表皮生长因子受体在胸腺瘤中的表达

目的探讨表皮生长因子受体(EGFR)在胸腺瘤中的表达及其意义。方法免疫组化SP法检测63例患者胸腺瘤(胸腺瘤组)和20例胸腺增生(胸腺增生组)组织中EGFR的表达,分析胸腺瘤EGFR表达与其病理分级及临床分期的相关性。结果胸腺瘤组EGFR表达阳性率高于胸腺增生组(52.4%vs.20.0%)(P<0.05)。直径>6cm的胸腺瘤EGFR表达阳性率高于直径≤6cm的胸腺瘤(P<0.05)。胸腺瘤EGFR表达水平与病理分级及临床分期呈正相关。胸腺瘤的预后和临床分期相关。结论 EGFR可能在胸腺瘤的进展和预后中发挥重要作用。EGFR可能成为胸腺瘤新的治疗靶点和预后的标志物。     

环氧化酶-2及表皮生长因子受体在非小细胞肺癌组织中的表达及临床意义

目的探讨环氧化酶-2（COX-2）与表皮生长因子受体（EGFR）在非小细胞肺癌（NSCLC）组织中的表达及与肺癌发生发展的关系。方法采用免疫组化（SP）法检测56例NSCLC和20例正常肺组织中COX-2与EGFR表达。结果56例NSCLC组织中，COX-2与EGFR表达阳性率分别为64．2％，67．8％，显著高于正常肺组织（P〈0．01），COX-2与EGFR表达与临床分期、病理分级、组织学分型、淋巴结转移密切相关（P〈0．05），肿瘤分期愈晚，细胞分化越羞，淋巴结转移越高，COX-2与EGFR表达阳性率越高，腺癌中COX-2表达明显高于鳞癌，鳞癌中EGFR表达高于腺癌（P〈0．05）。结论COX-2与EGFR在NSCLC中异常表达说明其在肺癌发生发展中有重要作用．可作为判断NSCLC的生物学行为及估计预后的指标。     

组织蛋白酶D、表皮生长因子受体在膀胱移行细胞癌中的表达及其相关性

目的 探讨组织蛋白酶Ｄ（ＣＤ）、表皮生长因子受体（ＥＧＦＲ）的表达与膀胱移行细胞癌（ＢＴＣＣ）生物学行为间的关系及其发生浸润转移的机制。方法 应用免疫组化ＡＢＣ法检测３３例ＢＴＣＣ及１２例正常膀胱组织中ＣＤ、ＥＧＦＲ的表达。结果 正常膀胱移行细胞ＣＤ均呈弱阳性表达,ＢＴＣＣ组肿瘤细胞ＣＤ中／强阳性表达率显著高于正常对照组（Ｐ〈０．０５）,且在不同病理分级,临床分期,单发与多发,初发与复发组间均有显     

2,3,7,8-四氯二苯-对-二噁英对BRL-3A细胞增殖、凋亡及胰岛素样生长因子2表达的影响

目的探讨2,3,7,8-四氯二苯-对-二噁英(TCDD)对大鼠肝BRL-3A细胞增殖、凋亡以及胰岛素样生长因子2(IGF2)表达的影响。方法培养BRL-3A细胞,TCDD 5,10,15和20 nmol.L-1作用24 h,MTT法检测细胞存活。BRL-3A细胞紫外线照射2 min或经无血清培养后,加入TCDD 10 nmol.L-1,流式细胞计数方法检测细胞凋亡。荧光定量PCR方法检测TCDD 10 nmol.L-1对BRL-3A细胞Igf2 mRNA表达的影响,Western印迹法检测IGF2蛋白表达。结果 TCDD 5,10,15和20 nmol.L-1作用24 h,BRL-3A细胞的存活率分别为(107.3±0.9)%,(122.6±1.2)%,(115.2±0.4)%和(112.3±1.1)%,明显高于正常对照组(P<0.05),TCDD 10 nmol.L-1对BRL-3A细胞增殖促进作用最强。紫外线照射2 min的溶剂对照组BRL-3A细胞的凋亡率为(26.4±5.0)%,加入TCDD 10 nmol.L-1细胞凋亡率明显降低为(12.2±3.2)%(P<0.05);无血清培养的溶剂对照组72和120 h BRL-3A细胞的凋亡率分别为(49.6±7.6)%和(51.6±9.1)%,加入TCDD 10 nmol.L-1组的细胞凋亡率显著降低,分别为(22.0±5.1)%和(31.0±5.5)%(P<0.05)。与溶剂对照组相比,TCDD 10 nmol.L-1组Igf2基因的表达随作用时间逐渐增高,TCDD作用24 h细胞Igf2 mRNA的表达增加了1.67倍,蛋白的表达增加了2.6倍(P<0.05)。结论 TCDD具有刺激BRL-3A细胞增殖和抑制该细胞凋亡的作用;TCDD可能通过上调BRL-3A细胞中IGF2的表达,调节细胞的增殖和凋亡。     

