Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer Is Associated with High Histological Grade

Li, Hongzhen; Ahonen, Tommi; Alanen, Kalle; Xie, Jianwu; LeBaron, Matthew J.; Pretlow, Thomas G.; Ealley, Erica L; Zhang, Ying; Nurmi, Martti; Singh, Baljit; Martikainen, Petri; Nevalainen, Marja T.

doi:10.1158/0008-5472.can-03-3499

Cited by 162 publications

(203 citation statements)

References 47 publications

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“…Stats are a family of cytoplasmic transcription factors that can be activated (i. showed that Stat5 expression is positively related to formation of metastatic lesions (28). Although the role of Stat5 in breast tumor progression is less clear, Stat5 phosphorylation has been implicated in the pathogenesis of chronic myelogenous leukemia (29), acute myeloid leukemia (30), and prostate cancer progression (31,32). Dephosphorylation of Stat5 is believed to be mediated by protein tyrosine phosphatases (33).…”

Section: Discussionmentioning

confidence: 99%

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Yang¹,

Yu²,

Yi³

et al. 2006

J. Proteome Res.

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Tumor metastasis is a complex multi-step process normally involving dysregulation of multiple signal transduction pathways. In this study we developed a novel approach to efficiently define dysreguated pathways associated with metastasis by comparing global gene and protein expressions of two distinct metastasis-suppressed models. Consequently, we identified common features shared by the two models which are potentially associated with metastasis.The efficiency of metastasis from the highly aggressive polyoma middle T-induced mouse mammary tumors was suppressed by either prolonged caffeine exposure or by breeding the animal to a low metastastic mouse strain. Molecular profiles of the primary tumors from both metastasis-suppressed classes were then derived to identify molecules and pathways that might underlie a common mechanism of metastasis. A number of differentially regulated genes and proteins were identified, including genes encoding basement membrane components, which were inversely related to metastatic efficiency. In addition, the analysis revealed that the Stat signal transduction pathways were potentially associated with metastasis inhibition, as demonstrated by enhanced Stat1 activation, and decreased Stat5 phosphorylation in both genetic and pharmacological modification models. Tumor cells of low-metastatic genotypes also demonstrated anti-apoptotic properties. The common changes of these pathways in all of the metastasis-suppressed systems suggest that they may be critical components in the metastatic cascade, at least in this model system. Our data demonstrate that analysis of common changes in genes and proteins in a metastatic-related context greatly decrease the complexity of data analysis, and may serve as a screening tool to identify biological important factors from large scale data.

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Section: Discussionmentioning

confidence: 99%

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Yang¹,

Yu²,

Yi³

et al. 2006

J. Proteome Res.

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“…40,45,57,72,78,79 Active Stat5a/b decreased both cell surface and total E-cadherin protein expression ( Figure 1A) and mRNA levels ( Figure 1B). At the same time, active Stat5a/b upregulated mesenchymal markers N-cadherin, vimentin, and fibronectin at both mRNA and protein levels in all three cell lines ( Figure 1, A and B).…”

Section: Jak2-stat5a/b Signaling Induces Expression Of Emt Markers Inmentioning

confidence: 99%

“…pcDNA-CMV-PrlR and pcDNA-CMV-WTStat5a were cloned into an adenoviral vector using BD Adeno-XTM Expression System 2 (BD Biosciences, Palo Alto, CA), as previously described, 38,41,44,45,61 and according to the manufacturer's protocol. Viral stocks of adPrlR, adWTStat5a, and adLacZ were expanded in large-scale cultures, purified by double cesium chloride gradient centrifugation, and titered side-by-side using standard plaque assay in QBI-293A cells.…”

Section: Adenoviral Generation and Gene Deliverymentioning

confidence: 99%

“…Immunohistochemical staining of xenograft tumors and clinical human PCs grown as ex vivo organ cultures was performed as described previously, 39,43,45,47,65 and primary antibodies used are listed in Table 2. Sections of CWR22Pc and CWR22Rv1 cell pellets, fixed with 10% formalin and paraffin embedded, were immunostained for Twist1 and BMI1 by immunofluorescence cytochemistry.…”

Section: Immunostaining Of Paraffin-embedded Tissue Sections and Cellmentioning

confidence: 99%

“…50,51 Stat5a/b is activated by phosphorylation of a conserved C-terminal residue by an upstream kinase, most commonly Jak2, 52e54 which leads to Stat5a/b dimerization, nuclear translocation, DNA binding, and regulation of gene transcription. 55,56 Known key factors activating Stat5a/b in PC include prolactin (Prl), 40,45,57 growth hormone, 58 erythropoietin, 59 and epidermal growth factor. 60 In clinical PC, the expression of active Stat5a/b is elevated in >60% of PC metastases.…”

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confidence: 99%

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

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

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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

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Depression and prostate cancer risk: A Mendelian randomization study

et al. 2020

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Background The association between depression and prostate carcinogenesis has been reported in observational studies but the causality from depression on prostate cancer (PCa) remained unknown. We aimed to assess the causal effect of depression on PCa using the two‐sample Mendelian randomization (MR) method. Methods Two sets of genetics instruments were used for analysis, derived from publicly available genetic summary data. One was 44 single‐nucleotide polymorphisms (SNPs) robustly associated with major depressive disorder (MDD) and the other was two SNPs related with depressive status as ever depressed for a whole week. Inverse‐variance weighted method, weighted median method, MR‐Egger regression, MR Pleiotropy RESidual Sum, and Outlier test were used for MR analyses. Results No evidence for an effect of MDD on PCa risk was found in inverse‐variance weighted (OR: 1.12, 95% CI: 0.97‐1.30, p = 0.135), MR‐Egger (OR 0.89, 95% CI: 0.29‐2.68, p = 0.833), and weighted median (OR: 1.08, 95% CI: 0.92‐1.27, p = 0.350). Also, no strong evidence for an effect of depressive status on PCa incidence was found using the inverse‐variance weighted method (OR 0.72, 95% CI: 0.35‐1.47, p = 0.364). Conclusions The large MR analysis indicated that depression may not be causally associated with a risk of PCa.

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Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer Is Associated with High Histological Grade

Abstract: ABSTRACT

Cited by 162 publications

References 47 publications

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

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

Depression and prostate cancer risk: A Mendelian randomization study

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