GRP78和KIAA1324在胃癌中的表达及与预后的关系

目的 探讨GRP78和KIAA1324蛋白在胃癌组织中的表达及其与预后生存的关系。方法 采用免疫组织化学法检测90例胃癌组织中GRP78和KIAA1324蛋白的表达,分析两者的表达与胃癌临床病理特征的关系。Kaplan-Meier法计算患者生存率,并行Log-rank检验。结果胃癌组织中GRP78和KIAA1324蛋白的阳性表达率分别为78.89％（71/90）和35.56％（32/90）。GRP78和KIAA1324蛋白表达与淋巴结转移、TNM分期有关（P＜0.05）,而与年龄、性别、肿瘤大小和组织学分级无关（P＞0.05）。GRP78与KIAA1324蛋白表达呈负相关（r=-0.469,P＜0.05）。GRP78阳性患者的中位生存期为49.78个月（95％CI：44.09～55.46个月）,较阴性患者的62.21个月（95％CI：53.29～71.14个月）短,差异有统计学意义（P＜0.05）;KIAA1324阳性患者的中位生存期为60.66个月（95％CI：53.63～67.69个月）,较阴性患者的47.85个月（95％CI：41.46～54.23个月）长,差异有统计学意义（P＜0.05）。结论 GRP78和KIAA1324蛋白在胃癌发生、发展中发挥重要作用,可能成为判断胃癌预后的指标。     

乳腺癌CD44v6和Survivin的表达与临床预后的相关性研究

研究CD44v6和Survivin的表达与乳腺癌临床病理特征和生存率的关系以及在乳腺癌和良性乳腺疾病的表达差异。方法:用免疫组化法检测64例乳腺癌标本和12例良性乳腺（对照组）标本CD44v6和Survivin表达。将乳腺癌病例按表达分成A组（双阳性组）、B组（单阳性组）和C组（双阴性组）,随访生存情况。结果:乳腺癌组和对照组中CD44v6阳性率分别为57.81%和25.00%（P=0.037）,Survivin阳性率分别为73.43%和8.33%（P<0.001）。乳腺癌组织中CD44v6和Survivin表达均高于对照组。CD44v6和Survivin的表达与年龄、肿瘤大小、组织学分级和分类均无明显相关（P>0.05）,但与临床分期和淋巴结转移明显相关（P<0.05）。A、B、C组的平均生存期分别为（84.07±6.69）、（103.89±6.77）、（115.50±7.42）个月。64例乳腺癌患者的平均生存期为（97.43±4.59）个月。A、B、C组的5年总生存率分别为74.19%、90.91%、100.00%;10年总生存率分别为35.48%、59.09%和72.73%（P=0.043）。结论:CD44v6和Survivin表达分布存在组织特异性。两者过量表达与年龄、肿瘤大小、组织学分级及组织学分类之间均无统计学差异,但与临床分期和淋巴结转移存在显著性差异。两者均阳性表达患者5年和10年生存率最低。CD44v6和Survivin均是乳腺癌的预后因素,有助于指导治疗和预测预后。      

乳腺癌组织中Survivin、p53表达及其与MVD的相关性

目的 探讨Survivin、p53蛋白在乳腺癌组织中的表达及其与微血管密度(MVD)的相关性.方法 采用免疫组织化学的二步法,检测56例乳腺癌组织中Survivin、p53蛋白的表达,应用Ⅷ因子染色免疫组织化学技术,检测乳腺癌组织中微血管密度.结果 Survivin蛋白在乳腺癌组织中的阳性表达率为78.4%(44/55).p53在乳腺癌组织中阳性表达率为35.7%(20/56).微血管密度在Survivin阳性组中均数为44±3.79,在Survivin阴性组中均数为26.25±4.79,两组比较,P＜0.05.微血管密度在p53阳性组中均数为39.25±6.50,在p53阴性组中均数为36.57±11.63,两组比较,P＞0.05.结论 Survivin蛋白在乳腺癌的发生、发展中起重要作用,可能与乳腺癌浸润转移有关.Survivin和p53可能通过不同途径参与乳腺癌的凋亡和浸润转移.     

