Project Title: Unraveling the role of MMP3 in ovarian cancer
Research overview. Worldwide cancer related deaths continue to increase due to their ability to become chemotherapy resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. While the mechanism of cisplatin resistance has been extensively studied, no effective treatments have resulted, making such research critical and important. During the search for new therapeutic strategies to reverse these horrendous trends, we identified matrix metalloproteinase 3 (MMP3) to be highly abundant in cisplatin resistant ovarian cancer cells, as compared to responsive ones, using differential gene expression studies. MMP3 belongs to the MMPs family of proteolytic enzymes that degrade multiple components of the extracellular matrix (ECM). The protein structure of MMPs includes a catalytic domain and a hemopexin (HPX) domain. Several synthetic and natural MMP inhibitors have been designed to inhibit the catalytic domain of MMPs. However, these studies were abandoned years ago due to the overt toxicities resulting from the non-specific profile of those inhibitors. However, exciting data from our laboratory seeks to reverse these disappointing trends by demonstrating that MMP3-targeting small-interfering RNAs (siRNAs) significantly reduced cell proliferation and the invasiveness ability of cisplatin resistant ovarian cancer cells. Our preliminary results are in agreement with evidence that the HPX domain of MMP3 could binds to proteins connecting the ECM with intracellular molecular pathways. Therefore, our hypothesis is that other regions of MMP3 (HPX domain) interact with proteins promoting cisplatin resistance. Using a combination of molecular biology tools and our extensive and well established ovarian cancer models, we will test this central hypothesis with the following specific aims: (1) determine whether MMP3 in ovarian cancer models mediates susceptibility to the chemotherapy agent cisplatin, (2) identify the protein directly interacting with MMP3 in cisplatin resistant ovarian cancer cells, and (3) determine the biological consequences and therapeutic effects of siRNA-mediated MMP3 targeting in ovarian cancer models. Results of this project will enhance our understanding of the molecular mechanisms of cisplatin resistance in ovarian cancer.
Skills/Techniques: PR-CLIMB students will acquire expertise in the use of several molecular-biology techniques including cell culture, real-time PCR, Western blots, cell transfections, colony formation and invasion assays and protein immunoprecipitation.
To contact Dr. Pable Vivas you can write to the address below
E-mail: [email protected]
Tel.: 787-772-8300 ext. 1404
Also visit his lab website: http://vivas-lab.rcm.upr.edu/
Skills/Techniques: PR-CLIMB students will acquire expertise in the use of several molecular-biology techniques including cell culture, real-time PCR, Western blots, cell transfections, colony formation and invasion assays and protein immunoprecipitation.
To contact Dr. Pable Vivas you can write to the address below
E-mail: [email protected]
Tel.: 787-772-8300 ext. 1404
Also visit his lab website: http://vivas-lab.rcm.upr.edu/