二甲双胍对人肝癌Hep-G2细胞表皮生长因子及其受体表达的影响

目的 观察二甲双胍对人肝癌Hep-G2细胞表皮生长因子（EGF）及其受体（EGFR）的影响.方法 体外培养人肝癌Hep-G2细胞,用不同浓度二甲双胍进行干预,3-（4,5-二甲基噻唑-2）-2,5-二苯基四氨唑溴盐法检测二甲双胍对Hep-G2细胞生长的影响;Hoechst 33342染色荧光显微镜观察细胞的形态学变化,流式细胞术观察细胞凋亡;蛋白质印迹法（Western blot）检测EGF、EGFR的表达.结果 二甲双胍对肝癌细胞的活性具有明显的抑制作用,且呈剂量依赖性;以10 mmol/L作用终浓度抑制效果最明显,其48 h的细胞吸光度为（0.477 ±0.025）,与对照组（0.602±0.026）比较差异有统计学意义（P＜0.01）;逐渐增加二甲双胍的作用浓度,细胞凋亡率随之逐渐增加,药物组细胞凋亡率分别为（10.76±0.96）％、（20.77±1.16）％,与对照组（5.21±0.13）％相比差异均有统计学意义（P＜0.05）;Hoechst33342染色可见明显的细胞皱缩,核染色质浓缩,核碎裂等凋亡形态学变化;Western blot结果显示,EGF及其受体蛋白的表达随着二甲双胍作用浓度的增加而逐渐下调.结论 在体外,二甲双胍能够抑制人肝癌Hep-G2细胞增殖及诱导细胞凋亡,其抗肿瘤机制可能与细胞内EGF及EGFR表达下调有关.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on blood and spleen natural killer (NK) cell activity in the mouse.

The immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD) were studied in male A/J mice after a loading dose of 5 μg TCDD/kg body wt. followed by 3 weekly maintenance doses of 1.42 μg TCDD/kg b.w. administered intraperitoneally. Tissue samples and immune cells were prepared on two occasions, i.e. on days 28 and 120 after the first injection of TCDD. This dose of TCDD evoked classical histological signs of liver damage and lipid accumulation, as well as thymic atrophy. Red (RBC) blood cell counts were significantly lowered in the TCDD group on day 28, but were normal on day 120. White (WBC) blood cell counts were normal in the TCDD group. Natural killer (NK) cell activity increased 3.4-fold (P < 0.01) and 2.2-fold (P < 0.01) in the blood and spleen, respectively, after 28 days, and these effects persisted on day 120. The increased NK-cell activity occurred concomitantly with a decreased proliferativc response of spleen lymphocytes to the T-cell mitogen concanavalin A after both 28 (65%) and 120 days (58%). The proliferative response of spleen cells to the B-ccll mitogen lipopolysaccharide seemed, however, unaffected. We have thus shown for the first time that TCDD induces an increased activity of NK cells that occurs simultaneously in the blood and spleen. This effect may indicate a general compensatory activation of the body's defences brought about by disturbances in the function of other arms of the immune system.     

Antiteratogenic effect of resveratrol in mice exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin

The effect of resveratrol, an aryl hydrocarbon receptor antagonist, on the teratogenicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated. Pregnant C57BL/6J mice were orally administered resveratrol (50 mg/kg) for 6 consecutive days, from gestational day (GD) 8 to GD13, followed by an oral challenge with TCDD (14 mug/kg) on GD12. TCDD caused severe fetal malformations including cleft palate (40.7%), renal pelvic dilatation (100%, mean score 3.060), and ureteric dilatation (100%, mean score 3.210) and tortuosity (95.1%). Resveratrol significantly reduced both the incidence of TCDD-induced cleft palate to 18.4% and the degrees of renal pelvic and ureteric dilatations caused by TCDD. The results suggest that pretreatment with resveratrol might bring a beneficial outcome for reducing the incidence and severity of fetal malformations caused by TCDD exposure in utero.     

