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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA225784-03
Application #
9994729
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2018-04-13
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of South Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33617
Qiu, Hong; Shi, Songshan; Yue, Jingwen et al. (2018) A mutant-cell library for systematic analysis of heparan sulfate structure-function relationships. Nat Methods 15:889-899
Qiu, Hong; Shi, Songshan; Wang, Shunchun et al. (2018) Proteomic Profiling Exosomes from Vascular Smooth Muscle Cell. Proteomics Clin Appl 12:e1700097