scholarly journals Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression

2020 ◽  
Vol 21 (13) ◽  
pp. 4786 ◽  
Author(s):  
Fanny Bery ◽  
Sandy Figiel ◽  
Sana Kouba ◽  
Delphine Fontaine ◽  
Maxime Guéguinou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Ex Vivo ◽  
Ether Lipid ◽  
K Channel ◽  
Alkyl Ether ◽  
Mesenchymal Transition ◽  
Cancer Aggressiveness ◽  
Sk3 Channel

Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca2+-activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.

scholarly journals A Novel Calcium-Mediated EMT Pathway Controlled by Lipids: An Opportunity for Prostate Cancer Adjuvant Therapy

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1814 ◽  
Author(s):  
Figiel ◽  
Bery ◽  
Chantôme ◽  
Fontaine ◽  
Pasqualin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Ex Vivo ◽  
Cellular Migration ◽  
K Channel ◽  
Inverse Association ◽  
Mesenchymal Transition ◽  
Anticancer Effects ◽  
Cancer Spread

The composition of periprostatic adipose tissue (PPAT) has been shown to play a role in prostate cancer (PCa) progression. We recently reported an inverse association between PCa aggressiveness and elevated PPAT linoleic acid (LA) and eicosapentaenoic acid (EPA) content. In the present study, we identified a new signaling pathway with a positive feedback loop between the epithelial-to-mesenchymal transition (EMT) transcription factor Zeb1 and the Ca2+-activated K+ channel SK3, which leads to an amplification of Ca2+ entry and cellular migration. Using in vitro experiments and ex vivo cultures of human PCa slices, we demonstrated that LA and EPA exert anticancer effects, by modulating Ca2+ entry, which was involved in Zeb1 regulation and cancer cellular migration. This functional approach using human prostate tumors highlights the clinical relevance of our observations, and may allow us to consider the possibility of targeting cancer spread by altering the lipid microenvironment.

The relationship of HIF2 and the progression of PTEN-deficient mouse prostate tumors.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 30-30
Author(s):  
W. Y. Kim ◽  
B. Zhou ◽  
G. Thomas
Keyword(s):  
Prostate Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Deficient Mouse ◽  
Prostate Cancer Progression ◽  
Prostate Tumors ◽  
Mesenchymal Transition

30 Background: The hypoxia-inducible factor (HIF) transcription factor has already cemented its oncogenic role in the development of renal cell carcinoma (RCC). However, its role in the tumorigenesis of other solid tumors remains unspecificed. Our studies focus on a novel link between HIF and prostate carcinogenesis. Methods: Using both in vitro cell culture studies as well as in vivo studies (orthotopic xenograft and genetically engineered mouse models) we investigate the role of HIF in prostate cancer cell proliferation, invasion, and progression. Results: Both HIF1 and HIF2 appear to be necessary for the proliferation and invasion of prostate cancer cell lines in vitro. Preliminary analysis of a PTEN deficient mouse model of prostate cancer suggests that expression of a stabilized form of HIF2 promotes the development of a larger prostate tumor burden and a more aggressive histology (high grade prostate intraepithelial neoplasia [PIN] at earlier stages). Moreover, PTEN-deficient prostate tumors producing HIF2 are more proliferative and vascular and express increased levels of genes associated with epithelial to mesenchymal transition (EMT). Conclusions: There has been much interest in the role of angiogenesis and hypoxia in prostate cancer progression. Our preliminary data suggest that HIF2 is able to promote PTEN-deficient prostate cancer progression in mice by increasing proliferation, angiogenesis, and EMT. No significant financial relationships to disclose.

scholarly journals SAT-114 Loss of DHEA-Targeting SULT2b1b Sulfotransferase Exacerbates Aggressive Traits of Prostate Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Chung Seog Song ◽  
Sulgi Park ◽  
Shoulei Jiang ◽  
Pawel Osmulski ◽  
Brett T Marck ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Gene Knockout ◽  
Cell Mass ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Precursor Pool ◽  
Mrna Induction

