LncRNA UCA1 acts as a sponge of miR-204 to up-regulate CXCR4 expression and promote prostate cancer progression

AbstractProstate cancer (PCa) is a devastating malignant disease with a poor prognosis. The aim of current study is to investigate the role of lncRNA-urothelial carcinoma associated 1 (UCA1) in the progression of PCa. We evaluated the expression levels of UCA1 in a total of 16 benign prostatic hyperplasia tissues (BPH) and 40 PCa tissues, as well as PCa cells. The functional regulatory effects of UCA1 were investigated using a series of cell function approaches. Our data showed that UCA1 is frequently overexpressed in PCa tissues compared with BPH tissues (P<0.01). Moreover, the higher expression of UCA1 was observed in patients with Gleason score ≥8 (P<0.05). In consistent, we found the expression levels of UCA1 was higher in the PCa cell lines PC-3, LnCaP, and DU-145 than in the normal prostate epithelial cell line RWPE-1 (P<0.01). Functionally, we found knockdown of UCA1 in PC-3 significantly suppressed cell growth and invasion of PC-3, while overexpression of UCA1 in DU-145 cells promote cell growth and invasion. Mechanistically, UCA1 overexpression permitted activation of CXCR4 oncogenes through inhibition of miR-204 activity, as evidenced by the positive association of these two genes with UCA1 levels and inverse correlation with miR-204 expression in PCa tissues. Luciferase activity assay further confirmed the targetting relationship between UCA1 and miR-204, CXCR4, and miR-204. The up-regulation of UCA1 in PC-3 cells significantly impaired the inhibitory effect of miR-204 on CXCR4 expression. Taken together, our research revealed that UCA1 works as an oncogene by targetting miR-204. The UCA1-miR-204-CXCR4 regulatory network regulated the growth and metastasis of PCa, providing new insight in the management of patients with such malignancy.

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Dentatin Induces Apoptosis in Prostate Cancer Cells via Bcl-2, Bcl-xL, Survivin Downregulation, Caspase-9, -3/7 Activation, and NF-κB Inhibition

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/856029 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 28

Author(s):

Ismail Adam Arbab ◽

Chung Yeng Looi ◽

Ahmad Bustamam Abdul ◽

Foo Kit Cheah ◽

Won Fen Wong ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Growth ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Nuclear Translocation ◽

Annexin V ◽

Cell Membrane Permeability ◽

Epithelial Cell Line ◽

Caspase 9 ◽

Normal Prostate

This study was set to investigate antiproliferative potential of dentatin (a natural coumarin isolated fromClausena excavataBurm. F) against prostate cancer and to delineate the underlying mechanism of action. Treatment with dentatin dose-dependently inhibited cell growth of PC-3 and LNCaP prostate cancer cell lines, whereas it showed less cytotoxic effects on normal prostate epithelial cell line (RWPE-1). The inhibitory effect of dentatin on prostate cancer cell growth was due to induction of apoptosis as evidenced by Annexin V staining and cell shrinkage. We found that dentatin-mediated accumulation of reactive oxygen species (ROS) and downregulated expression levels of antiapoptotic molecules (Bcl-2, Bcl-xL, and Survivin), leading to disruption of mitochondrial membrane potential (MMP), cell membrane permeability, and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-9, -3/7 activities, and subsequent DNA fragmentation. In addition, we found that dentatin inhibited TNF-α-induced nuclear translocation of p65, suggesting dentatin as a potential NF-κB inhibitor. Thus, we suggest that dentatin may have therapeutic value in prostate cancer treatment worthy of further development.

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TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease

Cancers ◽

10.3390/cancers12123862 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3862

Author(s):

Motasim Masood ◽

Stefan Grimm ◽

Mona El-Bahrawy ◽

Ernesto Yagüe

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Transmembrane Protein ◽

Intracellular Localization ◽

Amyloid Β ◽

Inverse Correlation ◽

Response To Therapy ◽

Endocrine Function ◽

Type I ◽

Amyloid Β Protein

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer’s disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.

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

Biomedicines ◽

10.3390/biomedicines9101404 ◽

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.

