞Fas、FasL凋亡途径中Fas、FasL蛋白表达和凋亡相关调控因子Bcl-2蛋白表达的影响,国内外尚未见相关文献报道。探讨选择性COX-2抑制剂塞来昔布对BGC-823胃癌细胞抑瘤作用,从细胞周期调控系统,Fas、FasL凋亡系统与凋亡信号转导通路调控等层面,“立体”和系统地研究胃肿瘤细胞增殖和凋亡调控网络,揭示选择性COX-2抑制剂塞来昔布抑制BGC-823胃癌细胞增殖和凋亡调控机理,将为包括塞来昔布在内的选择性COX-2抑制剂抗胃癌等肿瘤的临床应用提供实验依据,为发现新的分子靶标提供新的思路。
第一章塞来昔布抑制BGC-823胃癌细胞增殖及对p16和p21表达的影响
目的:研究塞来昔布对体外培养的BGC-823胃癌细胞增殖的影响及对细胞周期依赖性蛋白激酶抑制因子p16和p21表达的影响。方法:采用MTT比色法检测塞来昔布对BGC-823胃癌细胞增殖的抑制;通过流式细胞仪技术研究不同浓度的塞来昔布对BGC-823胃癌细胞周期的影响;通过RT-PCR技术检测塞来昔布对细胞周期依赖性蛋白激酶抑制因子p16 mRNA及p21 mRNA表达的影响。结果:①塞来昔布浓度为20,40,60,80,100,120μmol/L,24hr时抑制率(%)分别为:7.63±2.66,13.33±0.95,18.83±0.91,24.63±1.55,33.20±1.14,55.00±6.50;48hr时抑制率(%)分别为:10.72±3.20,25.16±2.70,37.22±1.60,42.42±2.41,46.79±4.57,91.64±4.14:72hr时抑制率(%)分别为:10.91±1.61,31.39±3.20,54.82±1.25,62.41±5.51,74.88±1.02,98.17±0.69。塞来昔布各浓度组均抑制胃癌细胞BGC-823的生长,并呈时间和浓度依赖性。②流式细胞仪检测结果显示:塞来昔布浓度为0,20,40,60,80,100μmol/L时,G_1期细胞数比例分别为0.603±0.016,0.643±0.006,0.671±0.005,0.708±0.008,0.750±0.007,0.787±0.006;S期细胞数比例分别为0.307±0.006,0.223±0.003,0.209±0.005,0.193±0.015,0.157±0.005,0.122±0.006。塞来昔布随浓度增加G_1期细胞数比例逐渐增加,S期细胞数比例逐渐减少。各浓度组间细胞数比例两两比较,具有显著性差异(P＜0.05)。③RT-PCR结果显示不同浓度塞来昔布作用于BGC-823胃癌细胞后,塞来昔布各浓度组p16 mRNA和p21 mRNA扩增产物均有表达。塞来昔布浓度为0,20,40,60,80,100μmol/L时,p16 mRNA表达的相对丰度分别为:0.223±0.006,0.296±0.012,0.381±0.008,0.438±0.017,0.494±0.002,0.663±0.068;p21 mRNA表达的相对丰度分别为:0.435±0.045,0.642±0.098,0.730±0.014,0.813±0.069,0.907±0.058,1.030±0.051,p16 mRNA和p21 mRNA表达的相对丰度随塞来昔布浓度增加而增加。各浓度组间相对丰度两两比较,具有显著性差异(P＜0.05)。结论:①塞来昔布抑制BGC-823胃癌细胞增殖,呈时间和浓度依赖性。②塞来昔布干预BGC-823胃癌细胞增殖,使G_1期细胞数增多,S期细胞数减少,阻滞胃癌细胞周期于G_1期。③塞来昔布通过上调细胞周期依赖性蛋白激酶抑制因子p21mRNA和p16 mRNA表达,抑制BGC-823胃癌细胞周期进展。
第二章塞来昔布诱导BGC-823胃癌细胞凋亡及对Fas、FasL及Bd-2表达的影响
目的:研究塞来昔布诱导BGC-823胃癌细胞凋亡及对凋亡相关蛋白Fas、FasL及Bcl-2表达的影响。方法:通过流式细胞仪技术观察不同浓度的塞来昔布对BGC-823胃癌细胞凋亡的影响;通过WesternBlotting技术检测塞来昔布对凋亡相关蛋白Fas、FasL和Bcl-2表达的影响。结果:①流式细胞仪检测发现:塞来昔布浓度在0,20,40,60,80,100μmol/L时,凋亡细胞比率(%)分别为:0.503±0.018,5.870±0.325,11.396±0.267,17.567±0.376,24.439±0.326,52.933±2.575;随塞来昔布浓度增加凋亡细胞比率增加。各浓度组间凋亡细胞比率两两比较,具有显著性差异(P＜0.05)。②WesternBlotting结果显示:塞来昔布浓度为0,20,40,60,80,100μmol/L时,作用BGC-823胃癌细胞48h后,Fas蛋白相对含量分别是0.1113±0.0037,0.1017±0.0065,0.1975±0.0100,0.3297±0.0053,0.4595±0.0045,0.5204±0.0148;FasL蛋白相对含量分别是0.8070±0.0268,0.7311±0.0780,0.6254±0.0501,0.5465±0.0180,0.4378±0.0081,0.3760±0.0034;Bcl-2蛋白相对含量分别是0.5448±0.0049,0.5213±0.0326,0.4256±0.0421,0.3934±0.0305,0.2659±0.0121,0.2294±0.0081。在0～100μmol/L浓度范围内Fas蛋白表达上调和FasL、Bcl-2蛋白表达下调,均呈浓度依赖性。各浓度组间蛋白相对含量两两比较,具有显著性差异(P＜0.05)。结论:①塞来昔布诱导BGC-823胃癌细胞凋亡,在一定范围内呈浓度依赖性。②塞来昔布在一定浓度范围内,Fas蛋白表达呈浓度依赖性上调,FasL、Bcl-2蛋白表达呈浓度依赖性下调。③塞来昔布诱导胃癌细胞凋亡可能与Fas蛋白上调,FasL、Bcl-2蛋白下调有关。
第三章Fas、FasL在胃癌及局部淋巴结组织中表达意义
目的:探讨胃癌及局部淋巴结组织中Fas、FasL蛋白的表达与胃癌发生发展及转移的关系。方法:通过免疫组化方法研究64例胃癌及局部淋巴结组织和20例正常胃组织Fas和FasL蛋白的表达,并分析其与年龄、性别、病理亚型和有无淋巴结转移的关系。结果:①正常胃组织Fas蛋白阳性表达率高,在胃癌组织中Fas蛋白阳性表达率低;正常胃组织FasL蛋白阳性表达率低,在胃癌组织中FasL蛋白阳性表达率高。二者间阳性表达均有显著性差异(P＜0.001)。②Fas蛋白在有侵犯组淋巴结组织中阳性表达率高,在无侵犯组淋巴结组织中阳性表达率低,二者间阳性表达有显著性差异(P=0.003)。FasL在两组淋巴结组织中阳性表达无差异(P=0.593)。③Fas蛋白在高中分化组胃癌组织中阳性表达率高,在低分化组胃癌组织中阳性表达低,二组间阳性表达有显著性差异(P=0.015)。反之,FasL蛋白在高中分化组胃癌组织中阳性表达率低,在低分化组胃癌组织中阳性表达率高,二组间阳性表达有显著性差异(P=0.021)。④胃癌组织中Fas、FasL蛋白阳性表达率与年龄、性别及是否有淋巴结转移无明显关系。⑤胃癌组织中Fas和FasL两者间阳性表达率,两两比较有显著性差异(P＜0.001);两者表达无直线相关性(r_s=-0.425,P=0.575)。结论:①胃癌组织中Fas蛋白表达下调,FasL蛋白表达上调。②有侵犯淋巴结组织中Fas蛋白表达上调,无侵犯淋巴结组织中表达下调。③高分化胃癌组织中Fas蛋白阳性表达高于低分化胃癌组织;高分化胃癌组织中FasL蛋白阳性表达低于低分化胃癌组织。
Background Gastric carcinoma is the most common human malignancies,morbidity and mortality in our country home of the first types of tumors.Clinically,most of the early gastric cancer has no symptoms or no typical symptoms,which has brought difficulty to early diagnosis;on the clinical the majority of doctors' offices visiting of patients belong to advanced gastric cancer,which lose the opportunity to surgery or relapse easily after operation.As a result,improving the quality of life of patients with gastric cancer and disease-free survival of the chemotherapy appears to be very important.At present,common chemotherapeutics have more drug side effects,and the efficacy below the mark.Therefore,it is an urgent need to resolve the issue that the gastrointestinal cancer prevention and treatment need research and develop the new of safe and effective chemotherapy drugs.
Cell proliferation and apoptosis in cell biology are two important aspects of behavior.The incidence of tumor cell proliferation and apoptosis is caused by out of control.In recent years,it has attracted great attention about the expression of Fas and FasL in the digestive tract tumors,especially in precancerous lesions of gastric and gastric cancer, and its relationship with cell apoptosis.Fas as important death receptor of cell surface,binding FasL and activation of apoptosis signal transduction is an important way of induced apoptosis.FasL and Fas bind through intracytoplasmic Fas-associated death domain protein(FADD),that interact to activate caspase-8 zymogen to further caspase activation together a variety of class reaction,eventually leading to apoptosis.Past research has proved the expression of FasL in gastric cancer and gastric precancerous lesions,which can mediate gastric cancer and gastric precancerous lesions cell with expression of Fas apoptosis and mediate TIL cells expression of Fas apoptosis in gastric precancerous lesions and gastric cancer tissue,which make the gastric cancer cells escape the body's own immune clearance and become a potential biological basis of genesis and survival and development of gastric cancer.To depth study expression of Fas and FasL in gastric cancer and local lymph node tissues is of great significance to further clarify the Fas system in apoptosis of gastric cancer,development and immune escape mechanisms and provide experimental evidence for prevention and treatment.
NSAIDS can reduce the gastrointestinal cancer risk,which has become another hot spot in recent years in the field of prevention and treatment tumor.Abroad,a number of large-scale epidemiological studies, animal experiments and clinical studies have found that long-term use of the law of non-steroidal anti-inflammatory drugs(NSAIDS) can reduce the risk of the incidence of colon cancer.Our preliminary studies found that indomethacin(IN) and celecoxib have anti-colon tumor cell proliferation effect.Traditional NSAIDs,such as IN,can inhibit COX-2 at the same time COX-1,and thus the gastrointestinal tract and kidneys organ damage because of long-term use will have to limit its wide range and long-term of clinical applications.New NSAIDs,selectively inhibiting COX-2,are both anti-tumor effect and avoiding the side effects.
Oncology experts pay much attention to whether selective COX-2 inhibitors inhibit gastric cancer cell proliferation and induce apoptosis or not.Some study at home and abroad found that celecoxib has inhibited apoptosis and proliferation in gastric cancer cell,its role is limited to the molecular mechanism of celecoxib inhibition the activity of cyclooxygenase-2.Some studies show that COX-2 inhibitors can inhibit the activity of cyclooxygenase -2 and reduce the release of prostaglandin E2,thereby inhibiting cell proliferation and induced apoptosis.However, selective COX-2 inhibitors on gastric cancer cell proliferation and related regulatory genes p16 and p21 expression,and apoptosis-related proteins Fas,FasL and Bcl-2 protein expression in small studies.We explore the selective COX-2 inhibitor celecoxib on gastric cancer cells BGC-823 anti-tumor effect from the cell cycle regulation and control system,Fas, FasL system and the apoptosis signaling pathway level,and so on, "Stereo" and systematically research stomach tumor cell proliferation and apoptosis regulation and control network,revealed a selective COX-2 inhibitor celecoxib inhibited gastric cancer cell proliferation and apoptosis regulation and control mechanism,provided the experimental basis for clinical applications a selective COX-2 inhibitor anti-gastric tumors including celecoxib,as well as to provide new ideas for detecting new molecular targets.
