乳腺癌中GRP78、Survivin表达的相关性及与预后的关系

目的:探讨乳腺癌中GRP78、Survivin表达的相关性及其与乳腺癌患者预后的关系.方法:采用免疫组化Envision法检测169例乳腺癌石蜡标本中GRP78、Survivin的表达状况,并对其表达的相关性以及与乳腺癌患者预后的关系进行了统计分析.结果:在169例乳腺癌标本中,GRP78强表达为68例(40.2%),弱表达为101例(59.8%);Survivin强表达为96例(56.8%),弱表达为73例(43.2%).对二者相关性的分析表明二者表达的吻合度具有统计学意义,但吻合程度较弱.单因素生存分析结果表明GRP78(+)Survivin(+)组(1组)、GRP78(-)Survivin(+)组(2组)、GRP78(+)Survivin(-)(3组)之间的无病生存时间差异无显著性(P>0.05),但与GRP78(-)Survivin(-)组(4组)相比,其无病生存时间均较差,差异有显著性(P<0.05);1、2、3组间的总生存时间差异无显著性(P>0.05),但与4组相比,其总生存时间均较差,差异有显著性(P<0.05).多因素Cox回归分析表明GRP78、Survivin的表达状况是影响乳腺癌患者无病生存时间的独立预后因素(P<0.05),但不是总生存时间的独立预后因素(P>0.05).结论:乳腺癌中GRP78与Survivn存在着相关性,GRP78和/或Survivn强表达提示患者预后不良,GRP78、Survivin的表达状况对判断乳腺癌患者的预后具有一定的参考价值.     

GRP78和pERK在胃癌及非胃癌组织中的表达及临床意义

背景与目的：在胃癌的发生、发展过程中,内质网应激、细胞的修复及凋亡是重要的病理生理过程,而GRP78与pERK在其中发挥了重要的作用。研究葡萄糖调节蛋白78(glucose-regulatedproteins 78,GRP78)和磷酸化细胞外信号调节激酶(pERK)在胃腺癌、慢性萎缩性胃炎及浅表性胃炎组织中的表达,研究它们与胃癌发生、发展的关系。方法：RT-PCR法检测各25例胃腺癌、慢性萎缩性胃炎和浅表性胃炎新鲜组织中GRP78、pERK基因表达;免疫组化法分别检测各60例胃腺癌、慢性萎缩性胃炎和浅表性胃炎组织中GRP78、pERK蛋白表达,并分析其蛋白表达与临床病理参数间的相关性。结果：RTPCR半定量结果显示,胃癌组织中GRP78及pERK mRNA的相对表达水平(1.26±0.18、2.35±0.36)均明显高于慢性萎缩性胃炎组织(0.89±0.25、1.18±0.25)及浅表性胃炎组织(0.29±0.09、0.68±0.10),差异有统计学意义(P＜0.01)。免疫组织化学结果显示,GRP78及pERK蛋白在胃癌组织中的表达率(78.3%、88.3%)亦均高于慢性萎缩性胃炎(46.6%、43.3%)及浅表性胃炎组织(6.7%、5.0%),差异有统计学意义(P＜0.01)。胃癌组织中GRP78及pERK蛋白表达与胃癌分化程度、分期、淋巴结转移等有明显相关性。GRP78及pERK基因及蛋白表达水平在胃癌中均呈正相关(基因：r=0.307,P=0.000;蛋白：r=0.368,P=0.000)。单因素分析结果显示：组织学分级、浸润深度、TNM分期、淋巴结转移、GRP78高表达及pERK高表达与胃癌预后有关(P均＜0.05)。浸润全层、低分化、TNM分期晚、有淋巴结转移、GRP78高表达及pERK高表达患者生存时间短。多因素生存分析结果结果显示：GRP78高表达与GRP78低表达相比生存时间差异有统计学意义(P＜0.001)。GRP78高表达的胃癌患者生存时间短,提示GRP78是负性的预后因子。结论：GRP78和pERK在胃癌中高表达,GRP78和pERK在正常细胞向恶性细胞转化的过程中可能扮演了重要角色,检测pERK和GRP78的表达可能有助于对胃腺癌的预防、早期诊断及预后判断,同时为胃癌治疗寻找新的靶点。     