Abstract The prostate-expressed sulfotransferase SULT2B1b (SULT2B) regulates intracrine androgen homeostasis by mediating 3β-sulfation of DHEA, thus reducing the precursor pool in the androgen biosynthesis pathway. We explored how loss of SULT2B might influence prostate cancer progression. Results show that SULT2B ablation in castration-resistant prostate cancer (CRPC) cells, generated by stable RNA interference or gene knockout, led to robust activation of the ERK1/2 Map kinase survival signal and induction of epithelial to mesenchymal transition (EMT). EMT activation was concluded on the basis of increased levels of vimentin (a mesenchymal protein) and the EMT-activating transcription factors SNAI1 (Snail) and TWIST1, shown by Western blotting, mass spectrometry and single-cell mass cytometry. Loss of SULT2B was associated with enhanced motility and invasive activity of CRPC cells in vitro and their growth escalation in vivo as xenografts. Higher invasion and metastasis potential of SULT2B-ablated CRPC cells was further indicated by results that these cells are less adhesive (i.e. easily detachable) and less stiff (i.e. more pliable) based on atomic force microscopy analysis of individual cells. Notably, AKR1C3, an aldo-keto reductase, which is elevated frequently in advanced prostate cancer, showed marked upregulation in SULT2B-deficient cells. AKR1C3 regulates androgen receptor (AR) signaling by promoting androgen biosynthesis and functioning as an AR-selective coactivator. While levels of AR and DHT did not change, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several fold higher in SULT2B-silenced cells. The DHT-metabolizing AKR1C2 aldo-keto reductase was also upregulated, which likely accounts for a steady-state androgen level despite elevated AKR1C3 expression. Phosphorylation of ERK decreased in AKR1C3-silenced cells, signifying a causal link between AKR1C3 upregulation and ERK1/2 activation. SULT2B was undetectable immunohistochemically in tissue microarrays of clinical CRPC metastases, while SULT2B-negative samples showed AKR1C3-positive immunostaining. Primary prostate cancer exhibited variable, Gleason score independent SULT2B levels -- varying from strong positive to significantly reduced or undetectable. The reciprocal expression pattern for SULT2B and AKR1C3 in clinical CRPC suggests that AKR1C3 upregulation, ERK1/2 activation and increased aggressive traits of SULT2B-ablated cells, observed in vitro in cell models, may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for delaying disease progression in SULT2B-deficient prostate cancer.Funding Support: 1I01BX000280, VA (BC); W81XWH-14-1-0606, DOD (BC); IK6 BX004207, VA (BC); P50 CA97186, NIH & W81XWH-12-1-0208, DOD (EAM)

scholarly journals Expression of E-cadherin and specific CXCR3 isoforms impact each other in prostate cancer

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Bo Ma ◽  
Ahmad Khazali ◽  
Hanshuang Shao ◽  
Yuhan Jiang ◽  
Alan Wells
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Surface Expression ◽  
Cell Phenotype ◽  
Reciprocal Regulation ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
E Cadherin

Abstract Background Carcinoma cells shift between epithelial and mesenchymal phenotypes during cancer progression, as defined by surface presentation of the cell-cell cohesion molecule E-cadherin, affecting dissemination, progression and therapy responsiveness. Concomitant with the loss of E-cadherin during the mesenchymal transition, the predominant receptor isoform for ELR-negative CXC ligands shifts from CXCR3-B to CXCR3-A which turns this classical G-protein coupled receptor from an inhibitor to an activator of cell migration, thus promoting tumor cell invasiveness. We proposed that CXCR3 was not just a coordinately changed receptor but actually a regulator of the cell phenotype. Methods Immunoblotting, immunofluorescence, quantitative real-time PCR and flow cytometry assays investigated the expression of E-cadherin and CXCR3 isoforms. Intrasplenic inoculation of human prostate cancer (PCa) cells with spontaneous metastasis to the liver analyzed E-cadherin and CXCR3-B expression during cancer progression in vivo. Results We found reciprocal regulation of E-cadherin and CXCR3 isoforms. E-cadherin surface expression promoted CXCR3-B presentation on the cell membrane, and to a lesser extent increased its mRNA and total protein levels. In turn, forced expression of CXCR3-A reduced E-cadherin expression level, whereas CXCR3-B increased E-cadherin in PCa. Meanwhile, a positive correlation of E-cadherin and CXCR3-B expression was found both in experimental PCa liver micro-metastases and patients’ tissue. Conclusions CXCR3-B and E-cadherin positively correlated in vitro and in vivo in PCa cells and liver metastases, whereas CXCR3-A negatively regulated E-cadherin expression. These results suggest that CXCR3 isoforms may play important roles in cancer progression and dissemination via diametrically regulating tumor’s phenotype.

