CXCL13: a mediator of prostate cancer progression

CXCL13：前列腺癌进展的介质

• 批准号: 9256445
• 负责人: MARCELO G. KAZANIETZ
• 金额: $ 35.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256445
• 关键词: Animals; Antineoplastic Agents; Attention; Automobile Driving; BLR1 gene; Bioinformatics; Breast; CXCL13 gene; Cancer Etiology; Carcinoma; Cell model; Cells; Cessation of life; Collection; Data; Development; Diglycerides; Disease; Disease Progression; Drug Targeting; Engineering; Epithelial; Epithelial Cells; Etiology; Event; Gene Expression Profile; Genes; Growth; Guanine Nucleotide Exchange Factors; Head and Neck Cancer; Human; Human Characteristics; Immunocompetent; Impairment; In Vitro; Individual; Injection of therapeutic agent; Knock-out; Knockout Mice; Laboratories; Lesion; Lung; Lymphocyte Depletion; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Messenger RNA; Metastatic Prostate Cancer; Microarray Analysis; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Neoplasm Metastasis; Nude Mice; Oncogenic; PIK3CG gene; Pathology; Pathway interactions; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Production; Proliferating; Property; Prostate; Prostate Adenocarcinoma; Prostatic Neoplasms; Protein Isoforms; Protein Microarray Assay; Protein Overexpression; RNA Interference; Recurrence; Role; Signal Pathway; Signal Transduction; Site; Specimen; Stimulation of Cell Proliferation; Subfamily lentivirinae; Therapeutic; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tumor Suppressor Proteins; Tumorigenicity; Up-Regulation; autocrine; bone; cancer biomarkers; cancer therapy; cell motility; cell transformation; cellular engineering; chemokine; drug development; grasp; link protein; men; mouse model; novel; overexpression; prognostic; prostate cancer cell; prostate cancer cell line; prostate carcinogenesis; protein kinase C epsilon; public health relevance; rac GTP-Binding Proteins; receptor; small hairpin RNA; tumor; tumor progression; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer-related deaths among men in the US. A large body of evidence links protein kinase C epsilon (PKC) to cancer progression. PKC is markedly up-regulated in epithelial cancers, including prostate cancer, potentially reflecting its involvement in the etiology and progression o the disease. We found that prostate-specific PKC transgenic mice (PB-PKC) develop preneoplastic lesions (PINs), and remarkably, they develop invasive prostatic adenocarcinomas in a Pten haplodeficient background. Understanding the molecular basis of this cooperativity is highly relevant, as loss of the tumor suppressor Pten, a negative regulator of the PI3K pathway, is a common alteration of prostate cancer. We generated a number of cellular models recapitulating PKC overexpression and Pten loss, which display enhanced growth, motility, and invasiveness in vitro, and acquire tumorigenic potential in nude mice. Moreover, gene profiling and bioinformatics analysis revealed that PKC overexpressing/Pten depleted cells display a pattern of gene expression distinctive of human metastatic prostate cancer. We found that the "top hit" in this microarray analysis is the chemokine CXCL13. Notably, PKC cooperates with Pten loss to strongly induce CXCL13 mRNA levels and its release, and RNAi depletion of CXCL13 or its receptor (CXCR5) impairs the ability of PKC overexpressing/Pten-deficient cells to proliferate and migrate. Preliminary data also suggest that PKC and PI3K are downstream effectors of CXCR5, suggesting a positive amplification loop that may act as a vicious cycle. In Specific Aim 1, we will establish the relevance of the CXCL13:CXCR5 axis in prostate tumorigenesis using an inducible silencing approach. A potential contribution of stromal CXCL13 will be examined using immunocompetent mice and depletion of lymphocytes involved in CXCL13 production. In addition, knock-out CXCL13 and CXCR5 mice will be crossed with PB- PKC mice as an approach to assess the requirement of the CXCL13:CXCR5 axis in the development of prostate lesions and the activation of key mitogenic/survival pathways. In Specific Aim 2, we will examine the role of CXCL13:CXCR5 in metastasis using intraprostatic injections and also assess the role of this pathway in metastatic dissemination to bone. Mechanistic studies will be pursued to explore the potential relevance of Rac, a small G-protein, and its exchange factors (Rac-GEFs) in the motile/invasive phenotype driven by the PKC-PI3K-CXCL13-CXCR5 pathway. In Specific Aim 3, we will focus on the mechanisms involved in CXCL13 induction by PKC and PI3K, specifically dissecting the roles of Akt, Erk, Stat3, NF-B and specific p110 PI3Ks in controlling CXCL13 production. We will also investigate PKC as a potential CXCR5 downstream effector. Lastly, in Specific Aim 4 we will establish the relevance of the PKC/Pten-CXCL13 association in human prostate tumors using a large collection of prostate cancer specimens, and assess correlations with disease progression and recurrence. In addition to the mechanistic implications, the proposed studies may have major prognostic and therapeutic impact for personalized prostate cancer treatment.