CD168在胃癌组织中的表达及预后意义

目的 探讨胃癌组织中透明质酸介导的细胞游走受体(CD168)的表达情况与各临床病理因素及其预后的关系,评估其在胃癌侵袭转移过程中的作用及预测胃癌患者预后的价值.方法 采用免疫组织化学法检测72例胃癌组织和26例正常胃黏膜组织中CD168的表达情况.同时评估CD168的表达与临床病理因素(年龄、性别、组织学、肿瘤浸润深度、淋巴结转移和临床分期)之间的关系.用Kaplan-Meier法评估胃癌患者术后5年生存率.结果 胃癌组织中CD168阳性表达率为58.3％,与正常胃黏膜中的阳性表达率(19.2％)比较,差异有统计学意义(P=0.001);CD168阳性表达率与肿瘤分化程度(P=0.001)、淋巴结转移(P=0.003)、临床分期等(P=0.020)有显著相关性.CD168阳性表达率与年龄、性别、肿瘤大小和肿瘤浸润深度无显著相关性.胃癌患者的生存期分析显示,CD168阴性组5年生存率(67.2％)显著高于CD168阳性组5年生存率(29.8％),两组间差异有统计学意义(P=0.01).结论 CD168高表达与胃癌的浸润和转移密切相关,可以作为预测胃癌预后的一个生物学指标.     

GRP78和TopoⅡ在胃腺癌组织中的表达及意义

目的：研究GRP78和TopoⅡ蛋白在胃腺癌组织中的表达及两者的相关性,探讨两者在胃腺癌耐药性中的作用。方法：运用免疫组化法检测60例胃腺癌和20例癌旁组织中GRP78和TopoⅡ的表达。结果：GRP78在癌旁组织呈弱阳性表达,在胃腺癌组织中呈中、强阳性表达,且在腺癌组织中的血管内皮细胞也有表达。GRP78在腺癌中的表达与性别、年龄等无关,而与肿瘤大小、分化程度、浸润深度、有无淋巴结转移密切相关（ P＜0.01）。TopoⅡ在高中分化腺癌中表达高于低分化腺癌（ P＜0.05）,而与性别、年龄、肿瘤大小、浸润深度、有无淋巴结转移均无关（P ＞0.05）。GRP78与 TopoⅡ的表达无明显相关性（P ＞0.05）。结论：GRP78在胃腺癌中高表达,对胃癌耐药性有一定影响,GRP78在胃腺癌中是否降低TopoⅡ的表达有待进一步研究。     

CD44V6和E-cadherin表达与胃癌转移及预后的关系

目的探讨胃癌中CD44V6和E-cadherin(E-cad)蛋白表达的意义.方法应用免疫组化Envision法检测80例胃癌中CD44V6和E-cad蛋白的表达,并分析其与临床病理参数的关系.结果80例胃癌中,CD44V6蛋白阳性率77.5%,显著高于正常胃黏膜组织的阳性率(P＜0.001);E-cad蛋白在胃癌中阳性率为46.3%,显著低于正常胃黏膜组织的阳性率(P＜0.001);CD44V6高表达和E-cad低表达与胃癌TNM分期、浆膜浸润、淋巴结转移呈显著正相关(P＜0.05),而与年龄和组织学类型无关;CD44V6和E-cad表达呈负相关(P＜0.001).结论CD44V6阳性和E-cad阴性表达与胃癌浸润转移密切相关,CD44V6阳性和E-cad阴性者更具有侵袭性和转移性.联合检测CD44V6和E-cad有助于判断胃癌的预后.     

