The roles of prostate progenitor cells and survivin in inflammation-induced prostate epithelial hyperplasia

Abstract

Prostate inflammation is a common health concern as an important risk factor for prostate cancer and Benign Prostatic Hyperplasia (BPH). Inflammation induces epithelial apoptosis and epithelial hyperplasia, suggesting that inflammation promotes the tissue repair and regeneration process. Progenitor cells are critical in maintaining epithelial homeostasis in adult tissues. However, the roles of prostate progenitor cells, especially during prostate inflammation, are understudied. I proposed that prostate epithelial progenitor cells (PEPCs) are involved in inflammation-induced epithelial hyperplasia, and are driven by regulation from inflammatory pathways. Here, we showed that sphere formation ability of prostate epithelial cells is increased by inflammation. We identified that a population of prostate progenitor cells, named prostate epithelial progenitor cells, were expanded by inflammation under the regulation of IL-1/insulin-like growth factor 1 (IGF-1) signaling pathway, a previously identified critical regulation pathway of inflammation-induced epithelial hyperplasia. The expansion of PEPCs also correlated with the intensity of inflammation. We then identified that survivin was upregulated in prostate epithelial cells by inflammation and was mainly co-localized with proliferation markers in prostate epithelial cells. This upregulation depended on IL-1/IGF-1 signaling. In vivo treatment with the survivin inhibitor LQZ-7F reduced both survivin expression and proliferation in prostate epithelial cells during inflammation. Using our label retaining strategy, we compared the survivin expression pattern in two prostate regeneration models. We discovered that different populations of progenitor cells may be involved in different regeneration processes. We identified that survivin was expressed in a specific population of reactivated cells that respond to the inflammatory environment and was independent of the known slow-cycling stem cells found in the prostate epithelium. In summary, I have identified that PEPCs are involved in epithelial hyperplasia and are dependent on survivin signaling. My work defines how survivin serves as a key regulator of epithelial hyperplasia in an inflammatory environment.