Reduced expression of epidermal growth factor receptor-related protein in hepatocellular carcinoma: implications for cancer growth

BACKGROUND/AIMS: The mitogenic signaling pathway of epidermal growth factor receptor (EGFR) is activated in a variety of cancers, including hepatocellular carcinoma (HCC). The recently cloned EGFR-related protein (ERRP) has been proposed to be a negative regulator of EGFR. The expression of ERRP in non-malignant liver cells and in HCC, and its relation to cell proliferation, have not been examined. METHODS: Paraffin sections of formalin-fixed HCC specimens of 51 HCCs and 10 normal liver specimens were immunostained with anti-ERRP and anti-p53 antibodies. To determine the relationship between ERRP expression and cell proliferation, we performed double staining for ERRP and proliferating cell nuclear antigen (PCNA) in the same HCC specimens. RESULTS: In normal liver, ERRP was expressed in 100% of specimens, while in non-malignant liver tissue from HCC, ERRP expression was present in 50% of the specimens (p < 0.001). In contrast, ERRP expression was present only in 14% of the HCC specimens. The expression of ERRP in cancer cells was inversely correlated with proliferative activity and tumor size (p < 0.001, p < 0.05, respectively). No significant correlation was found between p53 expression and the expression of ERRP. CONCLUSIONS: Human HCC, which has been shown to be associated with increased activation of EGFR, exhibits a substantial reduction in ERRP expression. The inverse relationship between ERRP expression, proliferative activity of tumor cells and tumor size suggests that in some HCC, ERRP is a negative regulator of HCC growth.     

Correlation of human epidermal growth factor receptor protein expression and colorectal cancer

AIM: To investigate the correlation between human epidermal growth factor receptor (HER-2) protein expression and colorectal cancer (CRC) using a case-control study and meta-analysis.METHODS: Tumor tissue specimens from 162 CRC patients were selected for the case group. Fifty cases were randomly selected, and normal CRC tissue at least 10 cm away from the tumor margins of these cases was used to generate the control group. The expression of the HER-2 protein in the 162 CRC tissue samples and the 50 adjacent normal mucosa tissue samples was detected via immunohistochemistry. The experimental data were analyzed using SPSS 18.0 software, and R software version 3.1.0 was utilized for further verification.RESULTS: The expression of HER-2 protein in the 162 CRC tissue samples was significantly higher than in the normal tissue specimens. The data showed that the expression of HER-2 in CRC was related to the Dukes’ stage, the depth of invasion and lymph node metastasis. The HER-2-positive patients had lower 3- and 5-year OS rates than the HER-2-negative patients, but there was no significant difference. However, there was a statistically significant difference in the 3- and 5-year disease-free survival (DFS) rates of HER-2-positive and HER-2-negative patients. The results of the meta-analysis showed that the expression of HER-2 in CRC patients was statistically significantly increased over that of healthy people. The 3-year DFS rate in HER-2-positive patients was markedly lower than that in HER-2-negative patients.CONCLUSION: Down-regulation of HER-2 expression might be a dependable strategy for CRC therapy.     

Human epidermal growth factor receptor 2 expression in mixed gastric carcinoma

AIM: To investigate human epidermal growth factor receptor 2 (HER2) amplification and protein expression in mixed gastric carcinoma.METHODS: Fluorescence in situ hybridization and immunohistochemistry were used to detect HER2 amplification and protein expression in 277 cases of mixed gastric carcinoma. Protein staining intensity was rate as 1+, 2+, or 3+.RESULTS: Of the 277 cases, 114 (41.2%) expressed HER2 protein. HER2 3+ staining was observed in 28/277 (10.1%) cases, 2+ in 37/277 (13.4%) cases, and 1+ in 49/277 (17.7%) cases. A HER2 amplification rate of 17% was detected, of which 25/28 (89.3%) were observed in the HER2 3+ staining group, 17/37 (45.9%) in 2+, and 5/49 (10.2%) in 1+. Of the 47 patients with HER2 amplification who received chemotherapy plus trastuzumab, 22 demonstrated median progression-free and overall survivals of 9.1 mo and 16.7 mo, respectively, which were significantly better than those achieved with chemotherapy alone (5.6 mo and 12.1 mo, respectively) in 19 previously treated patients (Ps < 0.05).CONCLUSION: HER2 detection in mixed gastric carcinoma displays high heterogeneity. Relatively quantitative parameters are needed for assessing the level of HER2 amplification and protein expression.     