TNFAIP3和GRP78表达与鼻咽癌组织放疗敏感的相关性

目的:探讨TNFAIP3及GRP78在放射治疗鼻咽癌中的表达,研究其在放射治疗鼻咽癌中的意义。方法:取60例2006年1月13日-2006年11月26日第1次入院放射治疗的鼻咽癌患者,运用原位杂交方法检测放射治疗鼻咽癌中TNFAIP3及GRP78 mRNA的表达。结果:放疗敏感及放疗抗拒鼻咽癌中,TNFAIP3 mRNA中度及强阳性表达率分别为15.00%和45.00%,GRP78 mRNA中度及强阳性表达率分别为20.00%和47.50%,差异有统计学意义。放疗抗拒鼻咽癌中,TNFAIP3 mRNA中度及强阳性表达率与TNM分期呈正相关,III-IV期表达率为48.28%,I-II期表达率为36.36%。GRP78 mRNA中度及强阳性表达率与TNM分期呈正相关,III-IV期表达率为58.62%,I-II期表达率为18.18%,与T分期呈正相关,T3-T4期表达率为68.42%,T1-T2期表达率为28.57%。在有、无远处转移中,TNFAIP3 mRNA中度及强阳性表达率分别为81.81%和31.03%,GRP78 mRNA中度及强阳性表达率分别为72.73%和37.93%,差异有统计学意义。结论:TNFAIP3、GRP78参与了放疗抗拒鼻咽癌的发生和发展。     

乳腺癌手术切除患者放疗前后外周血单个核细胞中Survivin、OTUD3 mRNA变化及与预后的关系

目的 研究乳腺癌手术切除患者放疗前后外周血单个核细胞中生存素(Survivin)和去泛素化酶3(OUT domain-containing protein 3,OTUD3)mRNA的表达情况及与预后的关系。方法 选取79例乳腺癌并行扩大根治术的患者作为观察组,在切除手术后对观察组患者行为期2个月的放射治疗,另选取同期健康体检志愿者55例作为对照组。检测观察组放疗前后及对照组的外周血单个细胞核中Survivin-mRNA和OTUD3-mRNA表达情况,并且分析其变化及其与疾病预后的关系。结果 观察组放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达量均高于对照组,差异具有统计学意义(P<0.05)。观察组放疗后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA低于放疗前,差异具有统计学意义(P<0.05);检测放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达情况与年龄、肿瘤大小对比差异无统计学意义(P>0.05),与肿瘤分期、肿瘤分化和淋巴结转移情况对比差异具统计学关系;放疗前后外周血单个核细...     

乳腺癌组织Survivin表达与细胞增殖的关系

目的：探讨乳腺癌组织中Survivin表达的临床病理学意义及其与癌细胞增殖的关系。方法：应用免疫组织化学SP法检测Survivin、Ki-67蛋白在96例乳腺癌组织中及20例正常乳腺组织的表达,分析Survivin表达与Ki-67增殖指数及各临床病理因素的关系。结果：Survivin阳性表达乳腺癌的Ki-67增殖指数（35．32±21．28％）明显高于Survivin阴性者（20．42±11．34％）,Survivin表达与肿瘤细胞增殖呈正相关（P〈0．01）;Survivin在乳腺癌组织中的表达率为70．83％（68／96）,正常乳腺组织未见Survivin表达;Survivin蛋白的表达与临床分期、淋巴结转移和5年生存率有关（P〈0．05）,与年龄、是否绝经、肿瘤大小和组织学分级均无关。结论：Survivin不仅参与凋亡的调控,还促进细胞增殖。Survivin蛋白在乳腺癌中表达上调,提示其通过抑制凋亡在乳腺癌发生、发展中起重要作用,过度表达提示预后不良。     