ChapterⅠEffects of Celeeoxib on cell proliferation in human gastric cancer cell line BGC-823 and expression of p16 and p21
Objectives:To explore the effects of Celecoxib on cell proliferation of human gastric cancer cell line BGC-823 and expression of cell cycle regulation -related factor p16 and p21.Methods:MTT assay were used to quantify the influence of Celecoxib on the proliferation of gastric cancer cell line BGC-823.Flow cytometry(FCM) were used to measure the influence of Celecoxib on cell cycle of difference concentration celecoxib on BGC-823 cell.The expressions of p16 and p21 mRNA with difference concentration celecoxib on BGC-823 cell were observed by RT-PCR analysis.Results:①Celecoxib concentration 20,40,60,80,100,120μmol/L respectively,cultivating for 24hr the inhibition rate(%) were 7.63±2.66,13.33±0.95,18.83±9.10,24.63±1.55,33.20±1.14,55.00±6.50; 48hr when the inhibition rate(%),respectively:10.72±3.20,25.16±2.70,37.22±1.60,42.42±2.41,46.79±4.57,91.64±4.14;72hr when the inhibition rate(%),respectively:10.91±1.61,31.39±3.20,54.82±1.25,62.41±5.51,74.88±1.02,98.17±0.69Difference concentration celecoxib inhibited the cell growth rates of gastric cancer cell line BGC-823 in a time -dependent and concentration -dependent manner.②FCM showed:Celecoxib concentration 20,40,60,80,100,120μmol/L respectively,the proportion of G1 phase cells were 0.603±0.016,0.643±0.006,0.671±0.005,0.708±0.008,0.750±0.007,0.787±0.006;S phase cell ratio were 0.307±0.006,0.223±0.003,0.209±0.005,0.193±0.015,0.157±0.005,0.122±0.006;Celecoxib increased the proportion of cells in G_1 phase,whereas decreased the proportion of cells in the S phase in a concentration-dependent manner from 0 to 100μmol/L in BGC-823 cells.The proportion of cells between various concentration celecoxib groups has significant differences,(P＜0.05).③RT-PCR results showed that there were expressions of p16 and p21 amplified product by different concentrations of celecoxib on BGC-823 cells, relative abundance of expressions of p16 and p21 amplified product increased with celecoxib concentration.Celecoxib concentration 20,40,60,80,100,120μmol/L respectively,p16 PCR products relative abundance,respectively:0.223±0.006,0.296±0.012,0.381±0.008, 0.438±0.017,0.494±0.002,0.663±0.068:p21 PCR products relative abundance,respectively:0.435±0.045,0.642±0.098,0.730±0.014, 0.813±0.069,0.907±0.058,1.030±0.051.The relative abundance of p16 and p21 between various concentration celecoxib groups has significant differences,(P＜0.05).
Conclusions:①Celecoxib inhibited BGC-823 gastric cancer cell proliferation,showing time and dose-dependent manner.②Celecoxib inhibited BGC-823 gastric cancer cell proliferation;G1 phase cells increased and S phase cells decrease in celecoxib on BGC-823gastric cancer cell,which block cell cycle in G1 phase.③Celecoxib inhibited cell cycle progress of BGC-823 gastric cancer cell,which may be associated with up-regulation of the expression of cell cycle dependent protein kinase p16 and p21,and alteration cell cycle progression.
ChapterⅡEffects of Celecoxib on cell apoptosis in human gastric cancer cell line BGC-823 and expression of Fas,FasL and Bcl-2
Objectives:To explore the effect of Celecoxib on cell apoptosis of human gastric cancer cell line BGC-823 and expression of Fas,FasL and Bcl-2.Methods:Flow cytometry was used to quantify the influence of Celecoxib on the apoptosis of gastric cancer cell line BGC-823.The expressions of Fas,FasL,bcl-2 proteins were observed by Western blot analysis.Results:①Flow cytometry found that the ratio of apoptotic cells increased with the concentration of celecoxib increased;Celecoxib concentration at 0,20,40,60,80100μmol / L,ratio of apoptotic cells(%) were:0.503±0.018,5.870±0.325,11.396±0.267,17.567±0.376, 24.439±0.326,52.933±2.575.The apoptotic rates of cells between various concentration celecoxib groups has significant differences,(P＜0.05).②Western blotting analysis showed:Celecoxib concentration at 0,20,40,60,80,100μmol / L,cultivating for 48h on BGC-823 gastric cancer cells,Relative content of Fas protein were 0.1113±0.0037,0.1017±0.0065,0.1975±0.0100,0.3297±0.0053,0.4595±0.0045,0.5204±0.0148;Relative content of FasL protein were 0.8070±0.0268,0.7311±0.0780,0.6254±0.0501,0.5465±0.0180,0.4378±0.0081,0.3760±0.0034;Relative content of Bcl-2 protein were 0.5448±0.0049,0.5213±0.0326,0.4256±0.0421,0.3934±0.0305,0.2659±0.0121,0.2294±0.0081.The expression of Fas was up-regulated,whereas the expressions of FasL and bcl-2 proteins were down-regulated in a concentration-dependent manner from 0 to 100μmol/L in gastric cancer cell line BGC-823.The expressions of Fas,FasL and Bcl-2 proteins between various concentration celecoxib groups have significant differences(P＜0.05,respsctively).Conclusions:①Celecoxib-induced gastric cancer BGC-823 cell apoptosis,to a certain range of dose-dependent manner.②At a certain celecoxib concentration scope, Fas protein increased and FasL,Bcl-2 protein reduced were dose-dependent manner.③Celecoxib induced cell apoptosis in gastric cancer cell line BGC-823,which may be associated with up-regulation of the expressions of Fas protein and down-regulated of the expressions of FasL and bcl-2 protein.
ChapterⅢExpression significance of Fas and FasL in gastric cancer tissues and local lymph nodes tissues
Objective:To investigate the relationship between the expression of Fas and FasL protein with genesis,development and transfer of gastric cancer.Methods:FasL and Fas expression of 64 cases gastric cancer and 20 cases normal gastric tissue were studied by immunohistochemistry, and analysis the relationship between their age,gender,pathological subtype and lymph node metastasis with FasL and Fas expression.
Results:①Expression of Fas protein in normal gastric tissue is high, expression of Fas protein in gastric cancer tissue is low.Expression of FasL protein in normal gastric tissue is low;expression of FasL protein in gastric cancer tissue is high.The positive expressions between the two groups have significant differences,(P<0.001).②Expression of Fas in infringement lymph node tissue is high;Expression of Fas in non-infringement lymph node tissues is low.Fas positive expressions between the two groups have significant differences,(P=0.003).FasL positive expression between the two groups lymph tissues have no difference,(P=0.593).③Expression of Fas protein in highly and moderately differentiated gastric cancer tissue is high;Expression of Fas protein in poorly differentiated gastric cancer tissue is low.Expression of FasL protein in highly and moderately differentiated gastric cancer tissue is low;Expression of FasL protein in poorly differentiated gastric cancer tissue is high.The positive expressions between the two groups have significant differences,(P=0.015 and P=0.021,respectively).④There is no significant relationship between age,sex and whether or not lymph node metastases with expression of Fas and FasL in gastric cancer.⑤There was a significant difference between Fas and FasL positive expression rate in gastric cancer(P＜0.001);both the expression of non-linear correlation(rs=-0.425,P=0.575).Conclusions:①Fas expression in gastric cancer down-regulation,FasL expression in gastric cancer up-regulation.②Fas expression in infringement lymph node tissue up-regulation,in non-infringement lymph node tissues down-regulation.③Fas expressions in the well-differentiated gastric cancer were higher than it in poorly differentiated gastric cancer;FasL expressions in the well-differentiated gastric cancer tissues were lower than it in poorly differentiated gastric cancer.
引文
[1]Solomon DA,Kim JS,Jean W,Waldman T.Conspirators in a capital crime:co-deletion of p18INK4c and p16INK4a/p14ARF/p15INK4b in glioblastoma multiforme.Cancer Res,2008,68(21):8657 - 8660.
[2]刘海峰,刘为纹,房殿春.胃癌及其癌前病变中细胞凋亡与细胞增殖间关系的研究.世界华人消化杂志1999,7:649-651
[3]Fukuzawa K,Takahashi K,Furuta K,et al.Expression of fas/fas ligand(fasL)and its involvement in infiltrating lymphocytes in hepatoceilular carcinoma (HCC).J Gastroenterol,2001,36:681-688
[4]Lim SC.Fas-related apoptosis in gastric adenocarcinoma[J].Oncol Rep,2003,10:57-63
[5]Muzio,M,ChinnaiyanAM,Kischke1 FC,etal.FIICE,a novelFADD homologous ICE/CED-3-like proteases recruited to the CD95(Fas/APO-1)death-inducing signaling complex[J].Cell,1996.85:817-823
[6]沈定丰,徐冲羽.Fas在胃癌细胞及外周血淋巴细胞中的表达.上海第二医科大学学报,2000,20(4):299-301
[7]黄群,高晓燕,陈江,等.胃癌组织FasL表达上调与肿瘤浸润性淋巴细胞凋亡的关系.实用癌症杂志.2002,17(3):27-28
[8]Bennett MW,O'Connell J,O'Sullivan GC,et al.Expression of Fas ligand by human gastric adenocarcinomas:a potential mechanism of immune escape in stomach cancer.Gut,1999,44:156-162
[9]Chen YL,Wang JY,Chen SH,et al.Granulocytes mediates the Fas-L-associated apoptosis during lung metastasis of melanoma that determines the metastatic behaviour[J].Br J Cancer,2002,87(3):359-365
[10]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells.J Gastroenterol Hepatol,2002,17(1):32-38
[11]Hayashi H,,Takebe S,Osaki M,et al.Expression of Fas antigen and its mediation of apoptosis in human gastric cancer cell lines.Cancer Science, 1997,88(1):49-55
[12]Akre K,Ekst rom AM,Signorello LB,et al.Aspirin and risk for gastric cancer:a population-based case-cont rol study in Sweden.Br J Cancer,2001,84(7):965-968.
[13]Jacoby RF,Seibert K,Cole CE,et al.The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in t he min mouse model of adenomatous polyposiss.Cancer Res,2000,60(18):5040-5044.
[14]Reddy BS,Hirose Y,Lubet R et al.Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor celecoxib admin
[15]Fosslien E.Biochemistry of cyclooxygenase(COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia.Crit Rev Clin Lab Sci,2000,37(5):431-502.
[16]Lynch PM.COX-2 inhibition in clinical cancer prevention[J].Oncology,2001,15(3):21-26.istered during different stages of carcinogenesis.Cancer Res,2000,60(2):293-297.
[17]张桂英,冷爱民,贺智敏,等.消炎痛抑制人结肠癌细胞增殖和诱导凋亡的研究.中国现代医学杂志,1998,8(12):1-5
[18]Dixon DA.Dysregulated post-transcriptional control of COX-2 gene expression in cancer.Curr Pharm Des,2004,10(6):635-646
[19]Evans JF,Kargman SL.Cancer and cyclooxygenase-2(COX-2) inhibition.Curr Pharm Des,2004,10(6):627-634
[20]Peng JP,Liu LT,Chang HC,et al.Enhancement of chemotherapeutic drug-induced apoptosis by a cyclooxygenase-2 inhibitor in hypopharyngeal carcinoma cells.Cancer Lett,2003,201(2):157-163
[21]El-Rayes BF,Ali S,Sarkar FH,Philip PA.Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines.Mol Cancer Ther,2004,3:1421-1426
[22]Yip-Schneider MT,Nakshatri H,Sweeney CJ,et al.Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-κB pathway in pancreatic carcinoma cells.Mol Cancer Ther,2005,4:587-594
[23]Smith ML,Hawcroft G,Hull MA.The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells:evidence of different mechanisms of action.Eur J Cancer,2000,36(5):664-674
[24]向阳,孙敏,王和勇.COX-2及其抑制剂在肿瘤防治中的作用.生命科学,2008,20(1):81-84
[25]Shaik MS,Chatterjee A,Singh M.Effect of a selective cyclooxygenase-2inhibitor,nimesulide,on the growth of lung tumors and their expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-γ.Clinical Cancer Research,2004,10:1521-1529
[26]Ohno R,Yoshinaga K,Fujita T,et al.Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma.Cancer 2001,91:1876-1881
[27]彭杰,张桂英,肖志强。塞来昔布对大肠癌细胞株HT-29增殖和凋亡的影响。中南大学学报(医学版).2004,29(3):261-265
[28]李建英,于皆平,罗和生,等。选择性COX2抑制剂对胃癌细胞增殖的影响。癌症,2002,21(6):625-629
[29]Lou J,Fatima N,Xiao Z,et al.Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells.Cancer Epidemiol.2006,15(9):1598 - 1606.
