Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Abstract

Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/beinduced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stemlike properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells. Most prostate cancer (PC)erelated deaths are because of development of metastatic disease. A central process in metastatic dissemination of PC is epithelial-to-mesenchymal transition (EMT), during which cancer cells attain more motile and invasive properties, invade through the basement membrane, and survive in systemic circulation. 1e3 Extravasation at distant organ sites is followed by adhesion of cancer cells to extracellular matrix proteins, such as fibronectin, 4e6 leading to formation of premetastatic niches and subsequent formation of macroscopic metastases. 7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter

Whole-Transcriptome Analysis of CD133+CD144+ Cancer Stem Cells Derived from Human Laryngeal Squamous Cell Carcinoma Cells

“…Our data revealed STAT5A as a target of miR-4521 and miR-339-5p, both of which also interact with hg19_circ_0005033. Particularly, STAT5A induces stem-like cell properties and the epithelial-to-mesenchymal transition in prostate cancer [45]. hg19_circ_0005033 may upregulate STAT5A to promote the phenotype of LSCC stem cells by binding miRNAs targeting STAT5A.…”

β-Arrestin 1’s Interaction with TC45 Attenuates Stat signaling by dephosphorylating Stat to inhibit antimicrobial peptide expression

“…Shrimp Stat is similar to mammalian Stat5a/b. In mammals, Jak2 and 34445 regulate Stat5a/b and the inhibitors are Socs246, TC-PTP47 and PTP1B48. The inhibitor SOCS2 has also been cloned in shrimp38.…”

Prostate Cancer Stem Cells and Nanotechnology: A Focus on Wnt Signaling

“…Prostate cancer stem cells can also be derived from reprograming of differentiated cells via epithelial-mesenchymal transition (EMT), in which epithelial cells lose their polarity and cell–cell adhesion and gain migratory and invasive properties of mesenchymal cells (Kong et al, 2010; Talati et al, 2015; Lee et al, 2016). Kong et al (2010) reported that overexpression of platelet-derived growth factor D (PDGFD) resulted in the loss of epithelial markers and increasing mesenchymal markers in prostate cancer cells.…”

“…5-Aza treated prostate cancer cells showed enhanced CD133 + CD44 + phenotype and prostasphere formation ability, and elevated expression of stem cell-related transcription factors KLF4 and Sox2 (Lee et al, 2016). Activation of Jak2-Stat5a/b signaling promotes metastasis by inducing EMT and stem cell properties in prostate cancer cells, as shown by sphere formation and expression of CSC markers BMI-1, CD44, and Sox2 (Talati et al, 2015). Recently, there is an emerging concept that EMT represents a spectrum of differentiation status ranging from fully epithelial to fully mesenchymal status (Nieto et al, 2016).…”