表皮生长因子受体及其抑制剂的研究

表皮生长受体因子属于受体酪氨酸激酶家族成员,其过度表达和/或基因突变与多种肿瘤的形成具有密切的联系。近年来,小分子表皮生长因子受体酪氨酸激酶抑制剂的开发已成为肿瘤治疗领域中的研究热点。这里就表皮生长因子受体及其小分子抑制剂进行简要综述。     

表皮生长因子受体和血管内皮生长因子与环氧化酶2在食管癌组织中的表达及其意义

目的 研究食管癌中表皮生长因子受体(EGFR)、血管内皮生长因子(VEGF)、环氧化酶2(COX-2)的表达及其与肿瘤组织病理特征之间的关系.方法 应用免疫组化的方法分别检测94例食管癌组织和30例邻近正常食管黏膜中EGFR、VEGF蛋白、COX-2蛋白表达水平,并分析三者与肿瘤组织病理特征之间的关系.结果 EGFR、VEGF、COX-2在94例食管癌组织中阳性表达率分别为69.2％(65/94)、73.4％(69/94)、84.0％(79/94);而在30例正常食管黏膜中阳性表达率分别为13.3％(4/30)、13.3％(4/30)、3.3％(1/30),2组间表达差异有统计学意义(P＜0.01);且EGFR、VEGF、COX-2与淋巴结转移和TNM分期有关(P＜0.05).结论 EGFR、VEGF、COX-2在食管癌组织中显著表达,且可能参与肿瘤发生、发展,可作为预测食管癌生物学行为的重要参考指标.     

Effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal brain growth and motor and behavioral development in offspring rats

The effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during pregnancy on fetal brain growth and neurobehavioral development in early developmental stages were investigated using rat offspring. TCDD in corn-oil (0.1microg/kg) was orally administrated to the dams from the 9th to 19th gestational day. When TCDD effects on the fetal brain weight were analyzed on the 19th gestational day, weight ratio of the brain to the whole body, and that of the forebrain without the cerebral cortex to the whole brain were larger in the exposed group than those of the control group, suggesting premature fetal brain development. TCDD effects on motor functions were investigated using newborns in an inclined plane task. Motor development assessed by righting response on an inclination was delayed in the exposed offspring in the 8th-12th postnatal day, especially in male. Also, TCDD effects on active avoidance behavior in a shuttle box were investigated using the offspring after weaning. Latency in the active avoidance learning was longer, and locomotor activity was reduced in the exposed male offspring in the 41st-44th postnatal day. The results demonstrated that maternal TCDD exposure delayed fetal brain growth and neurodevelopment of the offspring in early stage, especially in male rats.     

维生素A缺乏及补充对小鼠子代发育的影响

目的通过建立小鼠维生素A缺乏模型,研究维生素A对小鼠胎仔发育的影响。方法对维生素A缺乏之孕鼠分不同阶段补充维生素A,观察胎鼠发育情况。结果维生素A缺乏使胎鼠的体重、身长、尾长明显小于正常对照组(P＜0.05),囟门矢义冠内0.268cm×0.228cm,明显大于对照组的0.206cm×0.078cm;骨异常率为33.33％,对照组仅为7.32％,胸骨异常率为48.72％,对照组为2.44％,差异均有显著性明显大于正常对照组,胎仔骨骼发育异常,神经反射发育迟缓,且出现脑膨出及细小肾等畸形。交配后第7天补充组明显好于缺乏组,但与正常对照组相比仍有差异。交配后第0天补充组与正常对照组无差异。结论揭示维生素A对胚胎的生长发育十分重要。     

Liver-specific decrease in Tff3 gene expression in infant mice perinatally exposed to 2,3,7,8-tetrabromodibenzofuran or 2,3,7,8-tetrachlorodibenzo-p-dioxin

Polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/DFs) are byproducts of brominated flame retardants and can cause adverse health effects. Although exposure to polychlorinated (PC) DD/DFs induces toxic effects, including liver injury and neurobehavioral disorder, little is known about toxicities associated with PBDD/DF exposure. Thus, we examined effects of perinatal exposure to brominated congener on the infant mouse. Gene expression in several organs, such as the liver and brain, was analyzed in mouse offspring born to dams administered 2,3,7,8-tetrabromodibenzofuran (TBDF; 9 or 45 μg/kg body weight) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 3 μg/kg body weight) on gestational day 12.5. An increase in liver size was observed in TBDF- or TCDD-exposed offspring in infancy. Gene microarray analysis revealed that 163 and 36 genes were markedly upregulated and downregulated, respectively, in the liver of TBDF-exposed mice compared with those in vehicle-treated mice on postnatal day (PND) 5. Significant increases in Cyp1a1, Cyp1a2, Fmo3, and Pnliprp1 and decreases in Tff3, Ocstamp, Kcnk16, and Lgals2 mRNA levels in TBDF-exposed offspring on PNDs 5 and 12 were confirmed by quantitative PCR. In particular, a significant reduction in Tff3 mRNA in the liver, but not in the brain, small intestine, colon, and kidney, was observed in offspring perinatally exposed to TBDF or TCDD. Ultrasonic calls of TBDF- or TCDD-exposed offspring on PNDs 3–5 were impaired. Taken together, perinatal exposure to polyhalogenated dioxin/furan congeners disrupts gene expression patterns in the liver and ultrasonic calling during infancy. These results suggest that liver injury may contribute to neurobehavioral disorder.     

