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Normal Cellular Prion Protein in Pancreatic Cancer

胰腺癌中的正常细胞朊病毒蛋白

基本信息

批准号：
7577470
负责人：
MAN-SUN M SY
金额：
$ 14.13万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7577470
关键词：
Address Adenocarcinoma Cell Adhesions Animal Model Apoptosis Apoptotic Behavior Binding Cancer Etiology Cancerous Carcinoma Cause of Death Cell Line Cell model Cells Cessation of life Clinical Cytoskeleton Development Disease Divalent Cations Down-Regulation Duct (organ) structure Ductal Epithelial Cell Epithelial Cells Freezing Glycosaminoglycans Growth Human Immunoblotting In Vitro Lead Lesion Ligands Malignant neoplasm of pancreas Membrane Proteins Metals Migration Assay Modeling Monoclonal Antibodies Mus Mutation Neoplasm Metastasis Nerve Degeneration Outcome Pan Genus Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathogenesis Patients Play PrPC function Premalignant Prevalence Prion Diseases Prions Prognostic Marker Property Receptor Activation Retrospective Studies Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Small Interfering RNA Staging Staining method Stains Subgroup Survival Analysis Survival Rate TP53 gene Therapeutic Intervention Time Tissues Transgenic Animals Transgenic Mice Tumor Cell Line United States Up-Regulation Xenograft Model autocrine carcinogenesis cell type chronic pancreatitis established cell line human tissue in vivo insight migration mouse model outcome forecast pancreatic neoplasm promoter receptor tumor

项目摘要

The normal cellular prion protein (PrPC) is a GPI-anchored membrane protein present on many cell types. While the expression of PrPC is critical for a group of fatal neurodegenerative conditions, known as prion diseases, the normal functions of PrPC remain an enigma. We screened for PrPC expression in a panel of human tumor cell lines, and found that human pancreatic tumor cell lines consistently express high levels of PrPC and produce high amounts of PrPC in their culture supernatants. These findings lead us to investigate whether PrPC is up regulated in human pancreatic ductal adenocarcinoma (Pan-DAC) tissues by immunohistochemical staining with anti-PrPC monoclonal antibodies (Mabs). Tissues from patients with chronic pancreatitis and pre-cancerous conditions, such as pancreatic intraepithelial neoplasia (PanIN-1, 2, 3) were included as controls. PrPC is not detected in normal ductal cells, in chronic pancreatitis, in PanIN-1 or in PanIN-2 tissues. Only four cases (14%) of PanIN-3 express low levels of PrPC. PrPC expression is uniquely up regulated in 41% of Pan-ADCs. Furthermore, PrPC expression is associated with poorer prognosis. Patients with PrPC expression in carcinoma had a much shorter median survival time of 360 days compared to >1,000 days for patients without PrPC expression (P<0.001). In addition, siRNA down regulation of PrPC expression in a Pan-DAC cell line, BXPC-3 reduces the proliferation of BxPC-3 cells. These results suggest that PrPC expression may be important in the genesis of human Pan-DAC. This hypothesis was supported by studies using a transgenic mouse line, which had an activated K-ras, with deleted TGFa receptor 2, under the control of a pancreatic specific promoter, Ptfia, (Ptf1acre/+; K-rasG12D/+; Tgfbr2flox/flox). This transgenic mouse line develops Pan-ADC with features reminiscent of human Pan-DAC. PrPC expression was detected in Pan-DAC but not in ductal cells, Pan-IN tissues or normal pancreatic ductal cells in this transgenic mouse line. We hypothesize that PrPC is involved in carcinogenesis of a subgroup of Pan-ADCs, either through its ligand-receptor activation or dysfunctional apoptosis cascade. We proposed three specific aims, using in vitro cell models, transgenic animal models and additional human tissues to further investigate the role PrPC plays in the genesis of human Pan-DAC. Results from these studies will provide new insights into the pathogenesis and may also identify new targets for therapeutic intervention of this deadly disease. Project Narrative Pancreatic ductal adenocarcinoma (Pan-DAC) is the fourth leading cancer causing deaths in the United States with more than 30,000 deaths per year. The overall median survival for all Pan- DAC is 6 months and the 5-year survival rate is less than 10%. At present, the underlying mechanisms that cause Pan-DAC are still poorly understood. We found that a subset (41%) of human Pan-DAC has increased expression of the normal cellular prion protein, PrPC, and identified that such an increase in PrPC expression is associated with poor clinical outcome (P>0.001). We also found that human Pan-DAC cell lines that express more PrPC have a higher proliferative rate in vitro. In addition, in a transgenic mouse model of Pan-DAC, we found that PrPC is also up regulated in the tumors but not in the precancerous lesions. Therefore, our findings in human Pan-DAC are recapitulated in vitro in a cell model and in an animal model. We propose to further investigate the role PrPC plays in Pan-DAC development using in vitro cell models, additional patient tissues and a transgenic mouse model. Results from these studies will provide new insights into the pathogenesis of human Pan-DAC and may also identify new targets for therapeutic intervention of this deadly disease.

正常细胞朊病毒蛋白（PrPC）是一种gpi锚定的膜蛋白，存在于许多细胞膜上

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Association of prion protein expression with pancreatic adenocarcinoma survival in the SEER residual tissue repository.

DOI：
10.3233/cbm-2012-0256
发表时间：
2011
期刊：
Cancer biomarkers : section A of Disease markers
影响因子：
0
作者：
Sy MS;Altekruse SF;Li C;Lynch CF;Goodman MT;Hernandez BY;Zhou L;Saber MS;Hewitt SM;Xin W
通讯作者：
Xin W

The fatal attraction between pro-prion and filamin A: prion as a marker in human cancers.

朊病毒原和纤丝蛋白A之间的致命吸引力：朊病毒作为人类癌症的标志物。