An Association of Unique microRNA Turnover Machinery with Prostate Cancer Progression
Abstract
Prostate cancer (PCa) is ranked the second lethal disease among US men; the majority of mortality is resulted from the metastatic castration-resistant PCa (CRPC) relapse from hormonal therapy. Epithelial-to-mesenchymal transition (EMT) has been identified as a key mechanism leading to metastatic disease. Thus, developing effective targeted therapy to EMT becomes a high priority of PCa management. Clinically, recurrent CRPC is resistant to chemotherapy; the underlying mechanism(s) is not fully understood. One of the possible theories to explain the recurrence and ineffectiveness of cancer treatment is the cancer stem cell (CSC) model in which a subset of tumor cells is responsible for cancer initiation and progression as well as cancer recurrence. These CSCs share with normal stem cells the properties of self-renewal, immortal and differentiation into a variety of cell types including heterogeneous lineages of cancer cells. In addition, CSC can re-grow from a few cells resistant to therapy and left behind. Until now, it is known several potential molecular pathways are associated with CSC development in PCa; these pathways also overlap with pathways leading to EMT. Thus, one could develop "one stone multiple hits" strategy for EMT as well as CSC. In order to develop "effective agent," microRNA (miRNA) now becomes an emerging avenue of cancer therapy. miRNA is a short RNA molecule that has been shown to regulate 60% cellular mRNA with high specificity (sequence recognition) and efficiency (multi-miRNAs to one mRNA or one miRNA to multi-mRNAs). In general, based on their function, miRNA can be divided into oncomir (promoting cancer development) and tumor suppressor (inhibiting cancer development). This project is to unveil a protein complex as new machinery of controlling multiple tumor suppressive miRNA degradation that leads to cancer metastasis and CSC development. The goal of this proposal is to unveil its mechanism of action, the control of gene expression, and its clinical applicability as prognostic marker. Specifically, understanding the mechanism of action of this protein complex will help us to design better miRNAs as therapeutic to avoid its degradation after delivery. Unveiling the regulation by stromal factor will provide us more understanding the impact of tumor microenvironment on cancer progression. Evaluating clinical correlation from minimal invasive liquid biopsy will offer a new tool to distinguish aggressive cancer from indolent disease. Overall, the outcome of this study will provide a new knowledge for miRNA regulation, which is likely applied to other cancer types. Ultimately, this proposal can be further developed into a new therapeutic strategy to target one protein resulted in "multiple hits" on pathways leading to EMT and CSC; the outcome of this study should have an immediate clinical impact on PCa therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610474
Entities
People
- Jer-Tsong Hsieh
Organizations
- United States Army
- University of Texas Southwestern Medical Center