Fibroblast growth factor receptor 4 protein expression and clinicopathological features in gastric cancer

AIM:To investigate fibroblast growth factor receptor4(FGFR4)protein expression in Chinese patients with resectable gastric cancer(GC)and the association with clinicopathological characteristics and survival.who underwent curative surgical procedures were enrolled in this study.The protein expression of FGFR4 in formalin-fixed,paraffin-embedded(FFPE)GC tissues was determined by immunohistochemical(IHC)analysis.Patient clinicopathological data and survival information were also collected andχ2 statistical analysis was performed to analyze FGFR4 protein expression in the subgroups with differing clinicopathological characteristics including;gender,age,tumor location,differentiation,tumor-node-metastasis stage,macroscopic type,depth of invasion,lymph node metastases,distant metastasis,neural invasion and vascular invasion.Furthermore,some common molecular markers of GC in our cancer center,including p53,p27,topoisomeraseⅡα(TopoⅡα)were also determined by IHC and their association with FGFR4 protein expression evaluated.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using the log rank test.RESULTS:Seventy seven cases(44%)were found to have high expression of FGFR4 protein.Significantly different FGFR4 expression was observed between gastric cancers with differing expression of TopoⅡα(log rankχ2=9.4760,P=0.0236).No significant differences were observed between subgroups defined by any of the other clinicopathological characteristics.The median survival time of the FGFR4 high expression(77 cases)and low expression groups(98 cases)was27 mo and 39 mo,respectively.The five-year survival rates and median survival times of gastric cancers with high FGFR4 expression were worse than those with low expression(30.8%vs 39.2%,27 mo vs 39 mo),respectively,however,no significant difference was observed in survival time(log rankχ2=1.0477,P=0.3060).Survival analysis revealed that high expression of FGFR4 was a predictor of poor outcome in GC patients if the tumor was small(less than or equal to 3cm in size)(log rankχ2=5.5033,P=0.0190),well dif-ferentiated(log rankχ2=7.9757,P=0.0047),and of T1 or T2 stage invasion depth(log rankχ2=4.8827,P=0.0271).CONCLUSION:Our results suggest that high tumor expression of FGFR4 protein is not an independent risk factor for GC cancer initiation,but is a useful prognostic marker for GC patients when the tumor is relatively small,well differentiated,or in the early stages of invasion.     

表皮生长因子及其受体在糜烂胃黏膜中的表达

目的:观察胃窦黏膜糜烂区与糜烂旁胃黏膜、慢性萎缩性胃炎中表皮生长因子(epidermal growth factor,EGF)及其受体(epidermal growth factor receptor,EGFR)的表达,探讨其在胃黏膜损伤修复中的意义.方法:选择经胃镜及病理确诊的慢性萎缩性胃炎伴胃窦黏膜糜烂患者50例,距糜烂区3cm处40例,无糜烂慢性萎缩性胃炎40例,采用免疫组织化学染色法测EGF及EGFR的表达.结果:胃窦黏膜糜烂区EGF、EGFR阳性表达率分别为40%和30%,明显高于糜烂旁胃黏膜15%和10%及无糜烂慢性萎缩性胃炎20%和12.5%的阳性表达率(P<0.05),有统计学意义,无糜烂慢性萎缩性胃炎组略高于糜烂旁胃黏膜组,但无统计学差异.结论:EGF、EGFR在胃黏膜损伤后高表达,对促进胃黏膜修复有着重要意义.     

Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival.METHODS:One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study.HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization(FISH) and immunohistochemistry(IHC) analysis on formalin-fixed paraffinembedded gastric cancer samples from all patients.For scoring,Hofmann’s HER2 gastric cancer scoring system was adopted.All cases showing IHC3+ or FISH positiv-ity were defined as HER2 positive.Patient clinicopathological data and survival information were collected.Finally,χ 2 statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including;gender,age,tumor location,Lauren classification,differentiation,TNM staging,depth of invasion,lymph node metastases and distant metastasis.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection.RESULTS:According to Hofmann’s HER2 gastric cancer scoring criteria,31 cases(15.74%) were identified as HER2 gene amplified and 19 cases(9.64%) were scored as strongly positive for HER2 membrane staining(3+),25 cases(12.69%) were moderately positive(2+) and 153 cases(77.66%) were HER2 negative(0/1+).The concordance rate between IHC and FISH analyses was 88.83%(175/197).Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression,with 24 of these cases being eligible for Herceptin treatment according to United States recommendations,and 29 of these cases eligible according to EU recommendations.Highly consistent results were detected between IHC3+,IHC0/1 and FISH(73.68% and 95.42%),but l     

EGFR在结直肠癌组织中的表达及其意义

目的:探讨结直肠癌患者肿瘤组织中表皮生长因子受体(epidermal growth factor,EGFR)过表达与临床病理特征及其预后的关系和意义.方法:收集2004-01/2010-04在中国人民解放军南京军区福州总医院手术切除的结直肠癌组织标本1 228例,选择其中资料完整的病例1 100例,采用EliVisio...     

促愈颗粒对胃溃疡实验大鼠胃黏膜表皮生长因子及其受体表达的影响

[目的]研究促愈颗粒对乙酸烧灼型胃溃疡(GU)大鼠胃黏膜表皮生长因子(EGF)及其受体(EGFR)表达的影响。[方法]将大鼠随机分为4组:正常对照组,模型组,促愈颗粒组和雷尼替丁组。乙酸制备慢性GU大鼠模型后,于给药14 d和28 d后分2次处死大鼠,观察胃黏膜组织形态,免疫组织化学技术检测大鼠胃黏膜EGF及EGFR水平。[结果]与模型组比较,促愈颗粒组和雷尼替丁组囊状扩张腺体数量均显著减少(P<0.01,<0.05),EGF及EGFR水平均显著增高(P<0.01,<0.05),且促愈颗粒组作用均优于雷尼替丁组(均P<0.05)。[结论]促愈颗粒可能通过增加胃黏膜EGF和EGFR的水平,进而提高GU再生黏膜结构和功能成熟度,从而促进溃疡愈合,提高溃疡愈合质量,并防止溃疡复发。     

Clinical significance of epidermal growth factor (EGF) expression in gastric cancer

BACKGROUND/AIMS: Epidermal growth factor (EGF) is involved in cancer development and proliferation. We measured preoperative serum EGF, and serologically investigated the clinical significance of EGF expression in gastric cancer. We also performed immunohistological staining at the same time, and investigated its relationship with serum EGF. METHODOLOGY: There were 79 patients who underwent surgery for gastric cancer. For the measurement, one-step sandwich EIA was performed. Of 79 cases of gastric cancer in which the serum EGF level was measured, EGF immunostaining was performed in 50 cases. RESULTS: In Serology, the EGF level was 345.6 +/- 260.6 pg/mL in m-sm cases, and 212.2 +/- 170.4 pg/mL in mp-si cases (p < 0.05). The EGF level was 294.4 +/- 236.0 pg/mL in ly0 cases, and 194.2 +/- 142.5 pg/mL in ly1-3 cases (p < 0.05). The EGF level was 323.5 +/- 233.4 pg/mL in cases staged IA-IB, and 202.8 +/- 176.8 pg/mL in cases staged II-IV (p < 0.05). In immunohistology the EGF positivity rate was 36.4% in the differentiated types, and 67.9% in the poorly differentiated types (p < 0.05). The EGF positivity rate was 25.0% in m-sm cases, and 63.1% in mp-si cases (p < 0.05). CONCLUSIONS: The above findings suggest that EGF uptake by cancer cells increases when cancer cells are poorly differentiated, and that invasion in the surrounding tissue is severe.     

