microRNAs and Prostate Tumor ProgressionEducation
- B.A., 1969, Bradley University
- M.S., 1972, University of Houston
- Ph.D., 1979, Baylor College of Medicine, (Professor Salih J. Wakil)
- 1979-1980, Staff Fellow, Laboratory of Biochemistry, National Cancer Institute, NIH, w/ Dr. Bruce Paterson
- 1980-1982, Muscular Dystrophy Post-doctoral Fellowship, Laboratory of Biochemistry, National Cancer Institute, NIH, w/ Dr. Bruce Paterson, Staff Fellow, Laboratory of Biochemistry, National Cancer Institute, NIH, w/ Dr. Bruce Paterson
The overall goal of the laboratory is to understand how differential regulation of gene expression leads to cancer. Prostate cancer (PC) is the most common malignancy diagnosed in men and metastatic PC represents the second highest cause of mortality. Available treatment options for patients with hormone-refractory PC are palliative and remain mostly ineffective with a poor prognosis. Since relevant target molecules are unknown for PC, it is necessary to find new biomarkers that identify the transition from non-metastatic, androgen- dependent into metastatic forms of PC. Micro RNAs (miRNAs) are non-coding, single- stranded small RNAs that negatively regulate gene expression and constitute a new class of regulators that could be relevant targets for deducing PC as well as novel therapies to block prostate tumor progression.
To this end, the Zehner lab is identifying miRs that are differentially expressed during prostate tumor progression using state-of-the-art technologies which include bioinformatics, networking analysis, proteomics, miR array screening and deep sequencing (RNA-seq) approaches. The lab has developed Laser Capture Microdissection (LCM) methodologies to discern miRNAs that are dysreguated in tumor cells of increasing Gleason score compared to BPH and normal glandular epithelium. Tumor suppressor miRs that are lost during tumor progression, represent novel drugs, the restoration of which could block progression to a tumorigenic/metastatic state. The effect of restoring tumor suppressor miR expression in metastatic PC cell lines is monitored on cell growth, signaling pathways, apoptosis, migration, and invasion in vitro and on tumor growth in vivo. As shown here, restoration of the tumor suppressor miR17-3p reduced tumor growth by 50% in male, athymic nude mice. Conversely, miRs that are highly expressed in PC may be acting as oncomiRs. Their expression can be lowered by antagomiRs and the subsequent effect assessed in vitro and in vivo as described above. Tumor suppressor miRs and antagomiRs represent relevant new drugs to combat tumor progression whereas oncomiRs are new targets for drug development.
Recently, it has been discovered that miRs are secreted in protective capsules that are very stable in body fluids. Not only does secretion represent a novel method for signaling between cells, but miRs secreted into body fluids could be relevant biomarkers to identify and gauge prostate cancer. Currently, the lab is analyzing body fluids from normal individuals as markers for body fluid identification as well as from prostate patients to diagnose and ultimately follow treatment outcomes in PC patients.