表皮生长因子对肿瘤敏感性和肾毒性的影响

为探讨外源性表皮生长因子在肿瘤治疗中的可能应用,小鼠接种肉瘤（Ｓ１８０）,于接种后第２,６天腹腔注射顺铂（ＣＤＤＰ）２ｍｇ／ｋｇ,在ＣＤＤＰ处理的同时０小时,前１２,前２４小时皮下注射ＥＧＦ５μｇ／只及前２４小时腹腔注射ＥＧＦ５μｇ／只;大鼠一次腹腔注射ＣＤＤＰ５ｍｇ／ｋｇ,于ＣＤＤＰ处理前２４小时皮下注射ＥＧＦ２０μｇ／只。结果显示ＥＧＦ腹腔及皮下处理均能促进Ｓ１８０生长;ＥＧＦ只有于ＣＤＤＰ前皮下处理才能增高Ｓ１８０对ＣＤＤＰ敏感性;ＥＧＦ增高敏感性的同时,小鼠去瘤体重及大鼠血清ＢＵＮ、Ｃｒ水平均与对照组无差别     

表皮生长因子受体酪氨酸激酶抑制剂BPI-2009的抗肿瘤作用及其机制的研究

目的:探讨一种口服的表皮生长因子受体(epidermalgrowthfactorreceptor ,EGFR)酪氨酸激酶抑制剂(BPI 2 0 0 9)的抗肿瘤作用及其机制。方法:Westernblot方法检测BPI 2 0 0 9对酪氨酸激酶和EGFR自动磷酸化的抑制作用,MTT法检测BPI 2 0 0 9对多种肿瘤细胞的生长抑制作用,使用A4 31肿瘤模型的荷瘤裸鼠进行体内的肿瘤抑制试验。结果:通过对EGFR激酶抑制剂化学文库的筛选,发现BPI 2 0 0 9是一个有效的EGFR激酶抑制剂。BPI 2 0 0 9对EGFR激酶的半数抑制浓度(IC50 )为5nmol·L- 1,当其浓度达到6 2 .5nmol·L- 1的时候可以完全抑制EGFR激酶的活性,但在10 0nmol·L- 1时对Abl、Abl相关基因(Abl relatedgenes ,Arg)以及c- Src酪氨酸激酶都没有明显的抑制作用。BPI 2 0 0 9可以阻断EGFR介导的细胞内蛋白酪氨酸的磷酸化,IC50 为4 5nmol·L- 1。在肿瘤细胞生长抑制试验中,BPI 2 0 0 9对于肿瘤细胞的生长抑制作用与EGFR在细胞中的表达密切相关。人类肿瘤细胞A4 31移植瘤抑制试验的研究表明BPI 2 0 0 9经口给药每天1次在10 0mg·kg- 1,肿瘤抑制率达6 4% ,有明显的剂量效应关系,并没有发现明显的病态和体重下降。结论:BPI 2 0 0 9是一种有效的高选择性的以EGFR酪氨酸激酶为靶点的抗肿瘤药物。     

Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.     