[30]Elder DJ,Halton DE,Crew TE,et al.Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398.Int J Cancer,2000,86:553-560
[31]Buchanan FG,Holla V,Katkuri S,et al.Targeting Cyclooxygenase-2 and the Epidermal Growth Factor Receptor for the Prevention and Treatment of Intestinal Cancer.Cancer Res,2007,67(19):9380 - 9388.
[32]Arico S,Pattingre S,Bauvy C,et al.Celecoxib Induces Apoptosis by Inhibiting 3-Phosphoinositide-dependent Protein Kinase-1 Activity in the Human Colon Cancer HT-29 Cell Line.J.Biol.Chem.,July 26,2002;277(31):27613 - 27621
[33]Qadri SSA,Wang JH,Coffey JC,et al.Surgically Induced Accelerated Local and Distant Tumor Growth is Significantly Attenuated by Selective COX-2Inhibition.Ann.Thorac.Surg.,March 1,2005,79(3):990 - 995
[34] Uefuji K, Ich ikura T, Moch izuk i H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas[J]. J Surg Onco, 2001,76(1):26-30
[35] Kelloff GJ, Schilsky RL, Alberts, DS, et al. Sigman.Colorectal Adenomas: A Prototype for the Use of Surrogate End Points in the Development of Cancer Prevention Drugs.Clin. Cancer Res., June 1,2004, 10(11): 3908 - 3918.
[36] Rostom A, Dube C, Lewin G., et al. Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force.Ann Intern Med, March 6, 2007, 146(5): 376 - 389.
[37] Steinbach G, Lynch PM, Phillips RK, et al . The effect of celecoxib , a cyclooxygenase-2 inhibitor ,iri familial adenomatous polyposis[J] . N Engl J Med, 2000 ,342 (26): 1946-1952.
[38] Jankowski J, Hunt R. Cyclooxygenase-2 Inhibitors in Colorectal Cancer Prevention: Counterpoint.Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 1858-1861.
[39] Murray S. Do ASA and NSAIDs reduce the risk of colorectal cancer?. Can. Med. Assoc. J, November 8, 2005, 173(10): 1159-1160.
[40] Reddy BS, Hirose Y, Lubet R, et al. Chemoprevention of colon cancer byspecific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res, 2000, 60:293-297
[41] Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N. Engl. J. Med, 2007, 356(21): 2131 - 2142
[42] Martin TJ, Buechler NL, Eisenach JC. Intrathecal administration of a cylcooxygenase-1, but not a cyclooxygenase-2 inhibitor, reverses the effects of laparotomy on exploratory activity in rats. Anesth. Analg.September 1, 2006; 103(3): 690-695.
[43] Schneider C, Boeglin WE, Brash AR. Identification of Two Cyclooxygenase Active Site Residues, Leucine 384 and Glycine 526, That Control Carbon Ring Cyclization in Prostaglandin Biosynthesis. J. Biol. Chem., February 6, 2004; 279(6):4404-4414
[44]Chang YWE,Marlin JW,Chance TW,Jakobi R.RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility.Cancer Res.2006,66(24):11700 - 11708
[45]Gajraj NM.Cyclooxygenase-2 Inhibitors.Anesth Analg,2003,96(6):1720 -1738
[46]Abdalla SI,Sanderson IR,Fitzgerald RC.Effect of inflammation on cyclooxygenase(COX)-2 expression in benign and malignant oesophageal cells.Carcinogenesis,2005,26(9):1627-1633.
[47]Zhan J,Liu JP,Zhu ZH,et al.Relationship between COX-2 expression and clinicopathological features of colorectal cancers.Chinese Medical Journal,2004,8:1151-1154
[48]Leung WK,To KF,Go MYY,et al.Cyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma.International journal ofoncology,2003,23(5):1317-1322
[49]Maaser K,D(a|¨)ubler P,Barthel B,et al.Oesophageal squamous cell neoplasia in head and neck cancer patients:upregulation of COX-2 during carcinogenesis.Br J Cancer.2003,88(8):1217-22
[50]Cheng ASL,Chan HLY,Leung W,et al.Specific COX-2 inhibitor,NS-398,suppresses cellular proliferation and induces apoptosis in human hepatocellular carcinoma cells.International journal of ontology,2003,23(1):113-119
[51]Hida T.Overexpression of COX-2 and a potential clinical application of its inhibitors in lung cancer.Nippon Rinsho,2004,62(7):1357-62.
[52]Park SW,Lee SG,Song SH,et al.The effect of nitric oxide on cyclooxygenase-2(COX-2) overexpression in head and neck cancer cell lines International Journal of Cancer.2003,107(5):729 - 738
[53]Yoshimura R,Sano H,Masuda C,et al.Expression of cyclooxygenase-2 in prostate carcinoma.Cancer,2000,89:589-596
[54]Cha YI,DuBois RN.NSAIDs and Cancer Prevention:Targets Downstream of COX-2.Annual Review of Medicine,2007,58:239-252
[55]傅得兴,黄公怡。非甾体类抗炎药的不良反应及改进抗炎药物治疗的新发 展。中国新药杂志,2000,9:604-608.
[56]Chen WS,Wei SJ,Liu JM,et al.Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2(COX-2) expression and inhibited by a COX-2-selective inhibitor etodolac.Int J Cancer,2001,91(6):894-899
[57]彭杰,张桂英,肖志强。塞来昔布对大肠癌细胞株HT-29增殖和凋亡的影响。中南大学学报(医学版).2004,29(3):261-265
[58]徐美虹,刘雁平。塞来昔布对胃癌抑制作用的实验研究。肿瘤研究与临床,2002,14(2):78-80;
[59]刘纯伦,唐承薇,万学红,等。选择性环氧合酶-2抑制剂对胃癌细胞生长的影响。四川大学学报:医学版,2003,34(3):;480-483
[60]朱风尚,陈锡美,朱国英,等。特异性环氧合酶抑制剂对胃癌细胞BGC-823生长的影响。同济大学学报:医学版,2005,26(1):21-25
[61]Adolphe M,Deysson G,Lechat P.Action of some steroid and non-steroid anti-inflammatory agents on the cell cycle:cytophotometric study of the DNA content.Rev Eur Etud Clin Biol,1972,17:320-323
[62]Bayer BM,Beaven MA.Evidence the Indomethacin reversibly inhibits cell growth in the G1 phase of the cell cycle.Biochem pharmacol,1979,28:441-443
[63]徐美虹 吴开春。非甾体类抗炎药对胃癌细胞增殖的抑制作用。中华消化杂志,2002,4:199-201。
[64]Cheng J,Imanishi H,Amuro Y,et al.NS-398,a selected cyclooxygenase 2inhibitor,inhibited cell growth and induced cell cycle arrest in human hepatocellular carcinoma cell lines.Int J Cancer,2002,99(5):755-761
[65]马向涛,余力伟,王杉,等。环氧合酶-2抑制剂调控Stat5信号转导通路抑制结肠癌细胞增殖的分子机制。中华医学杂志,2005,36:2566-2569
[66]Dimberg J,Samuelsson A,Hugander A,et al.Differential expression of cyclooxygenase 2 in human colorectal cancer.Gut,1999,45:730-732
[67]Larrea M D,Liang J,Silva TD,et al.Phosphorylation of p27 Kipl Regulates Assembly and Activation of Cyclin D1-Cdk4.Mol.Cell.Biol,200828:6462-6472
[68]Lwin T,Hazlehurst LA,Dessureault S,et al.Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas.Blood,2007,110:1631-1638
[69]Sicinski P,Zacharek S,Kim C.Duality of p27 Kipl function in tumorigenesis.Genes Dev,2007 21:1703-1706
[70]Geisen C,Moroy T.The Oncogenic Activity of Cyclin E Is Not Confined to Cdk2 Activation Alone but Relies on Several Other,Distinct Functions of the Protein.J.Biol.Chem.,2002 277:39909-39918
[71]Shin JY,Kim HS,Lee KS,et al.Mutation and expression of the p27KIP1 and p57KIP2 genes in human gastric cancer.Exp Mol Med,2000,32(2):79-83
[72]Cao Q J,Einstein MH,Anderson PS,et al.Expression of COX-2,Ki-67,Cyclin D1,and P21 in endometrial endometrioid carcinomas.Int J Gynecol Pathol,2002,21(2):147-154
[73]Quintanilla-Martinez L,Davies-Hill T,Fend F,et al.Sequestration of p27Kip1protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL):implications for pathogenesis.Blood,2003 101:3181-3187
[74]Harbour JW,Dean DC.Rb function in cell-cycle regulation and apoptosis.Nature Cell Biology,2000,2:65-67
[75]Burgess A,Wigan M,Giles N,et al.Inhibition of S/G2 Phase CDK4 Reduces Mitotic Fidelity.J.Biol.Chem,2006,281(15):9987 - 9995
[76]Chen B,Pan H,Zhu L,et al.Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-Kinase-->AKT-->GSK-3β-->Cyclin D1-->pRB Pathway to Block Uterine Epithelial Cell Proliferation.Mol Endocrinol.,2005,19(8):1978-1990
[77]White J,Stead E,Faast R,et al.Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation.Mol Biol.Cell,2005,16(4):2018-2027.
[78]邹向阳,李连宏。细胞周期调控与肿瘤。国际遗传学杂志,2006,29(1):70-73
[79] Boulaire J, Fotedar A, Fotedar R.The functions of the cdk-cyclin kinase inhibitor p21 WAF1. Pathol Biol (Paris), 2000,48(3): 190-202
[80] Ilyin G P, Glaise D, Gilot D, et al. Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth .Am J Physiol Gastrointest Liver Physiol. 2003, 285:115-127
[81] den Hollander P, Dynein RK. Light Chain 1 Contributes to Cell Cycle Progression by Increasing Cyclin-Dependent Kinase 2 Activity in Estrogen-Stimulated Cells. Cancer Res, 2006; 66(11): 5941 - 5949.
[82] Yamashita H, Osaki M, Honjo S, et al.A selective cyclooxygenase-2 inhibitor,NS-398,inhibits cell growth by cell cycle arrest in a human malignant fibrous histiocytoma cell line.Anticancer Res,2003,23(6C):4671-4676
[83] Suzuki A, Hayashida M, Ito T, et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/pl6INK4a and Cdk2/Cyclin E complex activation. Oncogene, 2000,19(29): 3225-3234
[84] Singh RP , Agarwal C , Agarwal R. Inositol hexaphosphate inhibits growth, and induces Gl arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. Carcinogenesis, 2003, 24(3):555-563
[85] Malanchi I, Accardi R, Diehl F, et al. Human papillomavirus type 16 E6 promotes retinoblastoma protein phosphorylation and cell cycle progression.J. Virol, 2004, 78(24): 13769 -13778
[86] Mitchell PJ, Perez-Nadales E, Malcolm DS, et al. Dissecting the contribution of p16INK4A and the Rb family to the ras transformed phenotype. Mol Cell Biol, 2003,23(7): 2530 - 2542
[87] Sviderskaya EV, Hill SP, Evans-Whipp TJ, et al. p16Ink4a in melanocyte senescence and differentiation. J Natl Cancer Inst, 2002; 94(6): 446 - 454
[88] Ramsey MR, Krishnamurthy J, Pei XH, et al. Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues. Cancer Res, 2007; 67(10): 4732 - 4741
[89] Palmqvist R, Rutegard JN, Bozoky B, et al. Human colorectal cancers with an intact p16/cyclin D1/pRb pathway have up-regulated p16 expression and decreased proliferation in small invasive tumor clusters.Am J Pathol,2000;157(6):1947-1953
[90]Chaubert P,Gayer R,Zimmermann A,et al.Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma.Hepatology,2003,25(6):1376-1381
[91]Fatima N,Yi M,Ajaz S,et al.Altered gene expression profiles define pathways in colorectal Cancer cell lines affected by celecoxib.Cancer Epidemiology Biomarkers & Prevention,2008,17:3051-3061.
[92]李建英,于皆平.选择性COX-2抑制剂对胃癌细胞增殖的影响[J].癌症.2002,6:625-629.
