scholarly journals Expression and Subcellular Localization of Discoidin Domain Receptor 1 (DDR1) Define Prostate Cancer Aggressiveness

2021 ◽  
Author(s):  
R. Daniel Bonfil ◽  
Wei Chen ◽  
Semir Vranic ◽  
Anjum Sohail ◽  
Dongping Shi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Subcellular Localization ◽  
Cancer Progression ◽  
Normal Tissue ◽  
Multivariate Logistic Regression Model ◽  
Normal Prostate ◽  
Discoidin Domain Receptor ◽  
Potential Biomarker ◽  
Cancer Aggressiveness ◽  
Discoidin Domain Receptor 1

Abstract Background: The Discoidin Domain Receptor 1 (DDR1) is one of the two members of a unique family of receptor tyrosine kinase receptors that signal in response to collagen, which has been implicated in cancer progression. Here, we examined the expression of DDR1 in prostate cancer (PCa), and assessed its potential value as a prognostic marker, as a function of grade, stage and other clinicopathologic parameters.Methods: We investigated the association between the expression level and subcellular localization of DDR1 protein and PCa aggressiveness by immunohistochemistry, using tissue microarrays (TMAs) encompassing 200 cases of PCa with various Gleason scores (GS) and pathologic stages with matched normal tissue, and a highly specific monoclonal antibody. Results: DDR1 was found to be localized in the membrane, cytoplasm, and nuclear compartments of both normal and cancerous prostate epithelial cells. Analyses of DDR1 expression in low GS (≤7[3+4]) vs high GS (≥7[4+3]) tissues showed no differences in nuclear or cytoplasmic DDR1in either cancerous or adjacent normal tissue cores. However, relative to normal-matched tissue, the percentage of cases with higher membranous DDR1 expression was significantly lower in high vs. low GS cancers. Although nuclear localization of DDR1 was consistently detected in our tissue samples and also in cultured human PCa and normal prostate-derived cell lines, its presence in that site could not be associated with disease aggressiveness. No associations between DDR1 expression and overall survival or biochemical recurrence were found in this cohort of patients. Conclusion: The data obtained through multivariate logistic regression model analysis suggest that the level of membranous DDR1 expression status may represent a potential biomarker of utility for better determination of PCa aggressiveness.

scholarly journals Expression and subcellular localization of Discoidin Domain Receptor 1 (DDR1) define prostate cancer aggressiveness

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
R. Daniel Bonfil ◽  
Wei Chen ◽  
Semir Vranic ◽  
Anjum Sohail ◽  
Dongping Shi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Subcellular Localization ◽  
Cancer Progression ◽  
Normal Tissue ◽  
Multivariate Logistic Regression Model ◽  
Normal Prostate ◽  
Discoidin Domain Receptor ◽  
Potential Biomarker ◽  
Cancer Aggressiveness ◽  
Discoidin Domain Receptor 1

Abstract Background The Discoidin Domain Receptor 1 (DDR1) is one of the two members of a unique family of receptor tyrosine kinase receptors that signal in response to collagen, which has been implicated in cancer progression. Here, we examined the expression of DDR1 in prostate cancer (PCa), and assessed its potential value as a prognostic marker, as a function of grade, stage and other clinicopathologic parameters. Methods We investigated the association between the expression level and subcellular localization of DDR1 protein and PCa aggressiveness by immunohistochemistry, using tissue microarrays (TMAs) encompassing 200 cases of PCa with various Gleason scores (GS) and pathologic stages with matched normal tissue, and a highly specific monoclonal antibody. Results DDR1 was found to be localized in the membrane, cytoplasm, and nuclear compartments of both normal and cancerous prostate epithelial cells. Analyses of DDR1 expression in low GS (≤ 7[3 + 4]) vs high GS (≥ 7[4 + 3]) tissues showed no differences in nuclear or cytoplasmic DDR1in either cancerous or adjacent normal tissue cores. However, relative to normal-matched tissue, the percentage of cases with higher membranous DDR1 expression was significantly lower in high vs. low GS cancers. Although nuclear localization of DDR1 was consistently detected in our tissue samples and also in cultured human PCa and normal prostate-derived cell lines, its presence in that site could not be associated with disease aggressiveness. No associations between DDR1 expression and overall survival or biochemical recurrence were found in this cohort of patients. Conclusion The data obtained through multivariate logistic regression model analysis suggest that the level of membranous DDR1 expression status may represent a potential biomarker of utility for better determination of PCa aggressiveness.

