Gene Summary

Gene:NR3C1; nuclear receptor subfamily 3 group C member 1
Summary:This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glucocorticoid receptor
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NR3C1 (cancer-related)

Pak S, Kim W, Kim Y, et al.
Dihydrotestosterone promotes kidney cancer cell proliferation by activating the STAT5 pathway via androgen and glucocorticoid receptors.
J Cancer Res Clin Oncol. 2019; 145(9):2293-2301 [PubMed] Related Publications
PURPOSE: Androgen receptors (ARs) are expressed on a variety of cell types, and AR signaling plays an important role in tumor development and progression in several cancers. This in vitro study evaluated the effect of dihydrotestosterone (DHT) on the proliferation of renal cell carcinoma (RCC) cells in relation to AR status.
METHODS: Steroid hormone receptor expression was evaluated using RT-PCR and Western blotting. The effect of DHT on cell proliferation and STAT5 phosphorylation was evaluated in RCC cell lines (Caki-2, A498, and SN12C) and primary RCC cells using cell viability assays and Western blotting. ARs and glucocorticoid receptors (GRs) were knocked down with small interfering RNAs before assessing changes in cell proliferation and STAT5 activation.
RESULTS: DHT treatment promoted cell proliferation and increased STAT5 phosphorylation regardless of AR status. The AR antagonist bicalutamide reduced kidney cancer cell proliferation, regardless of AR status. AR and GR knockdown blocked STAT5 activation and reduced cell proliferation in all RCC cell lines. In patient-derived primary cells, DHT enhanced cell proliferation and this effect was diminished by treatment with the AR antagonists bicalutamide and enzalutamide and the GR antagonist mifepristone.
CONCLUSION: DHT promotes cell proliferation through STAT5 activation in RCC cells, regardless of AR status. DHT appears to utilize the AR and GR pathways to activate STAT5, and the inhibition of AR and GR showed antitumor activity in RCC cells. These data suggest that targeting AR and GR may be a promising new approach to the treatment of RCC.

Chrysovergis A, Papanikolaou V, Tsiambas E, et al.
P53/MDM2 Co-Expression in Laryngeal Squamous Cell Carcinoma Based on Digital Image Analysis.
Anticancer Res. 2019; 39(8):4137-4142 [PubMed] Related Publications
BACKGROUND: P53 is a key regulator of genomic stability and function, acting as a tumor suppressor protein. Our aim was to correlate P53 expression with murine double minute 2 (MDM2), a proto-oncogene that interacts with P53 and forms an auto-regulatory pathway, in laryngeal squamous cell carcinoma (LSCC).
MATERIALS AND METHODS: A total of 50 LSCC cases were included in the study. Immunohistochemistry was applied by using antibodies to P53 and MDM2 in the corresponding tissue sections. Protein expression levels for both molecules were measured by implementing a digital image analysis assay (immunostaining intensity levels, densitometric evaluation).
RESULTS: Overexpression of P53 protein was observed in 16/50 (32%) LSCC cases, while 22/50 (44%) cases strongly expressed MDM2 protein. Interestingly, in 13/50 (26%) cases, combined overexpression of P53/MDM2 was detected. Overall P53 was strongly positively correlated with MDM2 expression (p=0.001). Both P53 and MDM2 overexpression were significantly correlated with advanced stage of LSCC (p=0.032 and p=0.001, respectively). Additionally, MDM2 was found to be associated with poorer survival of patients (p=0.046).
CONCLUSION: Aberrant co-expression of P53 and MDM2 is associated with advanced stage in LSCC. Furthermore, MDM2 overexpression is a frequent and critical genetic event in LSCC and seems to negatively affect survival.

Bouras E, Karakioulaki M, Bougioukas KI, et al.
Gene promoter methylation and cancer: An umbrella review.
Gene. 2019; 710:333-340 [PubMed] Related Publications
Gene promoter methylation is a common epigenetic event, taking place in the early phase of tumorigenesis, which has a great potential as a diagnostic and prognostic cancer biomarker. In this umbrella review, we provide an overview on the association between gene-promoter methylation of protein-coding genes and cancer risk based on currently available meta-analyses data on gene promoter methylation. We searched MEDLINE via PubMed and the Cochrane Database of Systematic Reviews for meta-analyses that examine the association between gene-promoter methylation and cancer, published until January 2019 in English. We used AMSTAR to assess the quality of the included studies and applied a set of pre-specified criteria to evaluate the magnitude of each association. We provide a comprehensive overview of 80 unique combinations between 22 different genes and 18 cancer outcomes, all of which indicated a positive association between promoter hypermethylation and cancer. In total, the 70 meta-analyses produced significant results under a random-effects model with odds ratios that ranged from 1.94 to 26.60, with the summary effect being in favor of the unmethylated group in all cases. Three of the strong evidence associations involve RASSF1 methylation on bladder cancer risk (OR = 18.46; 95% CI: 12.69-26.85; I

Ioannidou A, Zachaki S, Daraki A, et al.
Paraoxonase 1 (PON1) Q192R and L55M Polymorphisms as Potential Predisposition Factors for Chronic Lymphocytic Leukemia.
Anticancer Res. 2019; 39(6):2861-2869 [PubMed] Related Publications
BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis.
MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization.
RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls.
CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.

