Prinicipal Investigator: Lianchun Wang, M.D.
Institution: University of South Florida, Tampa, FL
Prinicipal Investigator: Houjian Cai, Ph.D.
Institution: University of Georgia, Athens, GA
Heparan Sulfate in Prostate Cancer
Prostate cancer (PCa) is one of the most prevalent forms of malignancy and the second most common cause of cancer-related death in men. Uncovering novel mechanisms that control prostatic tumorigenesis may advance development of more effective therapeutics to treat this life-threatening disease. Heparan sulfate (HS), a type of polysaccharide, is an essential component of the cell microenvironment and plays an important role in cell-cell and cell-matrix interaction and signaling. Recent studies reported that expression of HS-synthesizing and modifying genes are dysregulated in human PCa specimens. Currently, it is not known what causes this aberrant HS expression, and, more importantly, what are the functional consequences of the aberrant HS expression in prostatic tumorigenesis. In this application, we propose to test our novel hypothesis ?Pten-loss in prostate leads to aberrant HS expression creating a unique cellular environment that potentiates prostatic tumorigenesis? by pursuing the following three Specific Aims: 1. Determine if aberrant HS expression in human prostate epithelial cells is induced by Pten-loss and correlates with malignancy of Pten- null human PCa; 2. Determine if aberrant HS expression induced by Pten-loss potentiates prostatic tumorigenesis; 3. Determine if aberrant HS expression induced by Pten-loss potentiates PCa-associated inflammation. The proposed studies will use both novel and established genetic, cellular, biochemical and bioinformatics approaches in conjunction with in vitro cell function and in vivo human and mouse PCa models. These serial investigations are anticipated to delineate a novel mechanism that drives aberrant HS expression in PCa, reveal the aberrant HS expression to be a novel biomarker for PCa early diagnosis and prognosis, and elucidate the pivotal roles and their underlying molecular mechanisms of the aberrant HS expression in prostatic tumorigenesis, which likely will contribute to the development of novel therapeutics for PCa treatment.
Public Health Relevance
This proposal is highly relevant to public health as the proposed studies are expected to delineate a novel mechanism that drives aberrant heparan sulfate expression in prostate cancer, reveal the aberrant heparan sulfate expression to be a novel biomarker for early diagnosis and prognosis of prostate cancer, and to elucidate the pivotal roles and underlying molecular mechanisms of the aberrant heparan sulfate expression in prostatic tumorigenesis, which likely will contribute to the development of novel therapeutics for prostate cancer treatment.
- Comprehensive Heparan Sulfate mutant mouse lung endothelial cell library: targeting all the Heparan Sulfate biosynthetic and remodeling genes expressed in mouse lung endothelial cells. We also have the gRNAs for the targeted genes.
- Serial conditional Heparan Sulfate mice (generated in other labs) and generating serial conditional Hs3st mice.
- Developing virus based CRISPRa and CRISPRi reagents to up- and down-regulate Heparan Sulfate in cells in vitro and in mice. Will generate the reagents to target all major Heparan Sulfate genes.
- Spheroid assay in vitro: This assay allows to assess the stem cell activity via the epithelium and stromal interaction, and the functional roles of any interested genes in the either epithelial or stromal compartment.
- Prostate regeneration system in vivo: Similar to the above, but this assay allows to assess the stem cell activity in vivo. Additionally, it is often used to evaluate the oncogenic potential of an interested gene (either over-expression or loss of expression) in vivo.
- Extracellular vesicles (both in vitro and vivo): The biological material offers an exploration platform for identification of biomarkers.