胃癌组织中生长抑素与表皮生长因子受体表达的相关性及意义

目的观察胃癌组织中生长抑素（ＳＳ）表达与表皮生长因子受体（ＥＧＦＲ）表达的相互关系，探讨其抑癌的可能机制．方法应用免疫组化ＬＳＡＢ法及即用型ＳＰ法，对１４７例各种组织学类型胃癌中ＳＳ及ＥＧＦＲ的表达进行观察比较，并对其中１２７例患者进行预后随访．结果胃癌中ＳＳ阳性表达率为２５７％．ＥＧＦＲ阳性表达率５４３％．ＳＳ阳性及ＳＳ阴性两组胃癌ＥＧＦＲ的表达有明显差异（Ｐ＜００１）．ＳＳ阳性胃癌组ＥＧＦＲ的表达明显减少；ＳＳ阴性胃癌组ＥＧＦＲ的表达增多．ＳＳ阳性胃癌较ＳＳ阴性胃癌生存期长，预后好（Ｐ＜００１）．相反，ＥＧＦＲ阳性胃癌较ＥＧＦＲ阴性胃癌生存期短，预后差（Ｐ＜００１）．尤其是伴有ＳＳ阴性表达的ＥＧＦＲ阳性胃癌预后更差．结论ＳＳ及ＥＧＦＲ在人体胃癌组织中的表达有一定拮抗性．ＳＳ阴性的ＥＧＦＲ阳性胃癌预后更差．ＳＳ的抑癌机制之一可能是干扰了生长因子的合成，影响了细胞内调节细胞生长信号的传递，从而抑制肿瘤生长     

Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats.

Expression of epidermal growth factor receptor (EGFR) was studied immunohistochemically in rat gastric mucosa during healing of acetic acid-induced ulcers. In normal control gastric oxyntic mucosa, EGFR was expressed in proliferative zone cells and in some parietal cells. In mucosa of the ulcer margin, at 3, 7, and 16 days after ulcer induction, there was a 75-fold increase (over controls) in the number of cells expressing EGFR. Seventy percent of ulcers healed by the 16th day, and all were healed by the 25th day. The mucosal scar that replaced the ulcer was composed of dilated glands lined with poorly or aberrantly differentiated cells showing persistence of increased EGFR expression. An increased EGFR expression indicates an important role of EGF in ulcer healing and scar formation.     

The role of epidermal growth factor receptor in prognosis and treatment of gastric cancer

Despite tremendous efforts to reduce deaths due to gastric cancer, it represents the second leading cause of cancer-related deaths worldwide. EGF receptor (EGFR) plays important roles in gastric carcinogenesis by regulation of cell cycle, angiogenesis and apoptosis. This review evaluates the functions, mechanisms and clinical uses of EGFR in gastric cancer. Although EGFR targeted single therapy shows limited effect, the combination of EGFR targeted agents with traditional chemotherapy regimens may bring about important progress in cancer therapy. More clinical trials should be performed to clarify both the prognostic and therapeutic value of EGFR in gastric cancer.     

Expression of epidermal growth factor receptor in gastric carcinomas.

BACKGROUND & AIMS: Epidermal growth factor receptor belongs to the family of type I receptor tyrosine kinases. Overexpression of epidermal growth factor receptor has been observed in a variety of cancers with or without amplification of the gene. Novel chemotherapies targeting receptor tyrosine kinases might be effective for the treatment of cancers in which overexpression of this protein is a feature. The aim of this study was to assess the potential efficacy of epidermal growth factor receptor-targeted therapy in gastric cancer. This was achieved by determining the frequency of increased epidermal growth factor receptor expression in gastric cancers and investigating the relationship between protein overexpression and gene amplification. METHODS: Immunohistochemical evaluation of 413 gastric cancers was carried out by using a monoclonal antibody to the epidermal growth factor receptor. The intensity of reactivity was scored by using a 4-tier system (negative, 1+, 2+, and 3+). All positive staining (>1+) tumors overexpressing the protein were then analyzed for gene amplification by fluorescence in situ hybridization by using a gene-specific probe. RESULTS: High levels of overexpression (2+ or 3+ staining) were found in 9 of 413 (2.2%) patients, whereas low levels of overexpression (1+) were found in 34 (8.2%) of the study cohort. Fluorescence in situ hybridization analysis showed that more than 10 copies of the gene were recognized in all 5 cancers with 3+ staining and in 2 of the 4 tumors with 2+ staining. CONCLUSIONS: Although a high level of overexpression of epidermal growth factor receptor is uncommon in gastric carcinomas, it almost exclusively occurs by gene amplification.     