GRP78在不同亚型宫颈癌细胞株中表达情况及对顺铂敏感性影响

目的：研究不同亚型宫颈癌细胞株中葡萄糖调节蛋白78（glucose regulated protein 78,GRP78）表达情况，以及GRP78表达水平对宫颈癌细胞顺铂敏感性的影响。方法：采用免疫组织化学法检测人乳头瘤病毒（human papillomavirus，HPV）16（+）SiHa、HPV18（+）HeLa以及HPV（-）C33a宫颈癌细胞中的GRP78表达，MMT、Western blot法检测以上3种细胞在不同浓度顺铂、衣霉素+顺铂处理后的细胞抑制率及GRP78表达水平，采用单因素方差分析，分析相同浓度下单用顺铂、衣霉素+顺铂联合处理后3种细胞的细胞抑制率及GRP78蛋白表达的差异。结果：SiHa、HeLa细胞GRP78阳性表达水平明显高于C33a细胞，SiHa细胞GRP78阳性表达水平最高（P＜0.01）。随着顺铂浓度增加，3种宫颈癌细胞抑制率增加呈浓度依赖性，且HeLa细胞抑制率最高（P＜0.05）。与单独顺铂组相比，衣霉素联合顺铂药物处理组中HeLa及SiHa细胞抑制率显著升高（P＜0.05），并且GRP78表达水平也明显升高（P＜0.01），且各细胞株中GRP78表达水平均随顺铂浓度增加而增加。结论：GRP78表达水平与宫颈癌细胞亚型有关，SiHa、HeLa细胞对顺铂敏感性高于C33a细胞。衣霉素导致GRP78明显高表达，增加了SiHa、HeLa细胞对顺铂的敏感性。     

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。     

miR-335、Survivin表达及对乳腺癌术后患者预后评估的价值

目的:探讨微小RNA335(microRNA-335,miR-335)和Survivin在乳腺癌患者组织中表达情况以及其表达水平对患者预后的影响。方法:收集我院2010年2月1日至2014年2月1日乳腺癌患者标本140例,通过实时免疫荧光定量聚合酶链反应（RT-PCR)法检测所有乳腺癌组织、癌旁组织中miR-335的表达情况;采用免疫组织化学方法检测癌组织、癌旁组织中Survivin的表达情况。应用SPSS 16.0软件对比miR-335、Survivin与乳腺癌患者临床病理之间的关系,以及对患者预后的影响。结果:miR-335在癌组织中的表达明显低于癌旁组织(25.36% vs 82.51%,P=0.003),Survivin在癌组织中的表达明显高于癌旁组织(80.13% vs 26.73%,P=0.001 6),miR-335在乳腺癌组织中的表达水平与肿瘤病理类型、分化程度、临床分期呈负相关（r=-0.47,P=0.02;r=-0.31,P=0.03;r=-0.75,P=0.04),而Survivin在乳腺癌组织中的表达水平与肿瘤病理类型、分化程度、临床分期呈正相关（r=0.52,P=0.03;r=0.63,P=0.01;r=0.37,P=0.03)。COX回归模型发现乳腺癌患者肿瘤TNM分期、淋巴结转移、分化程度、病理类型、ER、PR、Her-2、miR-335、Survivin表达均为影响乳腺癌患者PFS的因素。miR-335对于乳腺癌患者术后3年 PFS、OS预测曲线下面积分别为83.4%、78.6%(P<0.01);Survivin 对于乳腺癌患者术后3年PFS、OS预测曲线下面积分别为79.5%、70.6%(P<0.01)。差异有统计学意义（P<0.01,P<0.01)。结论:miR-335、Survivin在乳腺癌组织和癌旁正常组织中的表达存在明显差异,miR-335高表达、Survivin低表达时,提示乳腺癌患者手术预后良好。     

