Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an almost lethal disease. Thus, it is important to better understand its genetic progression from normal cells through precancerous lesions pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic cancer. Carriers of a germline mutation in BRCA2 have an increased risk of developing PDAC when compared with the general population. The purpose of our study was to examine the role of BRCA2 dysfuction in the progression of PDAC. Here we generated a novel in vitro model of pancreatic carcinogenesis. Cancerous PanIN-BR1 cells were established by stable transduction with lentiviral-mediated BRCA2 RNA interference in PanIN cell isolated from mice with oncogenic KrasG12D. Our data showed that silencing of BRCA2 promoted cell proliferation, migration and invasion in vitro. The tumorigenic potential of PanIN-BR1 were assessed by xenograft tumor formation in BALB/c nude mice. The expression of PCNA , Snail and Slug in the tumor xenografts was detected by immunohistochemistry. The staining for PCNA, Snail and Slug in PanIN-BR1-formed xenograft tissue was significantly more intense than PanIN-formed xenograft tissue. Microarray assay was also performed. Based on gene expression profiling and further validation by real-time PCR and Western Blot, we found that the expression of Cyclinb2, Cyclina2, Twist1, Wisp1 and Cxcr4 revealed a significant increase in the PanIN-BR1 cells, however, the expression of p15, p16 and Wisp2 showed a significant decrease in the PanIN-BR1 cells, compared to the PanIN cells. Collectively, these data reported here demonstrate that BRCA2 may be a promising therapeutic targets for PDAC progression.
Keywords: BRCA2, Kras, Gene expression profiling, PanIN, Pancreatic carcinogenesis
Anti-Cancer Agents in Medicinal Chemistry
Title:BRCA2 Dysfunction Promotes Malignant Transformation of Pancreatic Intraepithelial Neoplasia
Volume: 13 Issue: 2
Author(s): Qi Wang, Hongrui Liu, Tingting liu, Shizhen Shu, He Jiang, Shidan Cheng, Yaozong Yuan, Weiguo Yang and Lifu Wang
Affiliation:
Keywords: BRCA2, Kras, Gene expression profiling, PanIN, Pancreatic carcinogenesis
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an almost lethal disease. Thus, it is important to better understand its genetic progression from normal cells through precancerous lesions pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic cancer. Carriers of a germline mutation in BRCA2 have an increased risk of developing PDAC when compared with the general population. The purpose of our study was to examine the role of BRCA2 dysfuction in the progression of PDAC. Here we generated a novel in vitro model of pancreatic carcinogenesis. Cancerous PanIN-BR1 cells were established by stable transduction with lentiviral-mediated BRCA2 RNA interference in PanIN cell isolated from mice with oncogenic KrasG12D. Our data showed that silencing of BRCA2 promoted cell proliferation, migration and invasion in vitro. The tumorigenic potential of PanIN-BR1 were assessed by xenograft tumor formation in BALB/c nude mice. The expression of PCNA , Snail and Slug in the tumor xenografts was detected by immunohistochemistry. The staining for PCNA, Snail and Slug in PanIN-BR1-formed xenograft tissue was significantly more intense than PanIN-formed xenograft tissue. Microarray assay was also performed. Based on gene expression profiling and further validation by real-time PCR and Western Blot, we found that the expression of Cyclinb2, Cyclina2, Twist1, Wisp1 and Cxcr4 revealed a significant increase in the PanIN-BR1 cells, however, the expression of p15, p16 and Wisp2 showed a significant decrease in the PanIN-BR1 cells, compared to the PanIN cells. Collectively, these data reported here demonstrate that BRCA2 may be a promising therapeutic targets for PDAC progression.
Export Options
About this article
Cite this article as:
Wang Qi, Liu Hongrui, liu Tingting, Shu Shizhen, Jiang He, Cheng Shidan, Yuan Yaozong, Yang Weiguo and Wang Lifu, BRCA2 Dysfunction Promotes Malignant Transformation of Pancreatic Intraepithelial Neoplasia, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (2) . https://dx.doi.org/10.2174/1871520611313020012
DOI https://dx.doi.org/10.2174/1871520611313020012 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
![](/images/wayfinder.jpg)
- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Viral Vectors in Cancer Immunotherapy: Which Vector for Which Strategy?
Current Gene Therapy Incidental Extracardiac Findings on Coronary Computed Tomography Angiography: A Pictorial Review of Imaging Findings
Current Medical Imaging Integrative Analysis of miRNA-mediated Competing Endogenous RNA Network Reveals the lncRNAs-mRNAs Interaction in Glioblastoma Stem Cell Differentiation
Current Bioinformatics Natural Killer Cells Preferentially Target Cancer Stem Cells; Role of Monocytes in Protection Against NK Cell Mediated Lysis of Cancer Stem Cells
Current Drug Delivery Patent Selections :
Recent Patents on Biomarkers Targeting Cancer Stem Cells with Natural Products
Current Drug Targets Chitosan Nanoparticles for Melanoma Cancer Treatment by Photodynamic Therapy and Electrochemotherapy Using Aminolevulinic Acid Derivatives
Current Medicinal Chemistry Bioactive Compounds of <i>Polygonatum sibiricum</i> - Therapeutic Effect and Biological Activity
Endocrine, Metabolic & Immune Disorders - Drug Targets Biosafety of Adenoviral Vectors
Current Gene Therapy Cytostatic Properties of Some Angiotensin I Converting Enzyme Inhibitors and of Angiotensin II Type I Receptor Antagonists
Current Pharmaceutical Design Comparative Analysis of Current Modality of Therapy in Head and Neck Squamous Cell Carcinoma Correlating the Expression Level of p38α
Current Cancer Therapy Reviews The Involvement of Heat Shock Proteins and Related Molecules in the Resistance to Therapies in Breast and Gynecologic Cancer
Current Cancer Therapy Reviews Patent Selections
Recent Patents on Anti-Cancer Drug Discovery The Possible Involvement of Glycogen Synthase Kinase-3 (GSK-3) in Diabetes, Cancer and Central Nervous System Diseases
Current Pharmaceutical Design Role of PARP Inhibitors in Cancer Biology and Therapy
Current Medicinal Chemistry Green Tea Polyphenols as Proteasome Inhibitors: Implication in Chemoprevention
Current Cancer Drug Targets Stem Cell Based Preclinical Drug Development and Toxicity Prediction
Current Pharmaceutical Design Biomarkers for Early Detection of Liver Cancer: Focus on Clinical Evaluation
Protein & Peptide Letters Selenium Compounds and Apoptotic Modulation: A New Perspective in Cancer Therapy
Mini-Reviews in Medicinal Chemistry Glucose-6-phosphate Dehydrogenase: a Biomarker and Potential Therapeutic Target for Cancer
Anti-Cancer Agents in Medicinal Chemistry