Mechanisms of prostate cancer metastasis induced by Stat5a/b signaling
Abstract
The majority of prostate cancer-related deaths are due to metastatic progression, a process that is poorly understood. Active Stat5a/b predicts early disease recurrence in clinical prostate cancer, which typically manifests as development of metastatic disease. The focus of this thesis was to investigate the significance and underlying mechanisms of active Jak2-Stat5a/b signaling in metastatic dissemination of prostate cancer. The work presented here provides mechanistic evidence that active Stat5a/b promotes Epithelial-to-Mesenchymal Transition (EMT) of prostate cancer cells as indicated by increased Twist1, N-cadherin, vimentin, and fibronectin expression, while E-cadherin levels were down-regulated. Inhibition of Jak2-Stat5a/b signaling suppressed the molecular changes associated with active Stat5a/b-induced EMT in prostate cancer cells, in prostate cancer xenograft tumors, and patient-derived clinical prostate cancers. Induction of Jak2-Stat5a/b signaling disrupted epithelial monolayer of prostate cancer cells while inducing migration and adhesion of prostate cells to fibronectin. Furthermore, the work presented here demonstrates that transcription factor Twist1 is a mediator of prostate cancer EMT induced by Jak2-Stat5a/b. Specifically, Twist1 knockdown blocked functional endpoints of EMT induced by Jak2-Stat5a/b and suppressed Jak2-Stat5a/b-induced changes in the expression of EMT markers which was rescued by re-introduction of Twist1. Unexpectedly, while promoting EMT, Jak2-Stat5a/b signaling induced stem-like properties in prostate cancer cells including sphere formation and expression of stemness markers such as BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features as genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which was rescued by re-introduction of BMI1. Using human prolactin knock-in mice, we demonstrate that Jak2-Stat5a/b signaling promoted metastases formation of prostate cancer cells in vivo. Collectively, this work implicates that active Jak2-Stat5a/b promotes metastatic dissemination of prostate cancer by inducing EMT and stem-like properties of prostate cancer cells.
Subject Area
Pharmacology|Biochemistry
Recommended Citation
Talati, Pooja G, "Mechanisms of prostate cancer metastasis induced by Stat5a/b signaling" (2015). ProQuest ETD Collection - Thomas Jefferson University. AAI3705116.
https://jdc.jefferson.edu/dissertations/AAI3705116