Survivin、COX-2和bFGF在乳腺癌组织中的表达及相关性的探讨

目的：研究抗凋亡基因（Smwivin）、环氧化酶-2（COX-2）和碱性成纤维细胞生长因子（hFGF）在正常乳腺组织、乳腺良性疾病和乳腺癌组织中的表达及其相关性。方法：用免疫组化方法检测10例正常乳腺组织、45例乳腺良性疾病和60例乳腺癌中Survivin、COX-2和bFGF的表达,并分析其与乳腺癌的临床病理特征的相关性。结果：Survivin、COX-2和bFGF在良性乳腺疾病及与乳腺癌组织中的表达相比均有显著差异。Survivin、Cox-2和bFGF的表达都与乳腺癌淋巴结转移和TNM病理分期显著相关。结论：Survivin、COX-2存乳腺癌中的表达明显高于正常乳腺和良性乳腺疾病。bFGF在乳腺癌中的表达高于良性乳腺疾病。Survivin、COX-2和bFGF可能在乳腺癌的发生、生长和转移中起重要作用,其中COX-2和bFGF可能起协同作用,而Survivin则是三者中相对独立的一种因子。     

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.     

GRP78 expression correlates with histologic differentiation and favorable prognosis in neuroblastic tumors

Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum protein, is essential for the differentiation of neuroblastoma cells and is selectively induced when the cells are undergoing apoptosis. These findings suggest that GRP78 may affect the tumor behavior of neuroblastoma. Our study evaluates the association of clinicopathologic factors and patient survival with the expression of GRP78 in patients with neuroblastoma. GRP78 expression in 68 neuroblastic tumors was investigated semiquantitatively by immunohistochemistry. GRP78 mRNA and protein levels in 7 tumor tissues were also quantified by real-time PCR and Western blot respectively and correlated well with the immunohistochemical results. Forty (58.8%) of the 68 neuroblastic tumors showed positive GRP78 expression. The percentage of positive GRP78 immunostaining increased as the tumor histology became differentiated (p = 0.001). Furthermore, positive GRP78 expression strongly correlated with early clinical stages (P = 0.002) but inversely correlated with MYCN amplification (p = 0.001). Kaplan-Meier analysis showed that patients with positive GRP78 expression did have better survival than those with negative expression (5-year survival rate, 72.9% and 23.4% respectively, p < 0.001). Multivariate analysis further showed that GRP78 expression was an independent prognostic factor. Moreover, GRP78 expression predicted better survival in patients with either undifferentiated or differentiated histologies. GRP78 expression still had significant prognostic value when the analysis was restricted to tumors of advanced stages or without MYCN amplification. Thus, GRP78 can serve as a novel independent favorable prognostic factor for patients with neuroblastoma.     

Survivin与乳腺癌雌激素受体信号通路相关基因的相关性

目的:探讨乳腺癌中Survivin与雌激素受体（estrogen receptor,ER）信号通路相关基因的相关性。方法:采用Real-time PCR技术检测10例乳腺癌组织中Survivin的含量,选择含量最高的3例作为高表达组,含量最低的3例作为低表达组;采用人乳腺癌雌激素受体信号通路PCR芯片检测两组标本中相关基因表达的差异。结果:两组标本中Survivin的含量差异有统计学意义（P<0.05）。雌激素受体信号通路相关基因PCR芯片检测结果表明,Survivin低表达组的ER含量较高表达组降低,但差异无统计学意义（P>0.05）;Survivin低表达组的CDKN1B、NME1、ERBB2、TOP2A含量较高表达组显著降低,差异有统计学意义（P<0.05）。结论:在乳腺癌中,Survivin与CDKN1B、NME1、ERBB2、TOP2A的表达在mRNA水平上呈正相关,与ER的表达存在着正相关的趋势,表明Survivin与雌激素受体信号通路之间存在着一定的相关性。Survivin在乳腺癌的内分泌治疗中可能具有潜在的重要意义。     

Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions

The 78kDa glucose-regulated stress protein GRP78 is induced by physiological stress conditions such as hypoxia, low pH, and glucose deprivation which often exist in the microenvironments of solid tumors. Activation of this stress pathway occurs in response to several pro-apoptotic stimuli. In vitro studies have demonstrated a correlation between induced expression of GRP78 and resistance to apoptotic death induced by topoisomerase II-directed drugs. We were interested in characterizing this protein in human breast lesions for potential implications in chemotherapeutic intervention. Surgical specimens of human breast lesions and paired normal tissues from the same patients were flash frozen for these studies. Total RNA and/or protein were extracted from these tissues and used in northern and/or western blot analyses, respectively, to quantify the relative expression of GRP78. Northern blot analysis indicated that 0/5 benign breast lesions, 3/5 estrogen receptor positive (ER+) breast tumors, and 6/9 estrogen receptor negative (ER–) breast tumors exhibited overexpression of GRP78 mRNA compared to paired normal tissues, with fold overexpressions ranging from 1.8 to 20. Western blot analyses correlated with these findings since 0/5 benign breast lesions, 4/6 ER+ breast tumors, and 3/3 ER– breast tumors overexpressed GRP78 protein with fold overexpressions ranging from 1.8 to 19. Immunohistochemical analysis of these tissues demonstrated that the expression of GRP78 was heterogeneous among the cells comprising different normal and malignant glands, but confirmed the overexpression of GRP78 in most of the more aggressive ER– tumors. These results suggest that some breast tumors exhibit adverse microenvironment conditions that induce the overexpression of specific stress genes that may play a role in resistance to apoptosis and decreased chemotherapeutic efficacy.     

Survivin及P-糖蛋白在乳腺癌组织中的表达及意义

目的:探讨抗凋亡蛋白Survivin及多药耐药的P-糖蛋白在乳腺癌组织中的表达及其意义.方法:应用免疫组化方法检测217例乳腺癌及52例乳腺纤维瘤中Survivin蛋白和p-糖蛋白的表达,比较Survivin 蛋白和p-糖蛋白表达的差异、分析乳腺癌临床病理学指标(包括:病理类型、肿瘤大小、淋巴结转移、TNM分期、组织学分级等)与Survivin蛋白和p-糖蛋白表达的关系,并进行生存分析.结果:乳腺纤维腺瘤中Survivin蛋白和p-糖蛋白的阳性率分别为13.46％和9.62％,乳腺癌中Survivin蛋白和p-糖蛋白的阳性表达率分别为76.04％和73.27％,差异均有统计学意义(P＜0.05);相关性分析表明:Survivin抑凋亡蛋白及p-糖蛋白表达具有弱正相关性(P＜0.05).Survivin与TNM分期、淋巴结转移、组织学分级正相关;p-糖蛋白与组织学分级正相关(P＜0.05).Survivin蛋白阳性与p-糖蛋白阳性患者的平均生存时间分别与Survivin 蛋白阴性、p-糖蛋白阴性的差异具有统计学意义(P＜0.05).结论:Survivin蛋白与P-糖蛋白在乳腺癌组织中呈现高表达,且两者表达均与组织学分级正相关,影响患者生存时间,Survivin蛋白及p-糖蛋白表达具有弱正相关性.     

Survivin蛋白在乳腺癌中的表达及意义

目的:分析Survivin蛋白在乳腺癌中的表达与临床、病理特征的关系。方法:采用免疫组织化学PV法检测Survivin在38例浸润性乳腺癌及正常乳腺组织中的表达,分析Survivin表达与肿瘤临床、病理特征等的关系。结果:Survivin蛋白在乳腺癌中的阳性表达率86.84%,其表达率与淋巴结有无转移之间呈正相关性（P=0.01）。Survivin阳性表达率与肿物直径、病理分期、绝经与否、组织学分级之间无相关性（P>0.05）。Survivin阳性表达与ER、PR无相关性。结论:Survivin蛋白在乳腺癌的预后判断方面具有重要意义。     

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.