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

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0057 ◽

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.

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

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-07-0640 ◽

2007 ◽

Vol 13 (20) ◽

pp. 6040-6048 ◽

Cited By ~ 23

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

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10587 ◽

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.

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Long non-coding RNA-NEAT1, a sponge for miR-98-5p, promotes expression of oncogene HMGA2 in prostate cancer

Bioscience Reports ◽

10.1042/bsr20190635 ◽

2019 ◽

Vol 39 (9) ◽

Cited By ~ 6

Author(s):

Zhuifeng Guo ◽

Chang He ◽

Fan Yang ◽

Liang Qin ◽

Xuwei Lu ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Epithelial Cell Line ◽

Normal Prostate ◽

Non Coding Rna ◽

Normal Prostate Epithelial Cell ◽

Rna Immunoprecipitation ◽

Healthy Control ◽

Lncrna Neat1 ◽

Long Non Coding Rna

Abstract Increasing evidence demonstrated that noncoding RNAs (lncRNA, miRNA) play important roles in the cancer development. LncRNA NEAT1 functions as an oncogene in many cancers. However, the roles of NEAT1 in prostate cancer (PCa) remain largely unknown. In the present study, we aim to explore the molecular mechanism of NEAT1 in the development of PCa. We detected the expression levels of NEAT1 in a total of 16 benign prostatic hyperplasia tissues (BPH), 30 matched adjacent healthy control (HC) tissues and 30 PCa tissues, as well as PCa cell lines PC-3, DU-145, LNCaP and normal prostate epithelial cell line RWPE-1. The results showed that NEAT1 was significantly up-regulated in PCa tissues and PCa cell lines. Knockdown of NEAT1 can largely inhibit DU-145 and PC-3 cell growth and invasion. Bioinformatics analysis predicted NEAT1 has the binding site of miR-98-5p which can bind to the 3′UTR of HMGA2. And the expression level of NEAT1 has a positive correlation with HMAG2, while negative correlation with miR-98-5p in PCa cells. In addition, luciference assay and RNA immunoprecipitation (RIP) assay confirmed that NEAT1 can function as a competing endogenous RNA (ceRNA) by sponging miR-98-5p to active HMGA2. Moreover, silencing of HMGA2 can decrease the proliferation ability of PCa cells. Taken together, NEAT1/miR-98-5p/HMGA2 pathway is involved in the development and progression of PCa. NEAT1 could be recommended as a prognostic biomarker and inhibition of NEAT1 expression may be a promising strategy for PCa therapy.

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Ki-67 and PCNA expression in prostate cancer and benign prostatic hyperplasia

Clinical & Investigative Medicine ◽

10.25011/cim.v31i1.3136 ◽

2008 ◽

Vol 31 (1) ◽

pp. 8 ◽

Cited By ~ 54

Author(s):

WeiDe Zhong ◽

Jinyu Peng ◽

HuiChan He ◽

Dinglan Wu ◽

ZhaoDong Han ◽

...

Keyword(s):