胃癌中P16的表达及其与预后的关系

目的：研究多种肿瘤抑制基因（MTS1）编码产物P16的表达及其与胃癌的临床病理指标及预后的关系。方法：应用免疫组织化学LSAB方法，检测65例胃癌、10例正常胃粘膜组织和35例非癌病变组织中MTS1基因因产物的表达与胃癌的分化程度呈正相关，与浸润，淋巴结转移呈负相关，经随访提示P16阳性者术后三年生存率高于阴性者。结论：MTS1基因参与了胃癌的发展过程，并与胃癌的部分生物学行为有关。检测P16蛋白的表达可能成为胃癌诊断和判断预后的重要的分子生物学指标之一。     

111例胃癌CEA的免疫组化与预后关系

本文对111例胃切除标本的组织采用ABC免疫酶标技术进行癌胚抗原的反应观察及其预后关系的研究。结果表明:乳头状腺癌,管状腺癌,粘液癌主要为CEA(+),低分化癌、未分化癌与印戒细胞癌为CEA(++)。乳头状腺癌,管状腺癌以CEAⅡ型分布为主,其它类型以Ⅰ型分布为主。肿瘤组织中CEA的含量与肿瘤的淋巴结转移呈正比。在CEA反应不同的三组中,五年存活率有显著的差异。无淋巴结转移时,以CEA(-)组存活率最高;有淋巴结转移时,以CEA(+)组存活率最高;各组均以CEA(++)组存活率最低。     

nm23和p16基因协同表达与胃癌临床生物学特性及预后的关系

目的：检测与分析nm23,p16基因在胃癌组织中的表达,并随访5年以上,探讨其与胃癌术后复发转移及生存期的关系。方法：应用免疫组织化学法检测nm23,P16蛋白在胃癌组织中的表达,并随访5年以上,结果：84例胃癌标本中nm23阳性率46．43％,p16阳性率44．05％,胃癌组织及转移淋巴结中阳性率明显低于正常组织和胃良性息肉,而且这2类基因的表达与肿瘤侵袭深度及临床分期有关。随访中发现,阴性表达者死亡率高,转移复发率高,中位生存期短（P＜0．01）,结论：nm23,p16基因蛋白异常表达在胃癌的发生发展过程中起重要作用。有可能成为临床评价肿瘤生物学行为及判断预后约标志之一。     

CD147、CEA 在胃癌组织中的表达及预后价值

目的：研究胃癌组织中 CD147、CEA 的表达及其与胃癌患者临床病理参数和总体生存率之间的关系。方法：应用免疫组织化学（SP）法检测胃癌组织标本及癌旁胃组织中 CD147、CEA 的表达情况,并随访患者进行生存分析。结果：胃癌组织中 CD147、CEA 的阳性表达率均显著高于癌旁组织（P ＜0．05）。CD147、CEA 在胃癌中的表达均与胃癌的浸润深度、淋巴结转移和 TNM分期显著相关（P ＜0．05）。相关性分析发现, CD147与 CEA 在胃癌组织中的表达呈正相关（r ＝0．292,P ＝0．020）。经 Kaplan －Meier 生存分析显示, CD147、CEA 蛋白表达阳性的患者生存率均明显低于表达阴性组患者（P ＜0．05）。单因素分析发现肿瘤浸润深度、TNM分期、淋巴结转移、CD147、CEA 均为影响胃癌患者预后的重要因素;Cox 风险模型多因素分析发现肿瘤的 TNM分期、淋巴结转移、CD147、CEA 是影响胃癌预后的独立危险因素。结论：CD147和 CEA 的表达与胃癌的浸润和转移密切相关,两者在胃癌中的表达具有协同作用,它们可协同促进胃癌的侵袭和转移。CD147和 CEA 是胃癌预后的独立危险因素,可成为胃癌预后的新型标志物和治疗的新靶点。     