scholarly journals Transactivation of SOX5 by Brachyury promotes breast cancer bone metastasis

2019 ◽  
Vol 41 (5) ◽  
pp. 551-560 ◽  
Author(s):  
Ming Chen ◽  
Shitao Zou ◽  
Chao He ◽  
Jundong Zhou ◽  
Suoyuan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Cancer Aggressiveness ◽  
Metastatic Relapse

Abstract The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions which give rise to the high incidence of bone metastasis (BM) in breast cancer patients have long remained uncharacterized. In our study, in vitro and in vivo assays demonstrated that Brachyury (Bry) could promote breast cancer BM. Bry drives epithelial–mesenchymal transition (EMT) and promotes breast cancer aggressiveness. As an EMT driver, SOX5 involves in breast cancer metastasis and the specific function in BM. Chromatin immunoprecipitation (ChIP) assays revealed SOX5 is a direct downstream target gene of Bry. ChIP analysis and reporter assays identified two Bry-binding motifs; one consistent with the classic conserved binding sequence and the other a new motif sequence. This study demonstrates for the first time that Bry promotes breast cancer cells BM through activating SOX5. In clinical practice, targeting the Bry-Sox5-EMT pathway is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance and other aspects of breast cancer progression. Brachyury directly regulates the expression of SOX5 by binding to two motifs in its promoter region. The Bry-SOX5-EMT pathway may represent a potential target to develop treatments to prevent and treat bone metastasis from breast cancer.

CCN3/NOV as a functional driver and prognostic biomarker of prostate cancer bone metastasis.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 182-182
Author(s):  
VéRonique Ouellet ◽  
Matthew Dankner ◽  
Laudine Desreumaux-Communal ◽  
Estelle Schmitt ◽  
Dru Perkins ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Prognostic Biomarker ◽  
Ex Vivo ◽  
Mineral Density ◽  
Terminal Domain ◽  
Cancer Aggressiveness ◽  
Intracardiac Injection ◽  
Ccn3 Expression

182 Background: Prostate cancer commonly metastasizes to the bone, resulting in pathological fractures and poor prognosis. CCN3/NOV (Nephroblastoma overexpressed) has been implicated in promoting the formation of osteolytic prostate cancer (PC) bone metastases. The C-terminal domain of CCN3 binds growth factors, heparin sulfate proteoglycans, activates Notch signaling and promotes dimerization of CCN family members. We hypothesize that the CCN3 CT domain is required to promote osteolytic PC bone metastasis and that CCN3 represents a prognostic biomarker in primary PC tumors to predict recurrence to bone. Methods: CCN3WT and CCN3∆CT were overexpressed in LNCaP C4-2 cells. The role of CCN3 was assessed with in vitro proliferation, migration and invasion assays, and in vivo through intracardiac injection in male Nude mice (Nu/Nu). Ex vivo µCT scans were performed on bone specimens. CCN3 expression was assessed in two unique tissue microarrays (TMA) comprising over 1,500 primary prostate tumor using different anti-CCN3 antibodies with immunohistochemistry and immunohistofluorescnece, respectively. Results: While CCN3WT and CCN3∆CT had little effect in vitro on cell proliferation, migration or invasion, intracardiac injection of CCN3WT resulted in increased incidence of bone metastasis compared to empty vector control and CCN3∆CT. Ex vivo µCT revealed decreased bone mineral density in bones from mice injected with CCN3WT cells compared to control and CCN3∆CT expressing cells. In both TMAs studied, high CCN3 expression in tumor epithelium correlated with increased risk of biochemical relapse and bone metastasis at 5 years and 15 years post-resection, respectively. Conclusions: CCN3 requires its C-terminal domain for its bone metastatic function, and CCN3 is correlated with aggressive disease biology in prostate cancer. These findings point to CCN3 as a biomarker that can be useful to predict prostate cancer aggressiveness, while providing clarity on its role as a functional mediator of prostate cancer bone metastasis.