scholarly journals Characterization of Proteins Regulated by Androgen and Protein Kinase a Signaling in VCaP Prostate Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1404
Author(s):  
Hye-Jin You ◽  
Byong-Chul You ◽  
Jong-Kwang Kim ◽  
Jae-Min Park ◽  
Bo-Seul Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Castration Resistant Prostate Cancer ◽  
Normal Prostate ◽  
Prostate Cancer Development ◽  
Kinase A

Androgen signaling via the androgen receptor (AR) is involved in normal prostate development and prostate cancer progression. In addition to androgen binding, a variety of protein kinases, including cyclic AMP-dependent protein kinase A (PKA), can activate the AR. Although hormone deprivation, especially that of androgen, continues to be an important strategy for treating prostate cancer patients, the disease ultimately progresses to castration-resistant prostate cancer (CRPC), despite a continuous hormone-deprived environment. To date, it remains unclear which pathways in this progression are active and targetable. Here, we performed a proteomic analysis of VCaP cells stimulated with androgen or forskolin to identify proteins specific for androgen-induced and androgen-bypassing signaling, respectively. Patterns of differentially expressed proteins were quantified, and eight proteins showing significant changes in expression were identified. Functional information, including a Gene Ontology analysis, revealed that most of these proteins are involved in metabolic processes and are associated with cancer. The mRNA and protein expression of selected proteins was validated, and functional correlations of identified proteins with signaling in VCaP cells were assessed by measuring metabolites related to each enzyme. These analyses offered new clues regarding effector molecules involved in prostate cancer development, insights that are supported by the demonstration of increased expression levels of the eight identified proteins in prostate cancer patients and assessments of the progression-free interval. Taken together, our findings show that aberrant levels of eight proteins reflect molecular changes that are significantly regulated by androgen and/or PKA signaling pathways, suggesting possible molecular mechanisms of CRPC.

scholarly journals The role of the androgen receptor as a driver and mitigator of cellular stress

2020 ◽  
Vol 65 (2) ◽  
pp. R19-R33
Author(s):  
Dimitrios Doultsinos ◽  
Ian Mills
Keyword(s):  
Prostate Cancer ◽  
Protein Synthesis ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Nuclear Hormone Receptor ◽  
Biological Processes ◽  
Normal Prostate ◽  
Mtor Activity

Prostate cancer is a high-incidence male cancer, which is dependent on the activity of a nuclear hormone receptor, the androgen receptor (AR). Since the AR is required for both normal prostate gland development and for prostate cancer progression, it is possible that prostate cancer evolves from perturbations in AR-dependent biological processes that sustain specialist glandular functions. The archetypal example of course is the use of prostate specific antigen (PSA), an organ-type specific component of the normal prostate secretome, as a biomarker of prostate cancer. Furthermore, localised prostate cancer is characterised by a low proliferative index and a heterogenous array of somatic mutations aligned to a multifocal disease pattern. We and others have identified a number of biological processes that are AR dependent and represent aberrations in significant glandular processes. Glands are characterised by high rates of metabolic activity including protein synthesis supported by co-dependent processes such as glycosylation, organelle biogenesis and vesicle trafficking. Impairments in anabolic metabolism and in protein folding/processing will inevitably impose proteotoxic and oxidative stress on glandular cells and, in particular, luminal epithelial cells for which secretion is their primary function. As cancer develops there is also significant metabolic dysregulation including impaired negative feedback effects on glycolytic and anabolic activity under conditions of hypoxia and heightened protein synthesis due to dysregulated PI 3-kinase/mTOR activity. In this review we will focus on the components of the AR regulome that support cancer development as well as glandular functions focussing on the unfolded protein response and on regulators of mTOR activity.

scholarly journals Minor Type IV Collagen α5 Chain Promotes Cancer Progression through Discoidin Domain Receptor-1

PLoS Genetics ◽  
2015 ◽  
Vol 11 (5) ◽  
pp. e1005249 ◽  
Author(s):  
Qian Xiao ◽  
Yan Jiang ◽  
Qingbo Liu ◽  
Jiao Yue ◽  
Chunying Liu ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Type Iv Collagen ◽  
Discoidin Domain Receptor ◽  
Type Iv ◽  
Discoidin Domain Receptor 1

PrLZ Is Expressed in Normal Prostate Development and in Human Prostate Cancer Progression