RNA干扰技术抑制乳腺癌表皮生长因子受体的表达

目的 探讨采用化学合成小干扰RNA（siRNA）介导的RNA干扰（RNAi）技术是否能有效抑制乳腺癌细胞株MDA-MB231、MDA-MB-453S、ZR-75-30、ZR-75细胞表皮生长因子受体（EGFR）表达,以及抑制EGFR基因表达后乳腺癌细胞生物学特性的改变,以期为肿瘤治疗提供新的思路和实验依据.方法 （1）建立检测EGFR数量的方法,测定MDA-MB231、MDA-MB-453S、ZR-75-30、ZR-75细胞株EGFR的表达.（2）观察dsRNA-EGFR/Lipofectamine 2000对EGFR表达的抑制作用.（3）采用流式细胞仪测定细胞周期,采用ELISA法观察抑制EGFR表达后,MDA-MB231,MDA-MB-453S、ZR-75-30、ZR-75细胞生物学特性的改变.结果 MDA-MB231、MDA-MB-453S、ZR-75-30、ZR-75细胞株存在EGFR高表达.转染dsRNA-EGFR后可将MDA-MB231、MDA-MB-453S细胞对5-Fu的敏感性提高约4倍.细胞周期分析结果表明dsRNA-EGFR组G0-G1期细胞百分数较对照组增加了17.48%,进入S期的细胞百分数较对照组减少了19.20%.转染dsRNA-EGFR后可将ZR-75-30、ZR-75细胞对5-Fu的敏感性提高约7倍.结论 （1）乳腺癌细胞株存在EGFR高表达.（2）dsRNA-EGFR可序列特异性下调乳腺癌细胞EGFR基因水平,显著降低EGFR蛋白表达.（3）dsRNA-EGFR通过抑制EGFR表达可显著抑制细胞增生和细胞迁移,降低配体EGF的含量,将更多的细胞阻滞在G0-G1期,增加细胞对5-Fu的敏感性,有效逆转乳腺癌细胞的恶性表型,从而为乳腺癌基因治疗提供了新策略.     

吉非替尼治疗非小细胞肺癌的疗效与EGFR基因突变的关系

目的探讨吉非替尼治疗晚期非小细胞肺癌(NSCLC)的疗效与表皮生长因子受体(EGFR)基因突变的关系。方法选择36例Ⅲb期或Ⅳ期经铂类治疗方案无效的NSCLC患者,根据有无EGFR基因突变分为有EGFR基因突变组(A组,11例)与无EGFR基因突变组(B组,25例),均予以吉非替尼治疗,分析其疗效与EGFR基因突变的关系。结果 A组吉非替尼治疗有效率优于B组(81.8%vs.16.0%)(P<0.05)。结论 EGFR基因突变的检测可作为吉非替尼治疗NSCLC疗效的一个预测指标。     

二噁英对成骨肉瘤细胞增殖和胰岛素样生长因子2表达的影响

目的探讨环境类致癌因子二噁英(TCDD)对成骨肉瘤细胞增殖及胰岛素样生长因子2(IGF-2)mRNA和蛋白表达的影响。方法TCDD作用于人成骨肉瘤细胞SaOS-2细胞株24~48h。MTT法检测细胞增殖率;对硝基酚磷酸盐法测定细胞内碱性磷酸酶(ALP)活性;RT-PCR半定量分析细胞IGF-2 mRNA的表达;Western蛋白质印迹法测定细胞IGF-2和丝裂原激活蛋白激酶(MAPK)信号通路中p38 MAPK蛋白表达及其磷酸化水平。结果与对照组比较,TCDD 1,10和100nmol·L-1作用48h,使SaOS-2细胞内ALP活性分别增加38%,95%和142%。TCDD 1,10及100nmol·L-1作用24h后,SaOS-2细胞存活率分别增加21%,47%和56%,细胞内IGF-2 mRNA和IGF-2蛋白表达均增加。TCDD对SaOS-2细胞内p38 MAPK蛋白表达无明显影响,但明显降低其磷酸化水平。结论TCDD具有促进SaOS-2细胞增殖的作用。TCDD可能通过促进SaOS-2细胞内IGF-2的表达,并抑制MAPK信号通路中转录因子p38 MAPK活性而促进细胞增殖。     

表皮生长因子受体表达、肿瘤残留与鼻咽癌疗效的关系

目的 探讨同期放化疗治疗鼻咽癌表皮生长因子受体(EGFR)的表达和肿瘤残留情况对疗效和预后判断的价值.方法 200例鼻咽癌(NPC)患者应用免疫组织化学技术检测EGFR在癌组织中的表达,并分析鼻咽部及颈部肿瘤残留情况.结果 EGFR在200例NPC中阳性表达160例(80.0%),阴性表达40例(20.0%);EGFR阳性组和阴性组3年总生存率(OS)、无瘤生存率(DFS)、无区域复发生存率(LRFS)、无远处转移生存率(DMFS)分别为72.3%、63.6%、72.2%、63.8%和90.0%、90.0%、90.0%、90.0%(X2=3.95,X2=4.12,X2=3.98,X2=4.15,P＜0.05);有残留者局部复发率、远处转移率26.6%、32.5%明显高于无残留者8.1%、18.1%(X2=4.75,X2=4.94,P＜0.05);在多因素分析中,EGFR高表达与无病生存率(DFS)和总生存率(OS)显著相关(r=6.457,P＜0.05).结论 EGFR在HNC中表达率较高,过度表达者呈现不良预后的趋势;放射治疗后肿瘤残留可作为判断预后的一个指标.