Ming Jiang, M.D., Ph.D.
Research Associate Professor of Medicine
Dr. Ming Jiang's research interests are focused on three main topics: 1. Cross-talk of the Arachidonic Acid/COXs/LOXs/PPARgamma signaling pathway during prostatic pathogenesis: Epidemiological studies and animal experiments suggested a close link between dietary fat intake and the risk of prostate cancer. Omega-6 fatty acid, such as linoleic acid (LA), arachidonic acid (AA) and the AA metabolite prostaglandin E2 (PGE2) have been found to stimulate tumor growth. In contrast, oleic acid (OA) and omega-3 fatty acid, eicosapentaenoic acid (EPA) inhibited tumor growth. Eicosanoid synthesis involves the release of AA from cell membrane phospholipids by an enzyme called phospholipase A2 (PLA2). AA then undergoes metabolism by cyclooxygenases (COXs) and lipoxygenases (LOXs). Peroxisome proliferator-activated receptors (PPARs) are the ligand activated transcription factors belonging to the nuclear receptor superfamily. The PPAR family is composed of PPARalpha, PPARbeta/delta and PPARgamma. PPARgamma can be activated by docosahexanoic acid, certain nature prostaglandin metabolite 15-deoxy-delta 12, 15-prostaglandin J2 (15dPGJ2), 15-hydroxyeicosatetraenoic acid (15-HETE), polyunsaturated fatty acid (PUFA), nonsteroidal anti-inflammatory drugs (NSAID), and members of the thiazolinedione family. We are interested in understanding the roles played by changes in arachidonic acid metabolism and gene regulation in the pathogenesis of benign prostatic hyperplasia (BPH) and prostatic intraepithelial neoplasia (PIN), the presumptive precursor to prostate cancer. Changes in arachidonic acid metabolism and specifically a loss of 15-LOX-2 activity (the enzyme which generates the PPARgamma ligand 15-HETE in the human prostate) are a common early feature of prostate cancer. These changes are proposed to result in a reduction or loss of PPARgamma signaling early in the prostatic disease process. COX-2 expression is down-regulated by a negative feedback loop mediated through PPARgamma which has tissue-specific distribution and links the control of cellular fatty acid metabolism, peroxisomal and lysosomal maturation and differentiation. We have used PB-Cre4 and PPARgamma-floxed mice to generate male mice in which the PPARgamma gene (coding for both the PPARgamma1 and gamma2 isoforms) is excised in the prostatic luminal epithelium. These mice developed mouse prostatic intraepithelial neoplasia (mPIN) lesions as early as 3 months of age. A similar phenotype was also seen in a tissue recombination model in which shRNA was used to remove specifically the PPARgamma2 isoform in wild-type mouse prostatic epithelial cells (mPrE). These experiments confirm that loss of epithelial PPARgamma signaling is sufficient to give rise to premalignant lesions in the prostate due to increased oxidative stress and active autophagy. 2. Functional remodeling of human normal/benign prostatic glandular tissues in a mouse model: We have established a number of spontaneously immortalized human prostate epithelial progenitor (HPrE) and stromal (HPrS) cell lines from normal and benign samples. Tissue recombinants made using HPrE cells and rat fetal urogenital sinus mesenchyme (UGM) showed functional well-differentiated prostatic glandular formation when grafted under the renal capsule of immunodeficient SCID mice for three months. Interestingly they also showed expression of the prostatic biomarkers, PSA, 15-LOX-2, AR and p63 proteins expression in the reconstituted epithelial luminal or basal cell layer. We are exploring gene functions using the genetic modification targeted at the human prostate cells in vitro and then investigating resultant phenotypes in a tissue recombination model in vivo. 3. Establishment of a spontaneous human prostate cancer-mouse multi-organ including bone metastasis model: We have established a novel intraductal mouse anterior prostate (AP)-orthotopic xenografting model of prostate cancer metastasis. Following grafting to the AP, both oste