胃癌组织人类表皮生长因子受体2基因扩增与蛋白表达的一致性

目的 检测胃癌组织中人类表皮生长因子受体2(HER2)基因扩增与蛋白表达结果的一致性.方法 收集2010年至2012年120例胃癌患者的胃癌组织标本,其中100份为手术标本,20份为胃镜活组织检查标本.应用免疫组织化学(IHC)方法检测120份标本的HER2蛋白表达情况.根据IHC检测结果,选取IHC切片中HER2阳性部位制作成组织芯片进行荧光原位杂交(FISH),检测HER2的基因扩增情况.对IHC检测灶性(+++)(≤10％的肿瘤细胞强染色)的标本进行不同着色强度部位对比FISH检测.统计学处理采用Kappa检验.结果 120份胃癌组织中,IHC检测显示77份为不同强度阳性染色,其中16份为(+++),6份为灶性(+++),37份为(++),18份为(+),IHC检测HER2蛋白表达阳性率为18.3％(22/120).FISH检测显示41份阳性,HER2基因扩增率为34.2％,其中21份IHC检测为(++),15份为(+++),5份为灶性(+++).IHC与FISH联合检测HER2阳性率为35.0％(42/120).IHC与FISH检测的符合率为91.6％(76/83).Kappa系数为0.960(P＜0.01).对5份FISH阳性且IHC检测为灶性(+++)标本的不同着色强度部位进行对比FISH检测,发现全部扩增.结论 组织芯片技术与IHC技术在胃癌组织中检出HER2具有一致性,并可提高HER2的检出率.     

表皮生长因子受体及增殖细胞核抗原在胃癌中的表达及意义

为探讨表皮生长因子受体 ( EGFR)及增殖细胞核抗原 ( PCNA)在胃癌中的表达 ,应用免疫组织化学技术 ,对胃癌和胃良性肿瘤组织中 EGFR和 PCNA分别进行定性和半定量检测 ,分析其与临床病理参数的关系。结果显示 1在胃良性肿瘤组织中 EGFR的表达率为 2 3 .0 8% ,PCNA L I为 2 7.80± 12 .2 0 ,明显低于胃癌组织中的表达率 ( 49.0 9% ,PCNA L I5 2 .73± 12 .2 5 ,P<0 .0 1)。2胃癌组织中 EGFR和 PCNA的表达与患者性别、年龄、病变部位、分型、组织学类型及分化程度无关 ( P均 >0 .0 5 ) ,而与临床分期、浸润深度及淋巴结转移情况相关 ( P <0 .0 5 ) ,表明联合检测 EGFR和 PCNA可作为判断胃癌恶性程度、预测淋巴结转移、制定合理治疗方案及评估预后的重要指标     

胃癌患者血清表皮生长因子的变化

目的探讨人血清表皮生长因子（ｈＥＧＦ）水平与胃癌的关系．方法胃癌患者３３例，男３０例，女３例，年龄３５岁～８１岁，平均６４９岁；慢性胃炎患者３８例，男２５例，女１３例，年龄１８岁～７５岁，平均４３２岁；正常人２０例，男１０例，女１０例．应用ＲＩＡ法检测血清中的ｈＥＧＦ．结果胃癌组血清ｈＥＧＦ（μｇ／Ｌ）为１３５±０６７，正常对照组为０９０±０３３，统计学差异非常显著（ｔ＝２８２５，Ｐ＜００１），慢性胃炎组血清ｈＥＧＦ为０８６±０３３，与正常对照组比较差异无显著性（ｔ＝０４１，Ｐ＞００５）．结论胃癌患者血清ｈＥＧＦ水平升高可能与胃癌发生密切相关．     

