FGF-1 and FGF-2 regulate the expression of E-cadherin and catenins in pancreatic adenocarcinoma.

E-cadherin is a transmembrane protein that mediates Ca2+-dependent cell-cell adhesion and is implicated in a number of biologic processes, including cell growth and differentiation, cell recognition and cell sorting during development. We have previously demonstrated that both cell-cell adhesion and invasion are modulated by fibroblast growth factor (FGF)-1 and FGF-2 in a panel of pancreatic adenocarcinoma cell lines (BxPc3, T3M4 and HPAF). Here, we examine further the role of FGFs in the expression and activation of the E-cadherin/catenin system. We demonstrate that both FGF-1 and FGF-2 upregulate E-cadherin and beta-catenin at the protein level in the BxPc3 and HPAF cell lines and modestly in T3M4 cells. FGF-1 and FGF-2 facilitate the association of E-cadherin and alpha-catenin with the cytoskeleton, as demonstrated by the increase in the detergent-insoluble fraction of E-cadherin in BxPc3 and HPAF cells. Since the correct function of the E-cadherin/catenin complex requires its association with the cytoskeleton, our data suggest that FGF-1 and FGF-2 contribute to the integrity and thus the function of the complex. Furthermore, FGFs facilitate the assembly of the E-cadherin/catenin axis. The effect is associated with elevation of tyrosine phosphorylation of E-cadherin, alpha-catenin, beta-4051 mu-catenin and gamma-catenin, but not p120ctn. These findings indicate that the E-cadherin/catenin system is a target of the FGF/FGFR system and that coordinated signals from both systems may determine the ultimate biologic responses.     

EXPRESSION OF E-CADHERIN/CATENIN COMPLEX IN BREAST CANCER

Objective： To detect the expressions of E-cadherin, α-catenin and β-catenin and analyze the relationship between Ecadherin-catenin adhesion complex and clinicopathological features in breast cancer. Methods： The expressions of E-cadherin, α-cadherin and β-catenin in specimens of 54 breast cancer, 21 normal breast tissues around tumor, 15 breast hyperplasia of usual type and 15 breast atypical hyperplasia were detected by immunohistochemical method. Results： In 21 normal breast tissues, E-cadherin and α-catenin were expressed on cell membrane of ductal and acinic cells, showing cellular contour and border among cells. The staining character of the three proteins in breast hyperplasia of usual type was the same as that in normal breast tissue. In breast atypical hyperplasia, the abnormal expression rates of E-cadherin, α-catenin and β-catenin were 6.7%, 13.3% and 26.7%, respectively. The total abnormal expression rate of E-cadherin-catenin complex was 33.3%. In breast cancer, the abnormal expression rates of E-cadherin, α＋catenin and β-catenin were 51.9%, 63.0% and 61.1%, respectively. The total abnormal expression rate of E-cadherin-catenin complex was 88.9%. Abnormal expression of E-cadherin and α-catenin were significantly correlated with histological grade. Abnormal expressions of α-catenin and β-catenin were significantly correlated with TNM staging, axillary lymph nodes metastasis and postoperative distant metastasis. Abnormal expression of E-cadherin-catenin complex was correlated with TNM staging, histological grade and axillary lymph nodes. Abnormal expression of β-catenin was negatively correlated with expression of HER-2. COX multiple factor analysis showed that E-cadherin or α-catenin or β-catenin was not independent prognostic indicator. Conclusion： Abnormal expressions of E-cadherin, α-catenin and β-catenin frequently occur in breast cancer. Abnormal expression of E-cadherin-catenin complex is correlated with differentiation disturbance and metastasis. Combined measurement of E-caherin, α-catenin and β-catenin may improve accuracy and sensitivity of predicting metastasis and prognosis of breast cancer.     

结直肠腺癌组织中MMP2、ADAM17及E-cadherin的表达及临床意义

目的探讨基质金属蛋白酶2(MMP2)、AD AM金属肽酶域17(AD AM17)及E-钙黏蛋白(E-cadherin)在结直肠腺癌组织中的表达及临床意义。方法采用免疫组化PV-9000法检测120例结直肠腺癌组织、56例结直肠腺瘤组织和30例正常结直肠黏膜组织中MMP2、ADAM17及E-cadherin的表达情况,并分析其与结直肠腺癌患者临床特征的关系。结果结直肠腺癌组织中MMP2、ADAM17阳性表达率均高于结直肠腺瘤组织和正常结直肠黏膜组织,E-cadherin阳性表达率低于结直肠腺瘤组织及正常结直肠黏膜组织,差异均有统计学意义(P<0.05)。不同肿瘤直径、分化程度、TNM分期及有无淋巴结转移、浆膜浸润结直肠腺癌患者的结直肠腺癌组织中MMP2、ADAM17、E-cadherin阳性表达率比较,差异均有统计学意义(P<0.05)。结论MMP2、ADAM17及E-cadherin与结直肠腺癌的侵袭和转移有关,对结直肠腺癌的临床诊断、预后判断及个体化治疗具有重要意义。     