scholarly journals MicroRNA-144 Suppresses Prostate Cancer Growth and Metastasis by Targeting EZH2

2021 ◽  
Vol 20 ◽  
pp. 153303382198981
Author(s):  
Xin-bo Sun ◽  
Yong-wei Chen ◽  
Qi-sheng Yao ◽  
Xu-hua Chen ◽  
Min He ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Proliferation And Apoptosis ◽  
High Incidence ◽  
Inhibit Cell Proliferation

Background: Prostate cancer is a common malignant tumor with a high incidence. MicroRNAs (miRNAs) have been shown to be important post-transcriptional regulators during tumorigenesis. This study aimed to explore the effect of miR-144 on PCa proliferation and apoptosis. Material and Methods: The expression of miR-144 and EZH2 were examined in clinical PCa tissues. PCa cell line LNCAP and DU-145 was employed and transfected with miR-144 mimics or inhibitors. The correlation between miR-144 and EZH2 was verified by luciferase reporter assay. Cell viability, apoptosis and migratory capacity were detected by CCK-8, flow cytometry assay and wound healing assay. The protein level of EZH2, E-Cadherin, N-Cadherin and vimentin were analyzed by western blotting. Results: miR-144 was found to be negatively correlated to the expression of EZH2 in PCa tissues. Further studies identified EZH2 as a direct target of miR-144. Moreover, overexpression of miR-144 downregulated expression of EZH2, reduced cell viability and promoted cell apoptosis, while knockdown of miR-144 led to an inverse result. miR-144 also suppressed epithelial-mesenchymal transition level of PCa cells. Conclusion: Our study indicated that miR-144 negatively regulate the expression of EZH2 in clinical specimens and in vitro. miR-144 can inhibit cell proliferation and induce cell apoptosis in PCa cells. Therefore, miR-144 has the potential to be used as a biomarker for predicting the progression of PCa.

scholarly journals Long noncoding RNA LINC00941 promotes pancreatic cancer progression by competitively binding miR-335-5p to regulate ROCK1-mediated LIMK1/Cofilin-1 signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jie Wang ◽  
Zhiwei He ◽  
Jian Xu ◽  
Peng Chen ◽  
Jianxin Jiang
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Loss Of Function ◽  
Mesenchymal Transition

AbstractAn accumulation of evidence indicates that long noncoding RNAs are involved in the tumorigenesis and progression of pancreatic cancer (PC). In this study, we investigated the functions and molecular mechanism of action of LINC00941 in PC. Quantitative PCR was used to examine the expression of LINC00941 and miR-335-5p in PC tissues and cell lines, and to investigate the correlation between LINC00941 expression and clinicopathological features. Plasmid vectors or lentiviruses were used to manipulate the expression of LINC00941, miR-335-5p, and ROCK1 in PC cell lines. Gain or loss-of-function assays and mechanistic assays were employed to verify the roles of LINC00941, miR-335-5p, and ROCK1 in PC cell growth and metastasis, both in vivo and in vitro. LINC00941 and ROCK1 were found to be highly expressed in PC, while miR-335-5p exhibited low expression. High LINC00941 expression was strongly associated with larger tumor size, lymph node metastasis, and poor prognosis. Functional experiments revealed that LINC00941 silencing significantly suppressed PC cell growth, metastasis and epithelial–mesenchymal transition. LINC00941 functioned as a molecular sponge for miR-335-5p, and a competitive endogenous RNA (ceRNA) for ROCK1, promoting ROCK1 upregulation, and LIMK1/Cofilin-1 pathway activation. Our observations lead us to conclude that LINC00941 functions as an oncogene in PC progression, behaving as a ceRNA for miR-335-5p binding. LINC00941 may therefore have potential utility as a diagnostic and treatment target in this disease.