Reduced expression of epidermal growth factor receptors in rat liver during aging

Proliferative responsiveness of hepatocytes to epidermal growth factor (EGF) declines during aging. The role of EGF receptors in mediating age-dependent changes of EGF-induced mitogenic signaling in liver remains incompletely understood. We assessed EGF receptor expression levels in whole liver specimens as well as in freshly isolated and cultured hepatocytes from young adult and senescent Fischer 344 male rats. Hepatic EGF receptor messenger RNA and protein levels, and the number of high- and low-affinity receptor binding sites, decreased with aging. Ligand-induced EGF receptor activation, determined by receptor dimerization and tyrosine phosphorylation, was reduced in old animals in parallel with the age-related decline in receptor expression. Stimulation of the extracellular signal-regulated kinase pathway by EGF was also attenuated in hepatocytes from old animals. Our results implicate decreased expression of EGF receptors as a key determinant of reduced mitogenic signaling responsive to EGF stimulation of liver during aging.     

Characterization of the epidermal growth factor receptor in the gastric mucosa

The effects of epidermal growth factor (EGF), a potent mitogen involved in mucosal protection, are mediated by specific cellular receptors. Here, we present the characteristics and binding properties of EGF receptors in the gastric mucosa. The studies were conducted using cell membranes isolated by subcellular fractionation of rat stomach mucosal scrapings. Specific binding of [125I]-EGF to the membrane preparations was assessed at room temperature for various periods of time and at different pHs. The results showed that the binding was proportional to the incubation time up to 1 h and was not affected by a pH change between 4.0 and 7.0. Scatchard analysis of the binding data infer the presence of 2 binding sites, one of high affinity (Kd = 1.34 nM, Bmax = 34 fmol/mg protein) and the other of low affinity (Kd = 484 nM, Bmax = 2.29 pmol/mg protein). Cross-linking experiments using disuccinimidyl suberate to link the [125I]-EGF to gastric membranes followed by polyacrylamide gel electrophoresis and autoradiography revealed that the major receptor for EGF was a protein of 170 kilodaltons. When the solubilized membranes were subjected to wheat germ agglutinin affinity chromatography, the purified material was found to act as substrate for EGF-stimulated phosphorylation. The major component which was labeled by the [gamma-32P]-ATP was also found to be a 170-kilodalton protein. The data are the first to provide evidence that the gastric mucosa possesses a functional EGF receptor and describe its binding characteristics.     

Studies of epidermal growth factor receptor inhibition in breast cancer

Until recently, there has been little knowledge on the growth control of oestrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) and invasive breast cancer. The recent development of DCIS models, such as transgenic mice, cell-line xenograft models and, importantly, in vivo human DCIS xenograft models has facilitated the investigation and understanding of the control of growth of early pre-invasive breast lesions. Recent studies have shown that ER-negative DCIS, unlike ER-positive DCIS, is hormone independent and does not respond to anti-oestrogen treatment. Moreover, DCIS of the comedo type utilises type I tyrosine kinase growth factors, such as epidermal growth factor receptor (EGFR) and c-erbB-2, in receptor signalling for growth. New data underscore the importance of EGFR as the major modulating growth factor receptor in the control of proliferation in the breast. Pre-clinical studies performed on human DCIS xenografts in nude mice suggest a potential role for EGFR tyrosine kinase inhibitors (EGFR-TKIs). More specifically, ZD1839, a novel orally active and selective EGFR-TKI, has been shown to produce a response in DCIS through a decrease in epithelial proliferation. These findings have enhanced our knowledge of signal transduction pathways in cancer and indicate that tyrosine kinase blockade of EGFR has potential for the treatment and chemoprevention of DCIS. It is hoped that further advances in this area and evaluation of EGFR-TKIs in Phase II/III clinical trials will allow their therapeutic potential as anticancer agents to be appreciated.