[93]Lim SC.Fas-related apoptosis in gastric adenocarcinoma.Oncol Rep 2003;10:57-63
[94]Imtiyaz HZ,Rosenberg S,Zhang Y,et al.The fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells.J.Immunol.2006.176:6852-6861
[95]庞瑞萍,胡品津,曾志军,等。塞来昔布诱导不表达环氧合酶-2的胃癌细胞凋亡研究。中国病理生理杂志,2006,22(5):842-845
[96]朱风尚,陈晚美,王毅军,等。罗非昔布对胃癌细胞BGC-823内在耐药的逆转作用。同济大学学报(医学版),2007,28(4):25-29
[97]朱风尚,陈锡美,王毅军,等。塞来昔布增强胃癌化疗药物疗效的机制研究。中国临床药理学杂志。2008,24(3):237-239
[98]Zhang Z,DuBois RN.Par-4,a proapoptotic gene,is regulated by NSAIDs in human colon carcinoma cells.Gastroenterology,2000,118(6):1012-1017
[99]Cheng ASL,Chan HLY,Leung W.et al.Specific COX-2 inhibitor,NS-398,suppresses cellular proliferation and induces apoptosis in human hepatocellular carcinoma cells.International journal ofoncology,2003,23(1):113-119
[100]Williams N.Tumor cells fight back to beat immune system.Science,1996,274(5291):1302
[101]Takahamal Y,Yamadal Y,Emotol K,et al.The prognostic significance of overexpression of the decoy receptor for Fas ligand(DcR3) in patients with gastric carcinomas[J].Gastric Cancer,2002,5(2):61-68
[102]Yaqub S,Henjum K,Mahic M,et al.Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner.Cancer Immunology,Immunotherapy,2008,57(6):813-821
[103]Chipuk JE,Fisher JC,Dillon CP,et al.Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins.PNAS,2008,105:20327-20332
[104]Tsujimoto Y,Shimizu S.Bcl-2 family:life-or-death switch.FEBS Lett,2000,466:6-10
[105]Marsden VS,O'Connor L,O'Reilly LA,et al.Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.Nature,2002 419(6907):634-7
[106]张有成,王杉,张辉,等。转录信号传导子和激活子3信号传导通路调控选择性环氧化酶2抑制剂抗结肠癌的机制。中华胃肠外科杂志,2004,7(5):404-406
[107]Shibakita M,Tachibana M,Dhar DK,et al.Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer.Clin Cancer Res 1999,5:2464-2469
[108]Zhu Q,Liu JY,Xu HW,et al.Mechanism of counterattack of colorectal cancer cell by Fas/Fas ligand system.World J Gastroenterol 2005,11:6125-6129
[109]Xu LN,Zou SQ,Wang JM.Action and mechanismof Fas and Fas ligand in immune escape of gallbladder carcinoma.World J Gastroenterol 2005,11:3719-3723
[110]Younes M,Schwartz M,Finnie D,Younes A.Overexpression of Fas ligand (FasL) during malignant transformation in the large bowel and in Barrett"s metaplasia of the esophagus.Human Pathology,1999,30(11):1309-1313。
[111]胡端敏,王少峰,冯一中。MMP-7与Fas蛋白在胃癌组织中的表达及意义。世界华人消化杂志,2006,14(33):3237-3240。
[112]Bennett MW,'Connell Jo,O'Sullivan GC,et al.Expression of Fas ligand by human gastric adenocarcinomas:a potential mechanism of immune escape in stomach cancer.Gut 1999,44:156-162。
[113]Memon SA,Hou J,Moreno MB,et al.Apoptosis induced by a chimeric Fas/FasL ICE receptor:lack of requirement for Fas or FADD binding proteins[J].J Immunol,1998,160(5):2046-2049.
[114]Compagni A,Christofori G.Recent advances inresearch on multistage tumorigenesis.Br J Cancer2000,83:1-5.
[115]Connell J,Bennett M W,Sullivan G C,et al.The Fas counterattack:a molecular mechenism of tumor immune privilege.Mol M ed,1997,3:294-300.
[116]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells[J].J Gastroenterol Hepatol,2002,17(1):32-38.
[117]Kume T,Oshima K,Yamashita Y,et al.Relationship between Fas ligand expression on carcinoma cell and cytotoxic T lymphocyte response in lymphoepithelioma like cancer of the stomach[J].Int J Cancer,1999,84(4):334-343.
[118]Zhao XH,Gu SZ,Tian HG,Quan P,Pan BR.Clinical significance of expression of apoptoticsignal proteins in gastric carcinoma tissue.World JGastroenterol 2005;11:3846-3849.
[119]胡端敏,王少峰,冯一中.MMP-7与Fas蛋白在胃癌组织中的表达及意义.世界华人消化杂志 2006,14(33):3237-3240
[120]Hallermalm K,.De Geer A,Kiessling R,et al.Autocrine Secretion of Fas Ligand Shields Tumor Cells from Fas-Mediated Killing by Cytotoxic Lymphocytes.Cancer Res.,September 15,2004,64(18):6775-6782
[121]Shain KH,Landowski TH,Dalton WS.Adhesion-Mediated Intracellular Redistribution of c-Fas-Associated Death Domain-Like IL-1-Converting Enzyme-Like Inhibitory Protein-Long Confers Resistance to CD95-Induced Apoptosis in Hematopoietic Cancer Cell Lines.J.Immunol,March 1,2002,168(5):2544-2553
[1]Wyllie AH,Kerr JF,Currie AR.Cell death:the significance of apoptosis[J].Int Rev Cytol.1980;68:251-306
[2]Chen YL,Wang JY,Chen SH,et al.Granulocytes mediates the Fasl-associated apoptosis during lung metastasis of melanoma that determines them etastatic behavior[J].Br J Cancer,2002,87(3):359-365
[3]Lee Tae-Bum,Min Young-Don,Lim Sung-Chui,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells.Journal of Gastroenterology & Hepatology.2002,17(1):32-38.
[4]高勇,张登海.Fas系统与肿瘤免疫逃避[J].国外医学肿瘤学分册,1998,25(6):327-329.
[5]吴雪平.Fas系统介导的细胞凋亡与肝脏疾病[J].国外医学免疫学分册,1999,22(2):68-71.
[6]Nagata S,Golstein P.The Fas death factor[J].Science,1995,267:1449-1456.
[7]Cascino I,Fiorucci G,Papoff G,et al.Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing[J].J Immunol,1995,154(5):2706-2713.
[8]刘海峰,刘为纹,房殿春.胃癌及其癌前病变中细胞凋亡与细胞增殖间关系的研究.世界华人消化杂志1999,7:649-651;
[9]Fukuzawa K,Takahashi K,Furuta K,et al.Expression of fas/fas ligand(fasL)and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC).J Gastroenterol 2001,36:681-688,
[10]Williams N.Tumor cells fight back to beat immune system[J].Science,1996,274(5291):1302
[11]Chinnaiyan AM,O' Rourke.K,Tewari M,etal.FADD,a novel death domain-containing protein,interacts with the death domain of Fas and initiates apoptosis[J].Cell,1995,81(19):505-512
[12]Kidd V J.Proteolytic activities that mediate apoptosis[J].Annu Rev Physiol,1998,60:533-573
[13]Lim SC.Fas-related apoptosis in gastric adenocarcinoma[J].Oncol Rep,2003,10:57-63
[14]Muzio,M,Chinnaiyan AM,Kischkel FC,etal.FI ICE,a novel FADD homologous ICE / CED-3-like proteases recruited to the CD95(Fas/APO-1)death-inducing signaling complex[J].Cell,1996.85:817-823,
[15]沈定丰,徐冲羽.Fas在胃癌细胞及外周血淋巴细胞中的表达.上海第二医科大学学报,2000,20(4):299-301,
[16]王强,赵毅,孙威,等。Fas、FasL及bcl-2在胰腺癌、癌旁组织中的表达及其意义。中华消化杂志,2001,21(4):252-253
[17]Leithauser F,Dhein J,Mechtersheinerg,et al.Constitutive and induced expression of APO-1,a new member of the nerve growth factor-tumor necrosis factor receptor super family in normal and malignantcells[J].Lab Invest,1999, 69(5):415-429
[18]Compagni A,Christofori G.Recent advances in research on multistage tumorigenesis[J].Br J Cancer,2000,83:1-5
[19]Chinnaiyan AM,Tepper CG,Sildin M F,et al.FADD / MORT lis a common mediator of CD95(Fas/APO-1)and Tumor necrosis factor receptor-induced apoptosis[J].J Biol Chem,1995 271(9):4961
[20]Misseri R,Meldrum C,Dinarello A,et al.TNF- mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling.Am J Physiol Renal Physiol 2005,288:F406-411.
[21]周华蓉 周新荣。IFN-γ和TNF-α诱导Fas表达在β胰岛细胞杀伤中的作用。中国免疫学杂志,2006,12:666-667
[22]Fukuzawa K,Takahashi K,Furuta K,et al.Expression of fas/fas ligand(fasL)and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC)[J].J Gastroenterol,2001;36:681-688
[23]Sato T,Irie S,Kitada S,and Reed JC.FAP-1:a protein tyrosine phosphatase that associates with Fas[J].Science,1995,268:411-415
[24]Yanagisawa J,Takahashi M,Kanki H,et al.The Molecular Interaction of Fas and FAP-1.[J].J Biol chem,1997,272:8539-8545
[25]Itoh N,Nagata S.A novel protein domain required for apoptosis.Mutational analysis of human Fas antigen[J].J Biol chem,1993,268:10932-10937
[26]Ungefroren H,Vose M,Jansen M.Human pancreatic adenocarcinomas expression Fas and Fas ligand yet are resistant to Fas-mediated apoptosis[J].Cancer Res,1998,58:1741-1749.
[27]Ungefroren H,Voss M,Bemstorff WV,et al.Immunological Escape Mechanisms in Pancreatic Carcinomal[J].Annals of the New York Academy of Sciences,1999.880:243-251.
[28]Irie S,Li Y,Kanki H,Ohyama T,et al.Identification of Two Fas-Associated Phosphatase-1(FAP-1) Promoters in Human Cancer Cells[J].Mitochondrial DNA,2001,11(6):519-526
[29]Vladimir N.Ivanov,Bergami PL,et al.FAP-1 Association with Fas(Apo-1)Inhibits Fas Expression on the Cell Surface.Molecular and Cellular Biology,2003,23(10):3623-3635
[30]刘征波,胡国龄,范学工,等。FASL、TRAIL在慢性乙型肝炎患者外周血淋巴AICD中的作用。中国免疫学杂志,2003,19(2):135-137
[31]Brigit Brenner,Klaus Ferlinz,Heike Grassm(?),Michael Weller,et al Fas/CD95/Apo-I activates the acidic sphingomyelinase via Caspases[J].Cell Death and Differentiation,1998,5(1):29-30.
[32]Yin XM,W KUN,Gross A,et al.Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis[J].Nature,1999,400(6747):886-891
[33]Luo X,Budihardjo I,Zou H,et al.Bid,a Bcl-2 Interacting Protein,Mediates cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors[J].Cell,1998,94:481-490
[34]谭晓华.神经酰胺:细胞凋亡信号转号的第二信使分子[J].国外医学:分子生物学分册,1999,21(1):10-14
[35]张涛,李百祥,富英群.鞘磷脂及神经酰胺对人结肠癌细胞(HT-29)的影响[J].卫生毒理学杂志,2003,17(2):81-83
[36]苏波,万艳平,廖端芳.细胞凋亡通路及转录调控中的Daxx[J].中国病理生理杂志.2005,21(3):617-620
[37]Yang X,Khosravi-Far R,Chang HY,Baltimore D.Daxx,a novel Fas-binding protein that activates JNK and apoptosis[J].Cell,1997,89(7):1067-1076
[38]Pluta AF,Earnshaw WC,Goldberg IG..Interphase-specific association of intrinsic centromere protein CENP-C with hDaxx,a death domain-binding protein implicated in Fas-mediated cell death[J].Cell Sci,1998,111(14):2029-2041.
[39]Juo P,Woo MS,Kuo CJ,et al.FADD is required for multiple signaling events downstream of the receptor Fas[J].Cell Growth Difer,1999,10:797-804.