Prostate Cancer ◽

Benign Prostatic Hyperplasia ◽

Early Diagnosis ◽

Prostatic Hyperplasia ◽

Nuclear Antigen ◽

Growth Fraction ◽

Resting Cells ◽

Ki 67 ◽

Normal Prostate ◽

Expression Levels

Objective: Ki-67 is a proliferation-associated nuclear antigen and is expressed in all cycling cells except for resting cells in the G0-phase. PCNA is an acidic nuclear protein and has been recognized as a histologic marker for the G1/S phase in the cell cycle. Ki-67and PCNA labeling indices are considered to reflect cell proliferation, particularly, growth fraction. The purpose of this study is to investigate the expression levels of Ki-67 and PCNA in prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and their potential on the early diagnosis of PCa. Methods: Human prostate cancer cell lines LNCaP and PC-3, human normal prostate epithelial cell line HuPEC, tissues from patients with PCa (121 cases) and BPH (45) and 36 normal cases were examined for the expression of Ki-67 and PCNA by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Then, the association of Ki-67 and PCNA expression with clinical grading of PCa was analyzed by immunohistochemistry staining. Results: The ratios of PCNA and Ki-67 expression levels in LNCaP and PC-3 were higher (P < 0.05, P < 0.001) than that in HuPEC. The two markers were differentially expressed in three tissues and showed increased expression in PCa (P < 0.05) and BPH (P < 0.05), relative to human normal prostate tissues. Compared with BPH, the ratio of Ki-67 and PCNA expressed in tumour tissue was increased (P < 0.05). The increase of Ki-67 was greater than that of PCNA. Expression of the two markers increased after different grading of PCa cases. The values of Ki-67/PCNA were: 0.073 in grade I PCa tissues, 0.119 in grade IIa PCa tissues, 0.141 in grade IIa PCa tissues, 0.234 in grade III PCa tissues. Conclusion: The combination of Ki-67 and PCNA, specific proliferative markers of PCa, may improve the accuracy of early diagnosis of prostatic cancer.

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Molecular biology of prostate cancer

10.1093/med/9780199659579.003.0059 ◽

2017 ◽

Author(s):

Ines Teles Alves ◽

Jan Trapman ◽

Guido Jenster

Keyword(s):

Prostate Cancer ◽

Transcription Factor ◽

Androgen Receptor ◽

Cell Growth ◽

Gene Fusion ◽

Cell Function ◽

Molecular Level ◽

Abiraterone Acetate ◽

Ets Family ◽

Prostate Cancers

Prostate cancer is a heterogeneous disease that arises through the acquisition of key malignant hallmarks. At the molecular level, prostate tumours are dependent upon the androgen receptor pathway, which affects cell function, growth, and behaviour through downstream androgen-regulated genes. Prostate cancer requires this activity and manipulates the AR pathway to maintain signalling. For example, mutation of the AR (to bind ligands other than androgens) or amplification/duplication of the AR allows signalling to continue in the absence of testosterone. Around 50% of prostate cancers have a gene fusion between the androgen-regulated component of the TMPRSS2 gene and a transcription factor (e.g. ETS family members ERG and ETV1). This results in aberrant androgen stimulated cell growth. Current research is using molecular knowledge to identify biomarkers, such as PCA3, and new therapies, such as enzalutamide or abiraterone acetate.

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The SIRT3 and SIRT6 Promote Prostate Cancer Progression by Inhibiting Necroptosis-Mediated Innate Immune Response

Journal of Immunology Research ◽

10.1155/2020/8820355 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Weiwei Fu ◽

Hong Li ◽

Haiyang Fu ◽

Shuchao Zhao ◽

Weiping Shi ◽

...

Keyword(s):

Prostate Cancer ◽

Immune Response ◽

Innate Immune Response ◽

Cancer Progression ◽

Nodal Metastasis ◽

Innate Immune ◽

Prostate Cancer Progression ◽

Class Iii ◽

Expression Levels ◽

Mrna And Protein Expression

The sirtuins (SIRTs), including seven family members, belong to class III histone deacetylase (HDAC) enzymes, which have been intensively investigated in cancers. Although the function of SIRTs in the cancer immunology is explored, SIRT-specific mechanisms regulating necroptosis-related innate immune response are not clear. In our present study, we found that both the mRNA and protein expression levels of SIRT3 and SIRT6 are significantly increased in the PCa tissues (HR, CI P = 3.30 E − 03 ; HR, CI P = 2.35 E − 08 ; and HR, CI P = 9.20 E − 08 ) and were associated with patients’ Gleason score and nodal metastasis. Furthermore, multivariate analysis showed that the PCa patients with higher expression levels of SIRT3 and SIRT6 had shorter overall survival (OS). Mechanistically, we found that SIRT3 and SIRT6 promote prostate cancer progress by inhibiting RIPK3-mediated necroptosis and innate immune response. Knockdown of both SIRT3 and SIRT6 not only activates TNF-induced necroptosis but also refreshes the corresponding recruitment of macrophages and neutrophils. Overall, our study identified that SIRT3 and SIRT6 are key regulators of necroptosis during prostate cancer progression.

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