P-gp和CD44v6在胃癌组织中表达及与预后的关系

目的 探讨P-gp和CD44v6在胃癌组织中表达的相关性及其临床意义。方法 应用免疫组织化学方法,检测97例胃癌组织中P-gp及CD44v6的表达,并分析P-gp和CD44v6与胃癌病理特征的关系、两者表达的相互关系及对预后的影响。结果 97例胃癌组织中P-gp和CD44v6的阳性率分别为40.21%(39/97)和58.76%(57/97),P-gp阳性表达情况与胃癌的临床分期、有无淋巴结转移及有无血管侵犯有关(P<0.05)。CD44v6阳性表达与病变大小、临床分期、有无淋巴结转移及有无血管侵犯有关(P<0.05)。P-gp阳性表达与CD44v6阳性表达具有正相关性(P<0.05),两者表达均阳性者3年生存率低于两者表达均阴性组。结论 P-gp和CD44v6的表达不仅与胃癌的生物学行为有关,同时两者的表达具有明显的正相关性,而且两者表达均阳性者预后差,提示联合检测两者有助于判断胃癌的预后。     

Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells

We studied potential interactions between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway. Induction of ER stress did not trigger significant apoptosis, but caused rapid activation of ERK1/2 in gastric cancer cells. Inhibition of MEK enhanced ER stress-induced apoptosis via a caspase-dependent, mitochondria-mediated mechanism. This was associated with blockage of ER stress-mediated up-regulation of GRP78. The latter appeared to be critical in antagonizing the apoptosis-inducing potential of ER stress. Thus, activation of MEK/ERK by ER stress is necessary for induction of GRP78 that protects against apoptosis in gastric cancer cells submitted to ER stress.     

A peptide derived from phage display library exhibits anti-tumor activity by targeting GRP78 in gastric cancer multidrug resistance cells

Multidrug resistance (MDR) remains a significant challenge to the clinical treatment of gastric cancer (GC). In the present study, using a phage display approach combined with MTT assays, we screened a specific peptide GMBP1 (Gastric cancer MDR cell-specific binding peptide), ETAPLSTMLSPY, which could bind to the surface of GC MDR cells specifically and reverse their MDR phenotypes. Immunocytochemical staining showed that the potential receptor of GMBP1 was located at the membrane and cytoplasm of MDR cells. In vitro and in vivo drug sensitivity assays, FACS analysis and Western blotting confirmed that GMBP1 was able to re-sensitize MDR cells to chemical drugs. Western blotting and proteomic approaches were used to screen the receptor of GMBP1, and GRP78, a MDR-related protein, was identified as a receptor of GMBP1. This result was further supported by immunofluoresence microscopy and Western blot. Additionally, Western blotting demonstrated that pre-incubation of GMBP1 in MDR cells greatly diminished MDR1, Bcl-2 and GRP78 expression but increased the expression of Bax, whereas downregulation of GRP78, function as a receptor and directly target for GMBP1, only inhibited MDR1 expression. Our findings suggest that GMBP1 could re-sensitize GC MDR cells to a variety of chemotherapeutic agents and this role might be mediated partly through down-regulating GRP78 expression and then inhibiting MDR1 expression. These findings indicate that peptide GMBP1 likely recognizes a novel GRP78 receptor and mediates cellular activities associated with the MDR phenotype, which provides new insight into research on the management of MDR in gastric cancer cells.     

粘蛋白MUC1和MUC2在胃癌组织中的表达及其预后意义

目的 :探讨粘蛋白MUC1和MUC2在胃癌组织中的表达及意义。方法 :采用免疫组织化学法的SP法检测 86例胃癌组织及 2 0例人正常胃粘膜中的MUC1和MUC2的表达。结果 :在正常胃粘膜中MUC1阳性表达率为 10 0 % ,而MUC2无阳性表达。在胃癌组织中MUC1和MUC2的表达率分别为 5 8 14 %和 6 3 95 %。胃癌组织中MUC1和MUC2的表达与肿瘤大小、浸润深度及分化程度无关 (P >0 0 5 ) ,但Ⅰ～Ⅱ期、淋巴结无转移组MUC1的表达明显比Ⅲ～Ⅳ期、淋巴结转移组低 ,而MUC2表达明显增高 (P <0 0 1)。Kaplan Meier分析发现MUC1高表达和MUC2低表达患者的生存时间明显低于MUC1低表达和MUC2高表达患者 (P <0 0 1)。结论 :MUC1和MUC2可预示胃癌的转移潜能 ,两者联合表达可作为评估预后的参考指标。     