[40]胡跃强,肖波,毕方方,等.大鼠局灶性脑缺血后FADD和Daxx的表达[J].中华神经科杂志,2007,40(11):762-767
[41]Ko YG,Kang YS,Park H,et al.Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein(Daxx) in the cytoplasm [J].J Biol Chem,2001,276(42):39103-39106.
[42]邓金牛,李春蕊,刘文励,等.去乙酰化酶抑制剂诱导白血病细胞凋亡过程中Daxx的表达变化[J].中华血液学杂志,2004,25(5):312-313
[43]Michaelson JS,Bader D,Kuo F,et al.Loss of Daxx,a promiscuously interacting protein,results in extensive apoptosis in early mouse development[J].Genes Dev,1999,13:1918-1923.
[44]Villunger A,Huang DC,Holler N,et al.Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX,and Fas-mediated cell death does not involve DAXX,RIP,or RAIDD[J].J Immunol,2000,165:1337-1343
[45] Younes M , Schwartz M , Finnie D , Younes A. Overexpression of Fas ligand (FasL) during malignant transformation in the large bowel and in Barrett"s metaplasia of the esophagus[J]. Human Pathology , 1999, 30 (11): 1309 - 1313
[46] Catherine Gratas, Yasuo Tohma, Christoph Barnas, et al. Up-regulation of fas (APO-1/CD95) ligand and down-regulation of fas expression in human esophageal cancer [J]. Cancer Research, 1998, 58: 2057-2062
[47] Muneaki Shibakital, Mitsuo Tachibana, Dipok K Dhar, et al. Prognostic significance of fas and fas ligand expressions in human esophageal cancer [J]. Clinical Cancer Research, 1999,5:2464-2469
[48] Younes M, Lechago J , Ertan A, et al . Decreased expression of fas (CD95/AP01) associated with goblet cell metaplasia in barrett's esophagus[J] . Human Pathology , 2000, 31 (4): 434 - 438
[49] Gratas C, Tohama Y, Barns C, et al. Up-regulation of Fas(APO-1 /CD95) ligand and down-regulation of Fas expression in human esophageal cancer. [J] Cancer Res,1998,58: 2057-2062.
[50] Michael W. Bennett, Joe O'Connell, Gerald C. O'Sullivan, et al. The Fas Counterattack In Vivo: Apoptotic Depletion of Tumor-Infiltrating Lymphocytes Associated with Fas Ligand Expression by Human Esophageal Carcinoma [J]. The Journal of Immunology, 1998, 160: 5669-5675.
[51] O'connell Jo, Bennett MW, O'sullivan GC, et al. Resistance to Fas (APO-1/CD95)-mediated apoptosis and expression of Fas ligand in esophageal cancer: the Fas counterattack [J]. Diseases of the Esophagus , 2001,12(2): 83-89
[52] Bennett MW, O 'Connell Jo, O'Sullivan GC, et al. Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer[J]. GUT, 1999;44:156-162。
[53] Pitti RM, Marsters SA, Lawrence DA, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer [J]. Nature, 1998, 396: 699-703
[54] Delmas D, RebeC, Lacour S , et al. Resveratrol-induced Apoptosis Is Associated with Fas Redistribution in the Rafts and the Formation of a Death-inducing Signaling Complex in Colon Cancer Cells [J]. J Biol Chem, 2003, 278 (42): 41482-41490.
[55] O'Connell J, Bennett MW, O'Sullivan GC , et al. Fas ligand expression in primary colon adenocarcinomas:evidence that the Fas counterattack is a prevalent mechanism of immune evasion in human colon cancer[J].The Journal of Pathology,1999,186(3):240-246
[56]O'Connell J,O'Sullivan GC,Collins JK,Shanahan F.The Fas counterattack:Fas-mediated T cell killing by colon cancer cells expressing Fas ligand[J].Journal of Experimental Medicine,1996,184:1075-1082,
[57]李世拥,于波,安萍,等。FasL基因表达对结直肠癌细胞肝转移影响的研究。中华外科杂志。2003,4(9):646-648
[58]左富义,李世拥,安萍,等。蛋白质酵母双杂交系统的建立及其在大肠癌肝转移研究中的意义中华外科杂志。2004,42(11):672-674
[59]Song E,Chen J,OuYang N,et al.Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis:an active mode of immune evasion in colon cancer[J].British journal of cancer,2001,85:1047-1054
[60]Giardina C,Boulares H,Inan MS.NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-α and Fas ligation:the role of reactive oxygen species[J].Molecular Cell Research,1999,1448(3):425-438
[61]朱风尚,陈锡美.COX-2抑制剂与消化道癌前病变的阻断治疗[J]。同济大学学报:医学版,2003,2:161-163
[62]郜恒骏。NSAIDs化学预防胃肠道癌症研究的新进展[J]。国外医学:消化系疾病分册,2001,2:86-89
[63]沈定丰,徐冲羽.Fas在胃癌细胞及外周血淋巴细胞中的表达[J].上海第二医科大学学报,2000,20(4):299-301
[64]Lim SC.Fas-related apoptosis in gastric adenocarcinoma[J].Oncol Rep 2003;10:57-63
[65]Imtiyaz HZ,Rosenberg S,Zhang Y,et al.The fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells.J.Immunol,2006,176:6852-6861,
[66]黄群,高晓燕,陈江,等。胃癌组织FasL表达上调与肿瘤浸润性淋巴细胞凋亡的关系[J].实用癌症杂志.2002.17(3):27-28
[67]Bennett MW,O'Connell J,O'Sullivan GC,et al.Expression of Fas ligand by human gastric adenocarcinomas:a potential mechanism of immune escape in stomach cancer[J].GUT 1999;44:156-162
[68]Takahamal Y,Yamadal Y,Emotol K,et al.The prognostic significance of overexpression of the decoy receptor for Fas ligand(DcR3) in patients with gastric carcinomas[J].Gastric Cancer,2002,5(2):61-68
[69]Chen YL,Wang JY,Chen SH,et al.Granulocytes mediates the Fasl-associated apoptosis during lung metastasis of melanoma that determines the metastatic behavior[J].Br J Cancer,2002,87(3):359-365.
[70]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells[J].J Gastroenterol Hepatol,2002,17(1):32-38.
[71]Lee SH,KimHS,Kim SY,et al.Increased expression of FLIP,an inhibitor of Fas-mediated apoptosis,in stomach cancer[J].APMIS,2003,111(2):309-314
[72]Irmber M,Thome M,Hahne M,et al.Inhibition of death receptor signals by cellular FI IP[J].Nature,1997,388(6638):190-195.
[73]Hayashi H,Tatebe S,Osaki M,et al.Expression of Fas Antigen and Its Mediation of Apoptosis in Human Gastric Cancer Cell Lines[J].Cancer Science,2005,88(1):49-55
[74]高勇,张登海.Fas系统与肿瘤免疫逃避[J].国外医学肿瘤学分册,1998,25(6):327-329
[75]Bellgrau D,Gold D,Selawry H,et al.A role for CD95 ligand in preventing graft rejection[J].Nature,1995.377:630-632.
[76]李佳莉,赵丽纯.Fas/FasL系统与肿瘤的免疫逃逸[J].国外医学:免疫学分册,2001,786-788
[77]蔡世荣 詹文华.Fas配体表达诱导同种胰岛移植免疫豁免[J].中华实验外科杂志,2001,18(1):58-59
[78]Streilein JW.Enhanced Perspective:Unraveling Immune Privilege[J].Science,1995,270:1158.
[79]Van Parijs L,Abbas AK.Role of Fas-mediated cell death in the regulation of immune responses[J].Immunity,1996,8(3):355-361
[80]Griffith TS,Brunner T,Fletcher SM,et al.Fas ligand induced apoptosis as a mechanism of immune privilege[J].Science,1995,270:1189-1192
[81]Hughes SJ,Nambu Y,Soldes OS,et al.Fas/APO-1(CD95) is not translocated to the cell membrance in esophagealadenocarcinoma[J].Cancer Res,1997,57:5571-5578.
[82]Tamiya S,Etoh K,Suzushima H,et al.Mutation of CD95(Fas/APO-1)gene in adult T-cell leukemia cells[J].Blood,1998,91:3935-3942
[83]Strand S,Hofmann WJ,Hug H,et al.Lymphocyte apoptosis induced by CD95(APO-1/Fas)ligand-expressing tumor cells-a mechanism of immune evasion[J].Nature Med,1996,2:1296-1361.
[84]Leithauser F,Dhein J,Mechtersheimer G,et al.Constitutive and induced expression of Apo-1.a new growth factor/tumor necrosis factor receptor superfamily,in normal and neoplastic cells[J].Lab Invest,1993,69:415-429.
[85]曹长安,郭颖,郭琳琅.肝癌组织中人白细胞共同抗原和凋亡相关基因Fas、bcl-2及bax的表达及意义[J].肿瘤防治研究,1999,26(2):94-95
[86]Muller M,Strand S,Hug H,et al.Drug-induced apoptosis in hepatoma cells is mediated by the CD95(Apo-1/Fas)receptor/ligand system and involves activation ofwild-type p53[J].J Clin Invest,1997,99:403-413.
[87]刘建夏,张学光,钱海鑫,等.Fas/FasL系统在肿瘤细胞耐药中的作用[J].癌症,1998,17(6):401-404.
[88]Hahne M,Rimoldi D,Schr(o|¨)ter M,et al.Melanoma Cell Expression of Fas(Apo-1/CD95) Ligand:Implications for Tumor Immune Escape[J].Science,1996,274:1363-1366
[89]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells[J].J Gastroenterol Hepatol,2002,17(1):32-38.
[90]Owen-Schaub L,Chan H,Cusack JC,et al.Fas and Fas ligand interactions in malignant disease[J].Int J Oncol,2000,17(1):5-12.
[91]Shiraki K,Tsuji N,Shioda T,et al.Expression of Fas ligand in liver metastases of human colonic adenocarcinomas[J].Proe Natl Acad SCi USA,1997,94:6420-6425.
[92]李国平.Fas抗原—配体系统与肝脏疾病研究进展[J].国外医学临床生物化学与检验学分册,1999,20(1):4-6.
[2]刘海峰,刘为纹,房殿春.胃癌及其癌前病变中细胞凋亡与细胞增殖间关系的研究.世界华人消化杂志1999,7:649-651
[3]Fukuzawa K,Takahashi K,Furuta K,et al.Expression of fas/fas ligand(fasL)and its involvement in infiltrating lymphocytes in hepatoceilular carcinoma (HCC).J Gastroenterol,2001,36:681-688
[4]Lim SC.Fas-related apoptosis in gastric adenocarcinoma[J].Oncol Rep,2003,10:57-63
[5]Muzio,M,ChinnaiyanAM,Kischke1 FC,etal.FIICE,a novelFADD homologous ICE/CED-3-like proteases recruited to the CD95(Fas/APO-1)death-inducing signaling complex[J].Cell,1996.85:817-823
[6]沈定丰,徐冲羽.Fas在胃癌细胞及外周血淋巴细胞中的表达.上海第二医科大学学报,2000,20(4):299-301
[7]黄群,高晓燕,陈江,等.胃癌组织FasL表达上调与肿瘤浸润性淋巴细胞凋亡的关系.实用癌症杂志.2002,17(3):27-28
[8]Bennett MW,O'Connell J,O'Sullivan GC,et al.Expression of Fas ligand by human gastric adenocarcinomas:a potential mechanism of immune escape in stomach cancer.Gut,1999,44:156-162
[9]Chen YL,Wang JY,Chen SH,et al.Granulocytes mediates the Fas-L-associated apoptosis during lung metastasis of melanoma that determines the metastatic behaviour[J].Br J Cancer,2002,87(3):359-365
[10]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells.J Gastroenterol Hepatol,2002,17(1):32-38
[11]Hayashi H,,Takebe S,Osaki M,et al.Expression of Fas antigen and its mediation of apoptosis in human gastric cancer cell lines.Cancer Science, 1997,88(1):49-55
[12]Akre K,Ekst rom AM,Signorello LB,et al.Aspirin and risk for gastric cancer:a population-based case-cont rol study in Sweden.Br J Cancer,2001,84(7):965-968.
[13]Jacoby RF,Seibert K,Cole CE,et al.The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in t he min mouse model of adenomatous polyposiss.Cancer Res,2000,60(18):5040-5044.
[14]Reddy BS,Hirose Y,Lubet R et al.Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor celecoxib admin
[15]Fosslien E.Biochemistry of cyclooxygenase(COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia.Crit Rev Clin Lab Sci,2000,37(5):431-502.