2007 ◽  
Vol 13 (20) ◽  
pp. 6040-6048 ◽  
Author(s):  
Ruoxiang Wang ◽  
Jianchun Xu ◽  
Nicola Mabjeesh ◽  
Guodong Zhu ◽  
Jianguang Zhou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Progression ◽  
Normal Prostate ◽  
Prostate Development

Gamma-Secretase, ErbB4 nuclear localization and neuregulin expression correlates with prostate cancer patient clinical outcome

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10587-10587
Author(s):  
I. Koumakpayi ◽  
C. Le Page ◽  
P. I. Karakiewicz ◽  
J. Diallo ◽  
L. Lessard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Nuclear Localization ◽  
Clinical Relevance ◽  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Breast Cancer Cell Lines ◽  
Inverse Association ◽  
Gamma Secretase ◽  
Normal Prostate

10587 Background: Membrane protein ErbB4 is a member of ErbB growth factor receptor family, which can be activated by neuregulins (NRG). Upon neuregulin activation, ErbB4 is cleaved within its transmembrane domain by presenilin γ-secratase (PSN) to release an intracellular domain that translocates into the nucleus. Although, ErbB4 ligand-dependant translocation of ErbB4 to the nucleus and its nuclear activity has been reported in breast cancer cell lines, there are few reports concerning ErbB4 nuclear localization and its clinical relevance. Here, we report for the first time the clinical relevance of ErbB4 nuclear localization, NRG, and PSN expression in prostate cancer tissues. Methods: Immunostaining using anti-ErbB4, anti-PSN2 and anti-neuregulin antibodies was done on a set of tissue microarrays (TMA) from 140 patients. The TMAs contained, 92 cores of normal prostate tissue obtained from 46 autopsy specimens from young males, 373 tumor and normal adjacent cores from 63 hormone sensitive PCa (HSPCa) patients, and 146 cores from 31 hormone refractory PCa (HRPCa) patients. Results: We found a statistically significant increase (p<0.01) in the percentage of ErbB4 nuclear localization (68.7% vs 53.2%), NRG expression (2.06 vs 1.41) and PSN2 expression (2.14 vs 1.53) when comparing cancerous tissues to normal tissue adjacent to cancer. Interestingly, a similar statistically significant increase in nuclear ErbB4 and NRG expression was observed when comparing HRPCa to HSPCa (p<0.001). In cancerous tissues, a strong correlation was found between nuclear ErbB4 and NRG expression (r=0.672), between nuclear ErbB4 and PSN2 expression (r=0.51), and between PSN2 and NRG expression (r=0.71). Nuclear ErbB4 and PSN2 inversely correlated with tumor stage and lymph node invasion. Kaplan Meier analysis of nuclear ErbB4 (p=0.030) and PSN2 expression (p=0.018) showed an inverse association with biochemical recurrence (BCR) of PCa. In multivariate analyses including these three markers and clinical parameters, only nuclear ErbB4 retained an independent prognosis value. Conclusion: Our results suggest that high nuclear ErbB4 along with increased PSN2 expression have a protective effect against prostate cancer progression and BCR. No significant financial relationships to disclose.

Use of nuclear androgen receptor status to predict early biochemical recurrence of prostate cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21073-21073
Author(s):  
J. Diallo ◽  
A. Aldejmah ◽  
M. Alam Fahmy ◽  
I. Koumakpayi ◽  
A. Mes-Masson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Early Onset ◽  
Biochemical Recurrence ◽  
Normal Tissue ◽  
Cellular Localization ◽  
Nuclear Staining ◽  
Normal Prostate ◽  
Kaplan Meier ◽  
Hormone Sensitive