E-钙粘蛋白基因多态性与食管癌、贲门癌的关系

背景与目的:E-钙粘蛋白(E-cadherin,CDH1)是钙粘蛋白家族中的一个成员,与肿瘤侵袭转移密切相关。该基因启动子区存在的多态性位点可通过改变转录活性而影响该蛋白的表达。本研究旨在探讨该基因启动子区C-160A和G-347GA单核苷多态性(single nucleotide polym orphism,SNP)与中国北方人食管鳞状细胞癌(esophagealsquam ous cellcarcinom a,ESCC)、贲门腺癌(gastric cardiacadenocarcinom a,GCA)易感性和淋巴结转移的关系。方法:采用聚合酶链反应-限制性片段长度多态性(polym erase chain reaction-restrictionfragm entlength polym orphism,PCR-RFLP)分析方法检测333名ESCC患者、239名GCA患者和343名健康对照的CDH1C-160A及G-347GA SNP的基因型。结果:CDH1C-160A及G-347GA SNP的基因型及等位基因型分布在总体ESCC患者、GCA患者和健康对照中无显著性差异(P=0.08)。根据吸烟状况及上消化道肿瘤家族史分层分析及淋巴结转移状况的分析也未发现CDH1SNPs对ESCC和GCA发病及淋巴结转移的影响。然而,与G-347GA G/G基因型相比,携带GA等位基因(G/GA GA/GA基因型)可显著增加GCA患病风险,经性别、年龄校正后的OR值为1.45(95%CI=1.03～2.04)。应用EH软件分析显示,CDH1单体型分布在ESCC患者组和健康对照组存在显著性差异     

角质细胞生长因子及E-钙黏蛋白在胰腺癌组织中的表达及其意义

目的 研究角质细胞生长因子(KGF)及E-钙黏蛋白(E-cadherin)在胰腺癌组织中的表达及其临床意义.方法 应用免疫组织化学SP法检测45例胰腺癌组织、22例癌旁正常胰腺组织中KGF及E-cadherin的表达,并结合临床病理资料进行分析.结果 KGF在胰腺癌组织阳性表达率为77.8%(35/45),比相应的癌旁正常胰腺组织表达明显增高,且与癌组织分化程度及临床分期相关(P值均＜0.05);E-cadherin在胰腺癌组织比相应的癌旁正常胰腺组织表达减低,高表达率为35.6%(16/45),且与癌组织分化程度、淋巴结转移及临床分期密切相关(分别为P＜0.05,P＜0.05,P＜0.01);在胰腺癌组织中,KGF与E-cadherin表达呈负相关(P＜0.01).结论 KGF与E-cadherin有望作为胰腺癌的增生、分化、侵袭以及转移的重要生物学指标.     

The long noncoding RNA H19 promotes cell proliferation via E2F-1 in pancreatic ductal adenocarcinoma

H19 is a long noncoding RNA differentially expressed in many tumors and participates in tumorigenesis. This study aimed to investigate the expression and function of H19 in pancreatic ductal adenocarcinoma (PDAC). Pure malignant cells were isolated from frozen sections of 25 PDAC cases by laser captured microdessection, and H19 expression level was detected by qRT-PCR. Knockdown and overexpression were employed to manipulate H19 levels in pancreatic cancer cells, then cell viability, proliferation, apoptosis and cell cycle, and the growth of xenografts were evaluated. E2F-1 levels in PDAC tissues were detected by Western blot and immunohistochemical analysis. We found that H19 was overexpressed in PDAC tissues and correlated to histological grade of PDAC. Knockdown of H19 in T3M4 and PANC-1 cells with high H19 endogenous level suppressed cell viability, proliferation and tumor growth, while H19 overexpression in COLO357 and CAPAN-1 with low H19 endogenous level enhanced cell viability, proliferation and tumor growth. Knockdown of H19 led to G0/G1 arrest, accompanied by decreased levels of E2F-1 and its downstream targets. E2F-1 was overexpressed in PDAC tissues with possible correlation with H19 expression level. In conclusion, H19 is overexpressed and plays oncogenic role in PDAC through promoting cancer cell proliferation via the upregulation of E2F-1.     

