This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Matrix metalloproteinases (MMPs) are promising targets for cancer therapy. However, recent clinical trials of MMP inhibitors have been disappointing. Certain MMPs may regulate apoptosis signaling pathways and sensitize tumor cells to apoptotic signals. Inhibition of these MMPs will promote tumor cell survival and this effect may offset the beneficial activity in inhibition of metastasis. Matrix metalloproteinase-9 (MMP-9) expression is significantly increased in malignant prostate cancers. In addition to its ability to cleave collagens and basement membrane components, MMP-9 also cleaves and activates the multifunctional cytokine TGF-?. TGF-? (having three isoforms in mammals: TGF-?1, ?2, ?3) is an important regulator of normal and malignant prostate. While TGF-?1 induces apoptosis in certain prostate cancer cells, TGF-?2 blocks apoptosis. By activating all three isoforms of TGF-?, MMP-9 may have different net effect on prostate cancer apoptosis depending on the status of expression of TGF-? isoforms, their receptors, and the downstream signaling molecules. There is a critical need to determine the effects of MMP-9 on apoptosis in prostate cancer. Presumable, inhibition of MMP-9 will be beneficial in patients where MMP-9-mediated TGF-? activation has an anti-apoptotic effect in cancer cells. Selection of appropriate patients according to the status of TGF-? signaling machinery may be critical for future clinical trials to evaluate the therapeutic efficacy of MMP-9 inhibitors. The objective of this research is to define the role of MMP-9 in prostate cancer apoptosis and how the effects of MMP-9 on apoptosis change along with prostate cancer progression. At the completion of this project, we expect to clarify the role of MMP-9 in apoptosis regulation in prostate cancer and how this role may change in relation with the changes of TGF-? signaling at different stages of prostate cancer progression. A.
Specific aims : 1. To determine how miR-205 and miR-31 regulate apoptosis in prostate cancer cells. 2. To investigate the mechanism of down-regulation of miR-205 and miR-31 in advanced prostate cancer. 3. To enhance response to chemotherapy by targeting miR-205 and miR-31. Hypothesis: 1. miR-205 and miR-31 regulate apoptosis in prostate cancer cells. 2. miR-205 and miR-31 are down-regulated by epigenetic silencing in prostate cancers. 3. Targeting miR-205 and miR-31 will enhance response to chemotherapy.
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