[16]Lynch PM.COX-2 inhibition in clinical cancer prevention[J].Oncology,2001,15(3):21-26.istered during different stages of carcinogenesis.Cancer Res,2000,60(2):293-297.
[17]张桂英,冷爱民,贺智敏,等.消炎痛抑制人结肠癌细胞增殖和诱导凋亡的研究.中国现代医学杂志,1998,8(12):1-5
[18]Dixon DA.Dysregulated post-transcriptional control of COX-2 gene expression in cancer.Curr Pharm Des,2004,10(6):635-646
[19]Evans JF,Kargman SL.Cancer and cyclooxygenase-2(COX-2) inhibition.Curr Pharm Des,2004,10(6):627-634
[20]Peng JP,Liu LT,Chang HC,et al.Enhancement of chemotherapeutic drug-induced apoptosis by a cyclooxygenase-2 inhibitor in hypopharyngeal carcinoma cells.Cancer Lett,2003,201(2):157-163
[21]El-Rayes BF,Ali S,Sarkar FH,Philip PA.Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines.Mol Cancer Ther,2004,3:1421-1426
[22]Yip-Schneider MT,Nakshatri H,Sweeney CJ,et al.Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-κB pathway in pancreatic carcinoma cells.Mol Cancer Ther,2005,4:587-594
[23]Smith ML,Hawcroft G,Hull MA.The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells:evidence of different mechanisms of action.Eur J Cancer,2000,36(5):664-674
[24]向阳,孙敏,王和勇.COX-2及其抑制剂在肿瘤防治中的作用.生命科学,2008,20(1):81-84
[25]Shaik MS,Chatterjee A,Singh M.Effect of a selective cyclooxygenase-2inhibitor,nimesulide,on the growth of lung tumors and their expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-γ.Clinical Cancer Research,2004,10:1521-1529
[26]Ohno R,Yoshinaga K,Fujita T,et al.Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma.Cancer 2001,91:1876-1881
[27]彭杰,张桂英,肖志强。塞来昔布对大肠癌细胞株HT-29增殖和凋亡的影响。中南大学学报(医学版).2004,29(3):261-265
[28]李建英,于皆平,罗和生,等。选择性COX2抑制剂对胃癌细胞增殖的影响。癌症,2002,21(6):625-629
[29]Lou J,Fatima N,Xiao Z,et al.Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells.Cancer Epidemiol.2006,15(9):1598 - 1606.
[30]Elder DJ,Halton DE,Crew TE,et al.Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398.Int J Cancer,2000,86:553-560
[31]Buchanan FG,Holla V,Katkuri S,et al.Targeting Cyclooxygenase-2 and the Epidermal Growth Factor Receptor for the Prevention and Treatment of Intestinal Cancer.Cancer Res,2007,67(19):9380 - 9388.
[32]Arico S,Pattingre S,Bauvy C,et al.Celecoxib Induces Apoptosis by Inhibiting 3-Phosphoinositide-dependent Protein Kinase-1 Activity in the Human Colon Cancer HT-29 Cell Line.J.Biol.Chem.,July 26,2002;277(31):27613 - 27621
[33]Qadri SSA,Wang JH,Coffey JC,et al.Surgically Induced Accelerated Local and Distant Tumor Growth is Significantly Attenuated by Selective COX-2Inhibition.Ann.Thorac.Surg.,March 1,2005,79(3):990 - 995
[34] Uefuji K, Ich ikura T, Moch izuk i H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas[J]. J Surg Onco, 2001,76(1):26-30
[35] Kelloff GJ, Schilsky RL, Alberts, DS, et al. Sigman.Colorectal Adenomas: A Prototype for the Use of Surrogate End Points in the Development of Cancer Prevention Drugs.Clin. Cancer Res., June 1,2004, 10(11): 3908 - 3918.
[36] Rostom A, Dube C, Lewin G., et al. Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force.Ann Intern Med, March 6, 2007, 146(5): 376 - 389.
[37] Steinbach G, Lynch PM, Phillips RK, et al . The effect of celecoxib , a cyclooxygenase-2 inhibitor ,iri familial adenomatous polyposis[J] . N Engl J Med, 2000 ,342 (26): 1946-1952.
[38] Jankowski J, Hunt R. Cyclooxygenase-2 Inhibitors in Colorectal Cancer Prevention: Counterpoint.Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 1858-1861.
[39] Murray S. Do ASA and NSAIDs reduce the risk of colorectal cancer?. Can. Med. Assoc. J, November 8, 2005, 173(10): 1159-1160.
[40] Reddy BS, Hirose Y, Lubet R, et al. Chemoprevention of colon cancer byspecific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res, 2000, 60:293-297
[41] Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N. Engl. J. Med, 2007, 356(21): 2131 - 2142
[42] Martin TJ, Buechler NL, Eisenach JC. Intrathecal administration of a cylcooxygenase-1, but not a cyclooxygenase-2 inhibitor, reverses the effects of laparotomy on exploratory activity in rats. Anesth. Analg.September 1, 2006; 103(3): 690-695.
[43] Schneider C, Boeglin WE, Brash AR. Identification of Two Cyclooxygenase Active Site Residues, Leucine 384 and Glycine 526, That Control Carbon Ring Cyclization in Prostaglandin Biosynthesis. J. Biol. Chem., February 6, 2004; 279(6):4404-4414
[44]Chang YWE,Marlin JW,Chance TW,Jakobi R.RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility.Cancer Res.2006,66(24):11700 - 11708
[45]Gajraj NM.Cyclooxygenase-2 Inhibitors.Anesth Analg,2003,96(6):1720 -1738
[46]Abdalla SI,Sanderson IR,Fitzgerald RC.Effect of inflammation on cyclooxygenase(COX)-2 expression in benign and malignant oesophageal cells.Carcinogenesis,2005,26(9):1627-1633.
[47]Zhan J,Liu JP,Zhu ZH,et al.Relationship between COX-2 expression and clinicopathological features of colorectal cancers.Chinese Medical Journal,2004,8:1151-1154
[48]Leung WK,To KF,Go MYY,et al.Cyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma.International journal ofoncology,2003,23(5):1317-1322
[49]Maaser K,D(a|¨)ubler P,Barthel B,et al.Oesophageal squamous cell neoplasia in head and neck cancer patients:upregulation of COX-2 during carcinogenesis.Br J Cancer.2003,88(8):1217-22
[50]Cheng ASL,Chan HLY,Leung W,et al.Specific COX-2 inhibitor,NS-398,suppresses cellular proliferation and induces apoptosis in human hepatocellular carcinoma cells.International journal of ontology,2003,23(1):113-119
[51]Hida T.Overexpression of COX-2 and a potential clinical application of its inhibitors in lung cancer.Nippon Rinsho,2004,62(7):1357-62.
[52]Park SW,Lee SG,Song SH,et al.The effect of nitric oxide on cyclooxygenase-2(COX-2) overexpression in head and neck cancer cell lines International Journal of Cancer.2003,107(5):729 - 738
[53]Yoshimura R,Sano H,Masuda C,et al.Expression of cyclooxygenase-2 in prostate carcinoma.Cancer,2000,89:589-596
[54]Cha YI,DuBois RN.NSAIDs and Cancer Prevention:Targets Downstream of COX-2.Annual Review of Medicine,2007,58:239-252
[55]傅得兴,黄公怡。非甾体类抗炎药的不良反应及改进抗炎药物治疗的新发 展。中国新药杂志,2000,9:604-608.
[56]Chen WS,Wei SJ,Liu JM,et al.Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2(COX-2) expression and inhibited by a COX-2-selective inhibitor etodolac.Int J Cancer,2001,91(6):894-899
[57]彭杰,张桂英,肖志强。塞来昔布对大肠癌细胞株HT-29增殖和凋亡的影响。中南大学学报(医学版).2004,29(3):261-265
[58]徐美虹,刘雁平。塞来昔布对胃癌抑制作用的实验研究。肿瘤研究与临床,2002,14(2):78-80;
[59]刘纯伦,唐承薇,万学红,等。选择性环氧合酶-2抑制剂对胃癌细胞生长的影响。四川大学学报:医学版,2003,34(3):;480-483
[60]朱风尚,陈锡美,朱国英,等。特异性环氧合酶抑制剂对胃癌细胞BGC-823生长的影响。同济大学学报:医学版,2005,26(1):21-25
[61]Adolphe M,Deysson G,Lechat P.Action of some steroid and non-steroid anti-inflammatory agents on the cell cycle:cytophotometric study of the DNA content.Rev Eur Etud Clin Biol,1972,17:320-323
[62]Bayer BM,Beaven MA.Evidence the Indomethacin reversibly inhibits cell growth in the G1 phase of the cell cycle.Biochem pharmacol,1979,28:441-443
[63]徐美虹 吴开春。非甾体类抗炎药对胃癌细胞增殖的抑制作用。中华消化杂志,2002,4:199-201。
[64]Cheng J,Imanishi H,Amuro Y,et al.NS-398,a selected cyclooxygenase 2inhibitor,inhibited cell growth and induced cell cycle arrest in human hepatocellular carcinoma cell lines.Int J Cancer,2002,99(5):755-761
[65]马向涛,余力伟,王杉,等。环氧合酶-2抑制剂调控Stat5信号转导通路抑制结肠癌细胞增殖的分子机制。中华医学杂志,2005,36:2566-2569
[66]Dimberg J,Samuelsson A,Hugander A,et al.Differential expression of cyclooxygenase 2 in human colorectal cancer.Gut,1999,45:730-732
[67]Larrea M D,Liang J,Silva TD,et al.Phosphorylation of p27 Kipl Regulates Assembly and Activation of Cyclin D1-Cdk4.Mol.Cell.Biol,200828:6462-6472
[68]Lwin T,Hazlehurst LA,Dessureault S,et al.Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas.Blood,2007,110:1631-1638
[69]Sicinski P,Zacharek S,Kim C.Duality of p27 Kipl function in tumorigenesis.Genes Dev,2007 21:1703-1706
[70]Geisen C,Moroy T.The Oncogenic Activity of Cyclin E Is Not Confined to Cdk2 Activation Alone but Relies on Several Other,Distinct Functions of the Protein.J.Biol.Chem.,2002 277:39909-39918
[71]Shin JY,Kim HS,Lee KS,et al.Mutation and expression of the p27KIP1 and p57KIP2 genes in human gastric cancer.Exp Mol Med,2000,32(2):79-83
[72]Cao Q J,Einstein MH,Anderson PS,et al.Expression of COX-2,Ki-67,Cyclin D1,and P21 in endometrial endometrioid carcinomas.Int J Gynecol Pathol,2002,21(2):147-154
[73]Quintanilla-Martinez L,Davies-Hill T,Fend F,et al.Sequestration of p27Kip1protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL):implications for pathogenesis.Blood,2003 101:3181-3187
[74]Harbour JW,Dean DC.Rb function in cell-cycle regulation and apoptosis.Nature Cell Biology,2000,2:65-67
[75]Burgess A,Wigan M,Giles N,et al.Inhibition of S/G2 Phase CDK4 Reduces Mitotic Fidelity.J.Biol.Chem,2006,281(15):9987 - 9995
[76]Chen B,Pan H,Zhu L,et al.Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-Kinase-->AKT-->GSK-3β-->Cyclin D1-->pRB Pathway to Block Uterine Epithelial Cell Proliferation.Mol Endocrinol.,2005,19(8):1978-1990
[77]White J,Stead E,Faast R,et al.Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation.Mol Biol.Cell,2005,16(4):2018-2027.
[78]邹向阳,李连宏。细胞周期调控与肿瘤。国际遗传学杂志,2006,29(1):70-73
[79] Boulaire J, Fotedar A, Fotedar R.The functions of the cdk-cyclin kinase inhibitor p21 WAF1. Pathol Biol (Paris), 2000,48(3): 190-202
[80] Ilyin G P, Glaise D, Gilot D, et al. Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth .Am J Physiol Gastrointest Liver Physiol. 2003, 285:115-127
[81] den Hollander P, Dynein RK. Light Chain 1 Contributes to Cell Cycle Progression by Increasing Cyclin-Dependent Kinase 2 Activity in Estrogen-Stimulated Cells. Cancer Res, 2006; 66(11): 5941 - 5949.