E-cadherinP120ctn在乳腺癌中的表达及意义

  目的  探讨E-钙黏蛋白(E-cadherin, E-cad)、P120连环蛋白(P120ctn)在乳腺浸润性导管癌(IDC)和浸润性小叶癌(ILC)中的表达及其鉴别诊断意义。  方法  收集解放军第113医院2007年12月至2012年5月间有完整随访资料的浸润性导管癌60例、浸润性小叶癌48例及混合性癌20例。采用免疫组织化学S-P法检测E-cad及P120的表达。  结果  E-cad在IDC和ILC中的阳性率分别为85%(51/60)和0, 其差异有统计学意义(P < 0.01);P120在IDC中阳性率为100%, 且均为细胞膜着色, 而在ILC中阳性率亦为100%, 但均为胞浆着色。E-cad和P120联合使用将20例混合癌确诊为IDC 16例及ILC 4例。IDC中E-cad的表达水平与肿瘤分期无关, 与淋巴结转移有关(P < 0.05)。  结论  E-cad和P120联合使用可以鉴别光镜下易混淆的IDC和ILC, 使组织分型更准确, 建议应用于乳腺癌的常规免疫组织化学检测。E-cad的表达水平与淋巴结转移有关。      

Overexpression of rhophilin 2 promotes pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the seventh leading cause of global cancer deaths. In recent years, targeted therapy has been used for pancreatic cancer; however, the drugs available for use in targeted therapy for pancreatic cancer are still very limited. Hence, identification of novel targeted molecules for PDAC is required. Rhophilin 2 (RHPN2) was proven to be a driver gene in glioblastoma. However, the function of RHPN2 in PDAC remains unknown. In the present study, the function of RHPN2 was investigated. The RHPN2 levels were overexpressed by pcDNA3.1-RHPN2 and downregulated by si-RHPN2. Cell proliferation was assessed using the MTT assay and apoptosis was assessed using flow cytometry. The results revealed that high RHPN2 levels in PDAC tissue were correlated with a low overall survival rate of patients with PDAC. Inhibition of RHPN2 reduced SW1990 and PANC1 proliferation and increased the rate of apoptosis. Network analysis demonstrated that centrosomal protein 78 expression was negatively correlated with RHPN2 expression. In conclusion, the present study demonstrated that RHPN2 may promote PDAC making it a potential candidate for targeted therapy.     

E-cadherin在胃腺癌组织中的表达及其临床意义

目的:探讨上皮钙黏蛋白E（E-cadherin）在胃腺癌组织中的表达及其临床意义。方法:收集61例我院胃腺癌组织和其癌旁正常组织的石蜡包块以及患者的临床病理资料。免疫组化法检测E-cadherin在胃腺癌组织及癌旁正常组织中的表达,通过自动化图像分析系统对结果进行定量分析,统计学分析E-cadherin的表达及其与胃癌临床病理特征的关系。结果:E-cadherin在胃癌组织表达明显低于相应的癌旁组织（P＜0.05）;E-cadherin的表达下调与胃腺癌TNM分期、分化程度和浸润深度相关（P＜0.05）,与性别、年龄、淋巴结转移无明显相关（P＞0.05）。结论:E-cadherin在胃腺癌组织中表达下调,提示E-cadherin可能在胃癌的侵袭过程中起重要作用。     

吲哚美辛通过E-Cad逆转高糖诱导的胰腺癌细胞增殖作用

目的:研究吲哚美辛对高糖环境下胰腺癌细胞增殖能力的影响,并探讨相关机制。方法:体外培养胰腺癌细胞株BXPC-3和 Panc-1,应用MTT法检测肿瘤细胞在不同干预条件下的增殖能力;应用Real time-PCR和Western blot检测细胞中E-Cad和COX-2的表达。应用小干扰RNA敲除肿瘤细胞中E-Cad的表达。结果:高糖可促进胰腺癌细胞增殖能力;而吲哚美辛可逆转高糖条件促进胰腺癌细胞的增殖,同时吲哚美辛可调控肿瘤细胞中E-Cad的表达,且小干扰胰腺癌细胞E-Cad后可逆转吲哚美辛对高糖引起的增殖抑制作用。结论:吲哚美辛可以抑制高糖诱导的胰腺癌细胞增殖,且该过程是通过上调E-Cad实现的,而非通过COX-2途径。     

Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated pancreatic stellate cells (PSCs) and PDAC cells plays an important role in the development of PDAC. By producing high levels of cytokines, chemotactic factors, growth factors and excessive extracellular matrix (ECM), PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells may represent a novel therapeutic approach to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.     