21073 Background: Prostate cancer (PCa) is a leading cause of cancer death in North American men. The androgen receptor (AR) has an established role in the progression of this disease; however, it is unclear at what stage it intervenes. It is also uncertain whether the AR can be a useful prognostic marker for PCa. In this study, we assessed AR expression and sub-cellular localization in normal prostate as well as in androgen sensitive and insensitive PCa (AIPCa) tissues, and evaluated the ability of the AR to predict biochemical recurrence (BCR). Methods: We used tissue micro-arrays containing prostate tissue cores obtained from cancer-free patients (n=43), AIPCa patients (n=36), and patients with hormone-sensitive cancers (n=64) from which were collected both cancerous and normal adjacent tissue. Using immmunohistochemistry, we stained the tissue micro-arrays with a monoclonal antibody recognizing the AR. Two observers assessed the frequency and intensity of both cytoplasmic and nuclear AR staining. AR cytoplasmic (Ci) and nuclear (Ni) indices were calculated by multiplying nuclear staining frequency and nuclear staining intensity. Kaplan Meier, and Cox multivariate analyses were done using SPSS. Results: We found that AR Ci increased significantly in AIPCa although a modest but significant increase in PCa Ci was observed compared to normal tissues. In contrast, AR Ni was significantly lower in cancer-free patients as opposed to that seen in normal tissue adjacent to cancer. Similarly, cancerous tissue exhibited higher AR Ni than its adjacent normal tissue (p<0.05, Kruskal-Wallis). Kaplan Meier analyses revealed that low AR Ni was predictive of an early onset of BCR (before 3-years) in the sub-cohort of hormone-sensitive patients (LR=6.51, p=0.011). Futhermore, low AR Ni remained an independent predictor of early BCR in a Cox multivariate model controlling for age, pre-operative PSA, lymph node invasion, Gleason score and surgical margin status (HR=2.28, 95% CI=1.04 - 5, p<0.05). Conclusions: We conclude that increased nuclear AR activity could be a pre-malignant step in PCa progression whereas its role within cancer cells may be more complex, as low AR nuclear activity was associated with early onset of BCR. No significant financial relationships to disclose.

scholarly journals Alterations in chromosome spatial compartmentalization classify prostate cancer progression

2021 ◽  
Author(s):  
Rebeca San Martin ◽  
Priyojit Das ◽  
Renata Dos Reis Marques ◽  
Yang Xu ◽  
Rachel Patton McCord
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
3D Structure ◽  
Gene Clusters ◽  
Metastatic Potential ◽  
Chromosome 21 ◽  
Prostate Cancer Progression ◽  
Normal Epithelium ◽  
Chromosome Conformation ◽  
Cancer Aggressiveness

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression, genomic aberrations, and cellular morphology. These processes are in turn dependent in part on the 3D structure of chromosomes, packaged inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, ranging from normal epithelium to bone metastasis. Here, we describe how chromatin compartmentalization identity (A- open vs. B-closed) changes with progression: specifically, we find that 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches could prelude transcription activation and are accompanied by changes in the structure, size, and boundaries of the topologically associating domains (TADs). Further, compartmentalization changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation: one of the main drivers of prostate cancer.  These results suggest that discrete, 3D genome structure changes play a deleterious role in prostate cancer progression. 

scholarly journals Identification of a novel Protein Disulfide-isomerase A3 (PDIA3) transcript variant as a potential biomarker associated with late stage prostate cancer

2019 ◽  
Author(s):  
Maria Araceli Diaz Cruz ◽  
Pontus Karlsson ◽  
Gustav Högberg ◽  
Sandra Karlsson ◽  
Ferenc Szekeres ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Cancer Progression ◽  
Vitamin D Receptor ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Receptor Protein ◽  
Lncap Cells ◽  
Transcript Isoforms ◽  
Potential Biomarker

Abstract Background Prostate cancer (PC) is a heterogeneous and unpredictable disease and becomes untreatable when the tumor progress to castrate-resistant (CR) or androgen independent (AI). A major clinical challenge in prostate cancer is the lack of diagnostic and prognostic tests that distinguish between benign and aggressive tumors. Isoforms of gene transcripts are emerging as suitable candidates to represent disease progression. Vitamin D receptor (VDR and PDIA3) transcript isoforms could be the target candidates of study since they have been related with anti-tumoral effects and carcinogenesis in several cancer types. Methods The current study investigates the role of vitamin D receptor transcript isoforms in prostate cancer progression by using Next Generation Sequencing (NGS), Droplet Digital PCR (ddPCR) and several functional prediction tools. Results The NGS analysis revealed a novel PDIA3 transcript isoform (PDIA3N) that is higher expressed than the PDIA3 isoform that codifies for the receptor protein, in prostate cells. The expression of PDIA3N was validated by droplet digital PCR (ddPCR) absolute quantification, which confirmed the findings from the NGS analyses. The PDIA3N isoform was present in higher levels than PDIA3, in the metastatic androgen dependent LNCaP cells. Furthermore, analysis of the novel PDIA3 isoform sequence indicate that the variations present in its sequence are altering the original protein function and structure as well as the predicted subcellular localization of the protein. Conclusions We conclude that, PDIA3N due to the high expression in LNCaP cells and its abnormality in predicted structure, localization and function, is a potential biomarker for prostate cancer disease that needs to be further investigated in prostate cancer samples.

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