Prostate cancer is a disease with considerable biological heterogeneity and clinical aggressiveness. Although prostate cancer is prevalent among elderly population, only a small proportion of prostate cancer become invasive, metastatic and life-threatening. Thus, identifying genes and the underlying mechanisms that convert prostate cancer from a relatively indolent disease to an aggressive one hold the key for reducing the mortality of the disease. Recently, by using """"""""differential subtraction chain"""""""", we identified a novel gene named """"""""myopodin"""""""" that is frequently deleted in aggressive type of prostate cancer. Regardless of Gleason grade, deletions of myopodin, either partial or complete, correlate with high rate of invasion, metastasis or clinical relapse of prostate cancer. Sequence analysis indicates that myopodin shares significant homology with synaptopodin, a protein expressed in neurons and kidney podocytes and responsible for forming physiological cell-cell contact for these cells. Interestingly, over 90% of the partial deletions of myopodin are located in the region sharing homology with synaptopodin. Overexpression of myopodin in PC-3 or LNCaP cells reduced the invasiveness of these cell lines by 3 fold or more in matrigel traverse analysis, and by 10 fold in tumor growth in vivo. Overexpression of myopodin induces actin bundling and retards migration in PC-3. Yeast two-hybrid and co-immunoprecipitation analyses indicate that myopodin binds zyxin, a critical regulatory protein in actin cytoskeleton reorganization, cell motility and mitosis. In our proposal, we hypothesize that myopodin plays an important role in regulating cell motility, maintaining the integrity of normal cell-cell contacts of prostate epithelium, and inhibits the invasiveness of prostate cancer cells, and propose the following specific aims: 1) to overexpress myopodin in PC-3, Du145 and LNCaP cells and subsequently to test the changes of invasiveness of these cells through anchorage independent growth assay, matrigel traverse analysis, diaphragm invasion analysis, metastasis assay and metalloproteinase assays; 2) to define the motifs and minimal domain of myopodin essential for regulation of invasion by constructing arrays of deletion mutants and test their ability to regulate invasiveness; 3) to identify the functional significance of myopodin/zyxin interaction by focusing on cell motility and cytoskeleton re-organization related analysis on myopodin transformed cells; and 4) To identify potential effector genes that might mediate the biological function of myopodin through a comprehensive analysis of gene expression of myopodin expressing cells. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098249-04
Application #
7083703
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Woodhouse, Elizabeth
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$257,276
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zuo, Ze-Hua; Yu, Yan P; Martin, Amantha et al. (2017) Cellular stress response 1 down-regulates the expression of epidermal growth factor receptor and platelet-derived growth factor receptor through inactivation of splicing factor 3A3. Mol Carcinog 56:315-324
He, D-M; Ren, B-G; Liu, S et al. (2017) Oncogenic activity of amplified miniature chromosome maintenance 8 in human malignancies. Oncogene 36:3629-3639
Chen, Zhang-Hui; Yu, Yan P; Tao, Junyan et al. (2017) MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice. Gastroenterology 153:1120-1132.e15
Chen, Zhang-Hui; Yu, Yan P; Zuo, Ze-Hua et al. (2017) Targeting genomic rearrangements in tumor cells through Cas9-mediated insertion of a suicide gene. Nat Biotechnol 35:543-550
Chen, Zhang-Hui; Yu, Yan P; Michalopoulos, George et al. (2015) The DNA replication licensing factor miniature chromosome maintenance 7 is essential for RNA splicing of epidermal growth factor receptor, c-Met, and platelet-derived growth factor receptor. J Biol Chem 290:1404-11
Luo, Jian-Hua; Liu, Silvia; Zuo, Ze-Hua et al. (2015) Discovery and Classification of Fusion Transcripts in Prostate Cancer and Normal Prostate Tissue. Am J Pathol 185:1834-45
Yu, Yan P; Liu, Silvia; Huo, Zhiguang et al. (2015) Genomic Copy Number Variations in the Genomes of Leukocytes Predict Prostate Cancer Clinical Outcomes. PLoS One 10:e0135982
Zuo, Ze-Hua; Yu, Yan P; Ding, Ying et al. (2015) Oncogenic Activity of miR-650 in Prostate Cancer Is Mediated by Suppression of CSR1 Expression. Am J Pathol 185:1991-9
Yu, Yan P; Michalopoulos, Amantha; Ding, Ying et al. (2014) High fidelity copy number analysis of formalin-fixed and paraffin-embedded tissues using Affymetrix Cytoscan HD chip. PLoS One 9:e92820
Yu, Yan P; Ding, Ying; Chen, Zhanghui et al. (2014) Novel fusion transcripts associate with progressive prostate cancer. Am J Pathol 184:2840-9

Showing the most recent 10 out of 40 publications