肺腺癌组织HDAC1、HDAC5和E-cadherin表达及相关性研究

目的检测组蛋白去乙酰化酶1(HDAC1)、组蛋白去乙酰化酶5(HDAC5)和上皮型钙粘蛋白(E-cadherin)在肺腺癌组织中的表达,并分析三者表达的相关性。方法采用免疫组化SP法检测93例肺腺癌组织和48例癌旁组织中HDAC1、HDAC5和E-cadherin的表达情况。分析三者表达与肺腺癌临床病理特征的关系,以及三者表达的相关性。结果肺腺癌组织中HDAC1的阳性表达率为58.06%,高于癌旁组织的20.83%,差异有统计学意义(P<0.05);癌旁组织中HDAC5和E-cadherin的阳性表达率分别为66.67%、68.75%,均高于肺腺癌组织的48.39%、45.16%,差异有统计学意义(P<0.05)。HDAC1和E-cadherin表达与年龄有关(P<0.05),E-cadherin表达还与分化程度有关(P<0.05);HDAC5表达与肺腺癌临床病理特征均无关(P>0.05)。HDAC1分别与HDAC5、E-cadherin表达呈负相关(r=-0.224、r=-0.236,P<0.05);HDAC5与E-cadherin表达无明显相关性(r=0.159,P>0.05)。结论在肺腺癌组织中联合检测HDAC1、HDAC5和E-cadherin可能对判断预后、合理选择药物有一定指导意义。     

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest major cancers, with a five year survival rate of less than 8%. With current therapies only giving rise to modest life extension, new approaches are desperately needed. Even though targeting polyamine metabolism is a proven anticancer strategy, there are no reports, which thoroughly survey the literature describing the role of polyamine biosynthesis and transport in PDAC. This review seeks to fill this void by describing what is currently known about polyamine metabolism in PDAC and identifies new targets and opportunities to treat this disease. Due to the pleiotropic effects that polyamines play in cells, this review covers diverse areas ranging from polyamine metabolism (biosynthesis, catabolism and transport), as well as the potential role of polyamines in desmoplasia, autophagy and immune privilege. Understanding these diverse roles provides the opportunity to design new therapies to treat this deadly cancer via polyamine depletion.     

TRAIL receptors are expressed in both malignant and stromal cells in pancreatic ductal adenocarcinoma

This study assesses the expression of all TNF-related apoptosis-inducing ligand (TRAIL) receptors in pancreatic ductal adenocarcinoma (PDAC) tumor tissue. We aimed to include TRAIL receptor expression as an inclusion parameter in a future clinical study using a TRAIL-based therapy approach for PDAC patients. Considering the emerging influence of PDAC desmoplastic stroma on the efficacy of anti-PDAC therapies, this analysis was extended to tumor stromal cells. Additionally, we performed PDAC stroma characterization. Our retrospective cohort study (N=50) included patients with histologically confirmed PDAC who underwent surgery. The expression of TRAIL receptors (DR4, DR5, DcR1, DcR2, and OPG) in tumor and stromal cells was evaluated by immunohistochemistry (IHC). The amount of tumor stroma was assessed by anti-vimentin IHC and Mallory’s trichrome staining. The prognostic impact was determined by the univariate Cox proportional hazards regression model. An extensive expression of functional receptors DR4 and DR5 and a variable expression of decoy receptors were detected in PDAC tumor and stromal cells. Functional receptors were detected also in metastatic tumor and stromal cells. A poor prognosis was associated with low or absent expression of decoy receptors in tumor cells of primary PDAC. After assessing that almost 80% of tumor mass was composed of stroma, we correlated a cellular-dense stroma in primary PDAC with reduced relapse-free survival. We demonstrated that TRAIL functional receptors are widely expressed in PDAC, representing a promising target for TRAIL-based therapies. Further, we demonstrated that a low expression of DcR1 and the absence of OPG in tumor cells, as well as a cellular-dense tumor stroma, could negatively impact the prognosis of PDAC patients.