Purified autoantibodies against glucose-regulated protein 78 (GRP78) promote apoptosis and decrease invasiveness of ovarian cancer cells

Circulating glucose-regulated protein 78 (GRP78) autoantibodies represent potential biomarker of epithelial ovarian cancer. However there is relatively limited identification of these antibodies in response to ovarian cancer. Here, we were interested in characterization of these antibodies and into their role in tumor development. We first purified GRP78 autoantibodies from sera of patients with ovarian cancer, and then tested them on SKOV-3 ovarian cancer cell line. A decrease of invasion and an increase of H(2)O(2)-induced apoptosis of SKOV-3 cells were observed, suggesting their protective role against ovarian cancer cells.     

GRP78 as potential predictor for breast cancer response to adjuvant taxane therapy

Few predictive markers exist for response to adjuvant chemotherapy in breast cancer. The 78‐kDa glucose‐regulated protein (GRP78) is a potent antiapoptotic factor, conferring drug resistance. Recently, we reported that high GRP78 expression in breast cancer specimens predicts a shorter recurrence‐free survival in patients who received doxorubicin‐based adjuvant chemotherapy. Interestingly, the opposite effect was observed in 25 patients who additionally received a taxane. To confirm this potentially paradigm shifting finding, we investigated whether GRP78 is associated with recurrence‐free survival in an independent cohort of taxane‐treated breast cancer patients. Immunohistochemical staining of GRP78 was performed on archival paraffin‐embedded formalin‐fixed tumor specimens obtained from 48 female breast cancer patients before chemotherapy treatment. These patients received doxorubicin and cyclophosphamide, followed by paclitaxel or docetaxel on a clinical trial. GRP78 expression level was evaluated by a pathologist, masked to all clinical and outcome data. Association between GRP78 expression and recurrence‐free survival was evaluated. GRP78 positivity predicts a better recurrence‐free survival, independent of other prognostic factors [hazard ratio (HR) for moderate positivity: 0.40 (95% confidence interval (CI): 0.087–1.83); HR for strong positivity: 0.16 (95% CI: 0.018–1.50); p_trend = 0.053]. In a pooled analysis with the previous 25 patients, almost identical HRs were obtained with p_trend = 0.024. This provides further evidence that GRP78 is a potential independent predictor for response to taxane‐based adjuvant chemotherapy in breast cancer.     

沉默调节蛋白4在胃癌组织中的表达及其预后价值

目的 探讨沉默调节蛋白4(sirtuin 4,SIRT4)在人胃癌组织中的表达及其与患者临床病理特征及预后的关系.方法 回顾性分析2013年10月一2014年10月于武汉市中心医院接受手术治疗的117例胃癌患者的临床资料.采用免疫组化法检测胃癌组织及其相应癌旁组织中SIRT4蛋白的表达,并分析SIRT4表达水平与患者临...     

IGFBP-3 sensitizes antiestrogen-resistant breast cancer cells through interaction with GRP78

IGFBP-3 is known to possess intrinsic biological activities such as anti-tumor property in addition to its IGF/IGF-R axis-dependent actions in a variety of human cancers including breast cancer. To investigate the molecular mechanisms underlying the intrinsic biological actions of IGFBP-3 on breast cancer cells, we performed yeast two-hybrid screening and found GRP78, known to cause drug-resistance, as a binding partner of IGFBP-3. Overexpression of IGFBP-3 in antiestrogen-resistant LCC9 cells showed that IGFBP-3 interacted with GRP78, resulting in disruption of the GRP78-caspase-7 complex, thereby activating caspase-7, and further inducing apoptosis. Combination of overexpression of IGFBP-3 and application of siRNAs against GRP78 led to decrease in cell viability upon ICI 182,780 treatment. These data suggest that IGFBP-3 could sensitize antiestrogen-resistant breast cancer cells to ICI 182,780 by preventing the anti-apoptotic function of GRP78.