scholarly journals PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties

2021 ◽  
Vol 22 (5) ◽  
pp. 2731
Author(s):  
Piotr Garnuszek ◽  
Urszula Karczmarczyk ◽  
Michał Maurin ◽  
Arkadiusz Sikora ◽  
Jolanta Zaborniak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Ex Vivo ◽  
Specific Binding ◽  
Biological Evaluation ◽  
In Vitro Assays ◽  
The Novel ◽  
Distribution Profile ◽  
System L

A new PSMA ligand (PSMA-D4) containing the Glu-CO-Lys pharmacophore connected with a new linker system (L-Trp-4-Amc) and chelator DOTA was developed for radiolabeling with therapeutic radionuclides. Herein we describe the synthesis, radiolabeling, and preliminary biological evaluation of the novel PSMA-D4 ligand. Synthesized PSMA-D4 was characterized using TOF-ESI-MS, NMR, and HPLC methods. The novel compound was subject to molecular modeling with GCP-II to compare its binding mode to analogous reference compounds. The radiolabeling efficiency of PSMA-D4 with 177Lu, 90Y, 47Sc, and 225Ac was chromatographically tested. In vitro studies were carried out in PSMA-positive LNCaP tumor cells membranes. The ex vivo tissue distribution profile of the radioligands and Cerenkov luminescence imaging (CLI) was studied in LNCaP tumor-bearing mice. PSMA-D4 was synthesized in 24% yield and purity >97%. The radio complexes were obtained with high yields (>97%) and molar activity ranging from 0.11 to 17.2 GBq mcmol−1, depending on the radionuclide. In vitro assays confirmed high specific binding and affinity for all radiocomplexes. Biodistribution and imaging studies revealed high accumulation in LNCaP tumor xenografts and rapid clearance of radiocomplexes from blood and non-target tissues. These render PSMA-D4 a promising ligand for targeted therapy of prostate cancer (PCa) metastases.

scholarly journals CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ya Fan ◽  
Jia Wang ◽  
Wen Jin ◽  
Yifei Sun ◽  
Yuemei Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Rna Sequencing ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Proteasomal Degradation ◽  
Circular Rnas ◽  
Mesenchymal Transition

Abstract Background E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. Recent studies characterized circular RNAs (circRNAs) playing an regulatory role as miRNA sponge in tumor progression, presenting a new viewpoint for the post-transcriptional regulation of cancer-related genes. Methods Examination of the expression of HRD1 protein and mRNA was implemented using public microarray/RNA-sequencing datasets and breast cancer tissues/cell lines. Based on public RNA-sequencing results, online databases and enrichment/clustering analyses were used to predict the specific combinations of circRNA/miRNA that potentially govern HRD1 expression. Gain-of-function and rescue experiments in vitro and in vivo were executed to evaluate the suppressive effects of circNR3C2 on breast cancer progression through HRD1-mediated proteasomal degradation of Vimentin, which was identified using immunoblotting, immunoprecipitation, and in vitro ubiquitination assays. Results HRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) against other subtypes and has an inverse correlation with Vimentin, inhibiting the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) process of breast cancer cells via inducing polyubiquitination-mediated proteasomal degradation of Vimentin. CircNR3C2 (hsa_circ_0071127) is also remarkably downregulated in TNBC, negatively correlated with the distant metastasis and lethality of invasive breast carcinoma. Overexpressing circNR3C2 in vitro and in vivo leads to a crucial enhancement of the tumor-suppressive effects of HRD1 through sponging miR-513a-3p. Conclusions Collectively, we elucidated a bona fide circNR3C2/miR-513a-3p/HRD1/Vimentin axis that negatively regulates the metastasis of TNBC, suggesting that circNR3C2 and HRD1 can act as potential prognostic biomarkers. Our study may facilitate the development of therapeutic agents targeting circNR3C2 and HRD1 for patients with aggressive breast cancer.

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