[82] Yamashita H, Osaki M, Honjo S, et al.A selective cyclooxygenase-2 inhibitor,NS-398,inhibits cell growth by cell cycle arrest in a human malignant fibrous histiocytoma cell line.Anticancer Res,2003,23(6C):4671-4676
[83] Suzuki A, Hayashida M, Ito T, et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/pl6INK4a and Cdk2/Cyclin E complex activation. Oncogene, 2000,19(29): 3225-3234
[84] Singh RP , Agarwal C , Agarwal R. Inositol hexaphosphate inhibits growth, and induces Gl arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. Carcinogenesis, 2003, 24(3):555-563
[85] Malanchi I, Accardi R, Diehl F, et al. Human papillomavirus type 16 E6 promotes retinoblastoma protein phosphorylation and cell cycle progression.J. Virol, 2004, 78(24): 13769 -13778
[86] Mitchell PJ, Perez-Nadales E, Malcolm DS, et al. Dissecting the contribution of p16INK4A and the Rb family to the ras transformed phenotype. Mol Cell Biol, 2003,23(7): 2530 - 2542
[87] Sviderskaya EV, Hill SP, Evans-Whipp TJ, et al. p16Ink4a in melanocyte senescence and differentiation. J Natl Cancer Inst, 2002; 94(6): 446 - 454
[88] Ramsey MR, Krishnamurthy J, Pei XH, et al. Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues. Cancer Res, 2007; 67(10): 4732 - 4741
[89] Palmqvist R, Rutegard JN, Bozoky B, et al. Human colorectal cancers with an intact p16/cyclin D1/pRb pathway have up-regulated p16 expression and decreased proliferation in small invasive tumor clusters.Am J Pathol,2000;157(6):1947-1953
[90]Chaubert P,Gayer R,Zimmermann A,et al.Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma.Hepatology,2003,25(6):1376-1381
[91]Fatima N,Yi M,Ajaz S,et al.Altered gene expression profiles define pathways in colorectal Cancer cell lines affected by celecoxib.Cancer Epidemiology Biomarkers & Prevention,2008,17:3051-3061.
[92]李建英,于皆平.选择性COX-2抑制剂对胃癌细胞增殖的影响[J].癌症.2002,6:625-629.
[93]Lim SC.Fas-related apoptosis in gastric adenocarcinoma.Oncol Rep 2003;10:57-63
[94]Imtiyaz HZ,Rosenberg S,Zhang Y,et al.The fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells.J.Immunol.2006.176:6852-6861
[95]庞瑞萍,胡品津,曾志军,等。塞来昔布诱导不表达环氧合酶-2的胃癌细胞凋亡研究。中国病理生理杂志,2006,22(5):842-845
[96]朱风尚,陈晚美,王毅军,等。罗非昔布对胃癌细胞BGC-823内在耐药的逆转作用。同济大学学报(医学版),2007,28(4):25-29
[97]朱风尚,陈锡美,王毅军,等。塞来昔布增强胃癌化疗药物疗效的机制研究。中国临床药理学杂志。2008,24(3):237-239
[98]Zhang Z,DuBois RN.Par-4,a proapoptotic gene,is regulated by NSAIDs in human colon carcinoma cells.Gastroenterology,2000,118(6):1012-1017
[99]Cheng ASL,Chan HLY,Leung W.et al.Specific COX-2 inhibitor,NS-398,suppresses cellular proliferation and induces apoptosis in human hepatocellular carcinoma cells.International journal ofoncology,2003,23(1):113-119
[100]Williams N.Tumor cells fight back to beat immune system.Science,1996,274(5291):1302
[101]Takahamal Y,Yamadal Y,Emotol K,et al.The prognostic significance of overexpression of the decoy receptor for Fas ligand(DcR3) in patients with gastric carcinomas[J].Gastric Cancer,2002,5(2):61-68
[102]Yaqub S,Henjum K,Mahic M,et al.Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner.Cancer Immunology,Immunotherapy,2008,57(6):813-821
[103]Chipuk JE,Fisher JC,Dillon CP,et al.Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins.PNAS,2008,105:20327-20332
[104]Tsujimoto Y,Shimizu S.Bcl-2 family:life-or-death switch.FEBS Lett,2000,466:6-10
[105]Marsden VS,O'Connor L,O'Reilly LA,et al.Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.Nature,2002 419(6907):634-7
[106]张有成,王杉,张辉,等。转录信号传导子和激活子3信号传导通路调控选择性环氧化酶2抑制剂抗结肠癌的机制。中华胃肠外科杂志,2004,7(5):404-406
[107]Shibakita M,Tachibana M,Dhar DK,et al.Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer.Clin Cancer Res 1999,5:2464-2469
[108]Zhu Q,Liu JY,Xu HW,et al.Mechanism of counterattack of colorectal cancer cell by Fas/Fas ligand system.World J Gastroenterol 2005,11:6125-6129
[109]Xu LN,Zou SQ,Wang JM.Action and mechanismof Fas and Fas ligand in immune escape of gallbladder carcinoma.World J Gastroenterol 2005,11:3719-3723
[110]Younes M,Schwartz M,Finnie D,Younes A.Overexpression of Fas ligand (FasL) during malignant transformation in the large bowel and in Barrett"s metaplasia of the esophagus.Human Pathology,1999,30(11):1309-1313。
[111]胡端敏,王少峰,冯一中。MMP-7与Fas蛋白在胃癌组织中的表达及意义。世界华人消化杂志,2006,14(33):3237-3240。
[112]Bennett MW,'Connell Jo,O'Sullivan GC,et al.Expression of Fas ligand by human gastric adenocarcinomas:a potential mechanism of immune escape in stomach cancer.Gut 1999,44:156-162。
[113]Memon SA,Hou J,Moreno MB,et al.Apoptosis induced by a chimeric Fas/FasL ICE receptor:lack of requirement for Fas or FADD binding proteins[J].J Immunol,1998,160(5):2046-2049.
[114]Compagni A,Christofori G.Recent advances inresearch on multistage tumorigenesis.Br J Cancer2000,83:1-5.
[115]Connell J,Bennett M W,Sullivan G C,et al.The Fas counterattack:a molecular mechenism of tumor immune privilege.Mol M ed,1997,3:294-300.
[116]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells[J].J Gastroenterol Hepatol,2002,17(1):32-38.
[117]Kume T,Oshima K,Yamashita Y,et al.Relationship between Fas ligand expression on carcinoma cell and cytotoxic T lymphocyte response in lymphoepithelioma like cancer of the stomach[J].Int J Cancer,1999,84(4):334-343.
[118]Zhao XH,Gu SZ,Tian HG,Quan P,Pan BR.Clinical significance of expression of apoptoticsignal proteins in gastric carcinoma tissue.World JGastroenterol 2005;11:3846-3849.
[119]胡端敏,王少峰,冯一中.MMP-7与Fas蛋白在胃癌组织中的表达及意义.世界华人消化杂志 2006,14(33):3237-3240
[120]Hallermalm K,.De Geer A,Kiessling R,et al.Autocrine Secretion of Fas Ligand Shields Tumor Cells from Fas-Mediated Killing by Cytotoxic Lymphocytes.Cancer Res.,September 15,2004,64(18):6775-6782
[121]Shain KH,Landowski TH,Dalton WS.Adhesion-Mediated Intracellular Redistribution of c-Fas-Associated Death Domain-Like IL-1-Converting Enzyme-Like Inhibitory Protein-Long Confers Resistance to CD95-Induced Apoptosis in Hematopoietic Cancer Cell Lines.J.Immunol,March 1,2002,168(5):2544-2553
[1]Wyllie AH,Kerr JF,Currie AR.Cell death:the significance of apoptosis[J].Int Rev Cytol.1980;68:251-306
[2]Chen YL,Wang JY,Chen SH,et al.Granulocytes mediates the Fasl-associated apoptosis during lung metastasis of melanoma that determines them etastatic behavior[J].Br J Cancer,2002,87(3):359-365
[3]Lee Tae-Bum,Min Young-Don,Lim Sung-Chui,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells.Journal of Gastroenterology & Hepatology.2002,17(1):32-38.
[4]高勇,张登海.Fas系统与肿瘤免疫逃避[J].国外医学肿瘤学分册,1998,25(6):327-329.
[5]吴雪平.Fas系统介导的细胞凋亡与肝脏疾病[J].国外医学免疫学分册,1999,22(2):68-71.
[6]Nagata S,Golstein P.The Fas death factor[J].Science,1995,267:1449-1456.
[7]Cascino I,Fiorucci G,Papoff G,et al.Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing[J].J Immunol,1995,154(5):2706-2713.
[8]刘海峰,刘为纹,房殿春.胃癌及其癌前病变中细胞凋亡与细胞增殖间关系的研究.世界华人消化杂志1999,7:649-651;
[9]Fukuzawa K,Takahashi K,Furuta K,et al.Expression of fas/fas ligand(fasL)and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC).J Gastroenterol 2001,36:681-688,
[10]Williams N.Tumor cells fight back to beat immune system[J].Science,1996,274(5291):1302
[11]Chinnaiyan AM,O' Rourke.K,Tewari M,etal.FADD,a novel death domain-containing protein,interacts with the death domain of Fas and initiates apoptosis[J].Cell,1995,81(19):505-512
[12]Kidd V J.Proteolytic activities that mediate apoptosis[J].Annu Rev Physiol,1998,60:533-573
[13]Lim SC.Fas-related apoptosis in gastric adenocarcinoma[J].Oncol Rep,2003,10:57-63
[14]Muzio,M,Chinnaiyan AM,Kischkel FC,etal.FI ICE,a novel FADD homologous ICE / CED-3-like proteases recruited to the CD95(Fas/APO-1)death-inducing signaling complex[J].Cell,1996.85:817-823,
[15]沈定丰,徐冲羽.Fas在胃癌细胞及外周血淋巴细胞中的表达.上海第二医科大学学报,2000,20(4):299-301,
[16]王强,赵毅,孙威,等。Fas、FasL及bcl-2在胰腺癌、癌旁组织中的表达及其意义。中华消化杂志,2001,21(4):252-253
[17]Leithauser F,Dhein J,Mechtersheinerg,et al.Constitutive and induced expression of APO-1,a new member of the nerve growth factor-tumor necrosis factor receptor super family in normal and malignantcells[J].Lab Invest,1999, 69(5):415-429
[18]Compagni A,Christofori G.Recent advances in research on multistage tumorigenesis[J].Br J Cancer,2000,83:1-5
[19]Chinnaiyan AM,Tepper CG,Sildin M F,et al.FADD / MORT lis a common mediator of CD95(Fas/APO-1)and Tumor necrosis factor receptor-induced apoptosis[J].J Biol Chem,1995 271(9):4961
[20]Misseri R,Meldrum C,Dinarello A,et al.TNF- mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling.Am J Physiol Renal Physiol 2005,288:F406-411.
[21]周华蓉 周新荣。IFN-γ和TNF-α诱导Fas表达在β胰岛细胞杀伤中的作用。中国免疫学杂志,2006,12:666-667
[22]Fukuzawa K,Takahashi K,Furuta K,et al.Expression of fas/fas ligand(fasL)and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC)[J].J Gastroenterol,2001;36:681-688
[23]Sato T,Irie S,Kitada S,and Reed JC.FAP-1:a protein tyrosine phosphatase that associates with Fas[J].Science,1995,268:411-415
[24]Yanagisawa J,Takahashi M,Kanki H,et al.The Molecular Interaction of Fas and FAP-1.[J].J Biol chem,1997,272:8539-8545
[25]Itoh N,Nagata S.A novel protein domain required for apoptosis.Mutational analysis of human Fas antigen[J].J Biol chem,1993,268:10932-10937
[26]Ungefroren H,Vose M,Jansen M.Human pancreatic adenocarcinomas expression Fas and Fas ligand yet are resistant to Fas-mediated apoptosis[J].Cancer Res,1998,58:1741-1749.
[27]Ungefroren H,Voss M,Bemstorff WV,et al.Immunological Escape Mechanisms in Pancreatic Carcinomal[J].Annals of the New York Academy of Sciences,1999.880:243-251.
[28]Irie S,Li Y,Kanki H,Ohyama T,et al.Identification of Two Fas-Associated Phosphatase-1(FAP-1) Promoters in Human Cancer Cells[J].Mitochondrial DNA,2001,11(6):519-526
[29]Vladimir N.Ivanov,Bergami PL,et al.FAP-1 Association with Fas(Apo-1)Inhibits Fas Expression on the Cell Surface.Molecular and Cellular Biology,2003,23(10):3623-3635
[30]刘征波,胡国龄,范学工,等。FASL、TRAIL在慢性乙型肝炎患者外周血淋巴AICD中的作用。中国免疫学杂志,2003,19(2):135-137
[31]Brigit Brenner,Klaus Ferlinz,Heike Grassm(?),Michael Weller,et al Fas/CD95/Apo-I activates the acidic sphingomyelinase via Caspases[J].Cell Death and Differentiation,1998,5(1):29-30.
[32]Yin XM,W KUN,Gross A,et al.Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis[J].Nature,1999,400(6747):886-891
[33]Luo X,Budihardjo I,Zou H,et al.Bid,a Bcl-2 Interacting Protein,Mediates cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors[J].Cell,1998,94:481-490
[34]谭晓华.神经酰胺:细胞凋亡信号转号的第二信使分子[J].国外医学:分子生物学分册,1999,21(1):10-14
[35]张涛,李百祥,富英群.鞘磷脂及神经酰胺对人结肠癌细胞(HT-29)的影响[J].卫生毒理学杂志,2003,17(2):81-83
[36]苏波,万艳平,廖端芳.细胞凋亡通路及转录调控中的Daxx[J].中国病理生理杂志.2005,21(3):617-620
[37]Yang X,Khosravi-Far R,Chang HY,Baltimore D.Daxx,a novel Fas-binding protein that activates JNK and apoptosis[J].Cell,1997,89(7):1067-1076
[38]Pluta AF,Earnshaw WC,Goldberg IG..Interphase-specific association of intrinsic centromere protein CENP-C with hDaxx,a death domain-binding protein implicated in Fas-mediated cell death[J].Cell Sci,1998,111(14):2029-2041.
[39]Juo P,Woo MS,Kuo CJ,et al.FADD is required for multiple signaling events downstream of the receptor Fas[J].Cell Growth Difer,1999,10:797-804.
[40]胡跃强,肖波,毕方方,等.大鼠局灶性脑缺血后FADD和Daxx的表达[J].中华神经科杂志,2007,40(11):762-767
[41]Ko YG,Kang YS,Park H,et al.Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein(Daxx) in the cytoplasm [J].J Biol Chem,2001,276(42):39103-39106.
[42]邓金牛,李春蕊,刘文励,等.去乙酰化酶抑制剂诱导白血病细胞凋亡过程中Daxx的表达变化[J].中华血液学杂志,2004,25(5):312-313
[43]Michaelson JS,Bader D,Kuo F,et al.Loss of Daxx,a promiscuously interacting protein,results in extensive apoptosis in early mouse development[J].Genes Dev,1999,13:1918-1923.
[44]Villunger A,Huang DC,Holler N,et al.Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX,and Fas-mediated cell death does not involve DAXX,RIP,or RAIDD[J].J Immunol,2000,165:1337-1343
[45] Younes M , Schwartz M , Finnie D , Younes A. Overexpression of Fas ligand (FasL) during malignant transformation in the large bowel and in Barrett"s metaplasia of the esophagus[J]. Human Pathology , 1999, 30 (11): 1309 - 1313
[46] Catherine Gratas, Yasuo Tohma, Christoph Barnas, et al. Up-regulation of fas (APO-1/CD95) ligand and down-regulation of fas expression in human esophageal cancer [J]. Cancer Research, 1998, 58: 2057-2062
[47] Muneaki Shibakital, Mitsuo Tachibana, Dipok K Dhar, et al. Prognostic significance of fas and fas ligand expressions in human esophageal cancer [J]. Clinical Cancer Research, 1999,5:2464-2469
[48] Younes M, Lechago J , Ertan A, et al . Decreased expression of fas (CD95/AP01) associated with goblet cell metaplasia in barrett's esophagus[J] . Human Pathology , 2000, 31 (4): 434 - 438
[49] Gratas C, Tohama Y, Barns C, et al. Up-regulation of Fas(APO-1 /CD95) ligand and down-regulation of Fas expression in human esophageal cancer. [J] Cancer Res,1998,58: 2057-2062.
[50] Michael W. Bennett, Joe O'Connell, Gerald C. O'Sullivan, et al. The Fas Counterattack In Vivo: Apoptotic Depletion of Tumor-Infiltrating Lymphocytes Associated with Fas Ligand Expression by Human Esophageal Carcinoma [J]. The Journal of Immunology, 1998, 160: 5669-5675.
[51] O'connell Jo, Bennett MW, O'sullivan GC, et al. Resistance to Fas (APO-1/CD95)-mediated apoptosis and expression of Fas ligand in esophageal cancer: the Fas counterattack [J]. Diseases of the Esophagus , 2001,12(2): 83-89
[52] Bennett MW, O 'Connell Jo, O'Sullivan GC, et al. Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer[J]. GUT, 1999;44:156-162。
[53] Pitti RM, Marsters SA, Lawrence DA, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer [J]. Nature, 1998, 396: 699-703
[54] Delmas D, RebeC, Lacour S , et al. Resveratrol-induced Apoptosis Is Associated with Fas Redistribution in the Rafts and the Formation of a Death-inducing Signaling Complex in Colon Cancer Cells [J]. J Biol Chem, 2003, 278 (42): 41482-41490.
[55] O'Connell J, Bennett MW, O'Sullivan GC , et al. Fas ligand expression in primary colon adenocarcinomas:evidence that the Fas counterattack is a prevalent mechanism of immune evasion in human colon cancer[J].The Journal of Pathology,1999,186(3):240-246
[56]O'Connell J,O'Sullivan GC,Collins JK,Shanahan F.The Fas counterattack:Fas-mediated T cell killing by colon cancer cells expressing Fas ligand[J].Journal of Experimental Medicine,1996,184:1075-1082,
[57]李世拥,于波,安萍,等。FasL基因表达对结直肠癌细胞肝转移影响的研究。中华外科杂志。2003,4(9):646-648
[58]左富义,李世拥,安萍,等。蛋白质酵母双杂交系统的建立及其在大肠癌肝转移研究中的意义中华外科杂志。2004,42(11):672-674
[59]Song E,Chen J,OuYang N,et al.Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis:an active mode of immune evasion in colon cancer[J].British journal of cancer,2001,85:1047-1054
[60]Giardina C,Boulares H,Inan MS.NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-α and Fas ligation:the role of reactive oxygen species[J].Molecular Cell Research,1999,1448(3):425-438
[61]朱风尚,陈锡美.COX-2抑制剂与消化道癌前病变的阻断治疗[J]。同济大学学报:医学版,2003,2:161-163
[62]郜恒骏。NSAIDs化学预防胃肠道癌症研究的新进展[J]。国外医学:消化系疾病分册,2001,2:86-89
[63]沈定丰,徐冲羽.Fas在胃癌细胞及外周血淋巴细胞中的表达[J].上海第二医科大学学报,2000,20(4):299-301
[64]Lim SC.Fas-related apoptosis in gastric adenocarcinoma[J].Oncol Rep 2003;10:57-63
[65]Imtiyaz HZ,Rosenberg S,Zhang Y,et al.The fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells.J.Immunol,2006,176:6852-6861,
[66]黄群,高晓燕,陈江,等。胃癌组织FasL表达上调与肿瘤浸润性淋巴细胞凋亡的关系[J].实用癌症杂志.2002.17(3):27-28
[67]Bennett MW,O'Connell J,O'Sullivan GC,et al.Expression of Fas ligand by human gastric adenocarcinomas:a potential mechanism of immune escape in stomach cancer[J].GUT 1999;44:156-162
[68]Takahamal Y,Yamadal Y,Emotol K,et al.The prognostic significance of overexpression of the decoy receptor for Fas ligand(DcR3) in patients with gastric carcinomas[J].Gastric Cancer,2002,5(2):61-68
[69]Chen YL,Wang JY,Chen SH,et al.Granulocytes mediates the Fasl-associated apoptosis during lung metastasis of melanoma that determines the metastatic behavior[J].Br J Cancer,2002,87(3):359-365.
[70]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells[J].J Gastroenterol Hepatol,2002,17(1):32-38.
[71]Lee SH,KimHS,Kim SY,et al.Increased expression of FLIP,an inhibitor of Fas-mediated apoptosis,in stomach cancer[J].APMIS,2003,111(2):309-314
[72]Irmber M,Thome M,Hahne M,et al.Inhibition of death receptor signals by cellular FI IP[J].Nature,1997,388(6638):190-195.
[73]Hayashi H,Tatebe S,Osaki M,et al.Expression of Fas Antigen and Its Mediation of Apoptosis in Human Gastric Cancer Cell Lines[J].Cancer Science,2005,88(1):49-55
[74]高勇,张登海.Fas系统与肿瘤免疫逃避[J].国外医学肿瘤学分册,1998,25(6):327-329
[75]Bellgrau D,Gold D,Selawry H,et al.A role for CD95 ligand in preventing graft rejection[J].Nature,1995.377:630-632.
[76]李佳莉,赵丽纯.Fas/FasL系统与肿瘤的免疫逃逸[J].国外医学:免疫学分册,2001,786-788
[77]蔡世荣 詹文华.Fas配体表达诱导同种胰岛移植免疫豁免[J].中华实验外科杂志,2001,18(1):58-59
[78]Streilein JW.Enhanced Perspective:Unraveling Immune Privilege[J].Science,1995,270:1158.
[79]Van Parijs L,Abbas AK.Role of Fas-mediated cell death in the regulation of immune responses[J].Immunity,1996,8(3):355-361
[80]Griffith TS,Brunner T,Fletcher SM,et al.Fas ligand induced apoptosis as a mechanism of immune privilege[J].Science,1995,270:1189-1192
[81]Hughes SJ,Nambu Y,Soldes OS,et al.Fas/APO-1(CD95) is not translocated to the cell membrance in esophagealadenocarcinoma[J].Cancer Res,1997,57:5571-5578.
[82]Tamiya S,Etoh K,Suzushima H,et al.Mutation of CD95(Fas/APO-1)gene in adult T-cell leukemia cells[J].Blood,1998,91:3935-3942
[83]Strand S,Hofmann WJ,Hug H,et al.Lymphocyte apoptosis induced by CD95(APO-1/Fas)ligand-expressing tumor cells-a mechanism of immune evasion[J].Nature Med,1996,2:1296-1361.
[84]Leithauser F,Dhein J,Mechtersheimer G,et al.Constitutive and induced expression of Apo-1.a new growth factor/tumor necrosis factor receptor superfamily,in normal and neoplastic cells[J].Lab Invest,1993,69:415-429.
[85]曹长安,郭颖,郭琳琅.肝癌组织中人白细胞共同抗原和凋亡相关基因Fas、bcl-2及bax的表达及意义[J].肿瘤防治研究,1999,26(2):94-95
[86]Muller M,Strand S,Hug H,et al.Drug-induced apoptosis in hepatoma cells is mediated by the CD95(Apo-1/Fas)receptor/ligand system and involves activation ofwild-type p53[J].J Clin Invest,1997,99:403-413.
[87]刘建夏,张学光,钱海鑫,等.Fas/FasL系统在肿瘤细胞耐药中的作用[J].癌症,1998,17(6):401-404.
[88]Hahne M,Rimoldi D,Schr(o|¨)ter M,et al.Melanoma Cell Expression of Fas(Apo-1/CD95) Ligand:Implications for Tumor Immune Escape[J].Science,1996,274:1363-1366
[89]Lee TB,Min YD,Lim SC,et al.Fas(Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells[J].J Gastroenterol Hepatol,2002,17(1):32-38.
[90]Owen-Schaub L,Chan H,Cusack JC,et al.Fas and Fas ligand interactions in malignant disease[J].Int J Oncol,2000,17(1):5-12.
[91]Shiraki K,Tsuji N,Shioda T,et al.Expression of Fas ligand in liver metastases of human colonic adenocarcinomas[J].Proe Natl Acad SCi USA,1997,94:6420-6425.
[92]李国平.Fas抗原—配体系统与肝脏疾病研究进展[J].国外医学临床生物化学与检验学分册,1999,20(1):4-6.