Karagiannis AK, Philippou A, Tseleni-Balafouta S, et al.
IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer.
Anticancer Res. 2019; 39(6):2811-2819 [PubMed] Related Publications
BACKGROUND/AIM: Recent knowledge implicates a differential expression of the insulin-like growth factor-I (IGF-I) mRNA splice variants (i.e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer.
MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue specimens of different types of thyroid cancers from 92 patients were assessed for IGF-IEc expression by immunohistochemistry. In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR).
RESULTS: From the total number of 92 samples, 2 were anaplastic, 10 medullary, 4 hyperplasias of C-cells, 11 follicular, 5 hurtle cell carcinomas, 2 poorly differentiated, 5 nodular hyperplasias, 1 lymphoma and 52 were papillary thyroid cancers. The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers.
CONCLUSION: IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer.

Bencheikh L, Diop MK, Rivière J, et al.
Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages.
Nat Commun. 2019; 10(1):1935 [PubMed] Free Access to Full Article Related Publications
Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.

Politi A, Tsiambas E, Mastronikolis NS, et al.
Combined EGFR/ALK Expression Analysis in Laryngeal Squamous Cell Carcinoma.
In Vivo. 2019 May-Jun; 33(3):815-819 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Epidermal growth factor receptor (EGFR) acts as an oncogene in malignancies. Our aim was to examine the role of combined EGFR/ anaplastic lymphoma kinase (ALK) expression as molecular markers in laryngeal squamous cell carcinoma (LSCC) patients.
MATERIALS AND METHODS: Fifty (n=50) tissue sections derived from twenty-five (n=25) primary LSCCs were analyzed by immunohistochemistry (IHC).
RESULTS: EGFR overexpression was observed in 17/25 (68%) cases. Concerning ALK, 23/25 (92%) demonstrated low expression. EGFR expression was associated with grade (p=0.049), whereas ALK expression was correlated with stage (p=0.048). ALK overexpression was detected at advanced-stage EGFR-positive cases. A biphasic EGFR protein expression pattern was observed in five (n=5) LSCC cases, whereas ALK expression was stable in all cases.
CONCLUSION: EGFR overexpression is frequently observed in LSCC combined with low ALK expression. LSCC patients with EGFR/ALK protein overexpression should be eligible for targeted therapeutic strategies.

Toumpeki C, Liberis A, Tsirkas I, et al.
The Role of ARID1A in Endometrial Cancer and the Molecular Pathways Associated With Pathogenesis and Cancer Progression.
In Vivo. 2019 May-Jun; 33(3):659-667 [PubMed] Free Access to Full Article Related Publications
AT-rich interaction domain 1A gene (ARID1A) encodes for a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, a chromatin remodeling complex, and it has been implicated in the pathogenesis of various cancer types. In this review, we discuss how ARID1A is linked to endometrial cancer and what molecular pathways are affected by mutation or inhibition of ARID1A. We also discuss the potential use of ARID1A not only as a prognostic biomarker, but also as a target for therapeutic interventions.

Sapalidis K, Machairiotis N, Zarogoulidis P, et al.
Genes' Interactions: A Major Contributor to the Malignant Transformation of Endometriosis.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
The genetic and epigenetic factors that contribute to the malignant transformation of endometriosis are still under investigation. The objective of the present study was to investigate the genetic link between endometriosis and cancer by examining and correlating the latest clinical observations with biological experimental data. We collected updated evidence about the genetic relationship between endometriosis and cancers by conducting a comprehensive search of PubMed and Scopus databases, focusing on the papers published between January 2018 and January 2019. New insights into the mechanism of the malignant transformation of endometriosis have been published recently. The use of state-of-the-art techniques and methods, such as the genome-wide association study analysis and the weighted gene co-expression analysis, have significantly altered our understanding of the association between endometriosis and endometriosis-associated cancer development. Interestingly, the interactions formed between genes seem to play a pivotal role in the phenotypic expression of mutations. Therefore, the effect of single nucleotide polymorphisms and the function of the expression quantitative trait loci on genes' expression have been the subject of many recent works. In addition, it has been discovered that genes, the mutations of which have been related to the development of endometriosis, play a role as hub genes. This may lead to new areas of research for understanding the mechanism of malignant transformation of the disease. Significant steps forward have been made towards the identification of factors that control the malignant transformation of endometriosis. Still, due to rarity of the event, a better-organized scheme for sampling on a global level should be adopted.

Xu C, Wu P, Gao J, et al.
Heptadecanoic acid inhibits cell proliferation in PC‑9 non‑small‑cell lung cancer cells with acquired gefitinib resistance.
Oncol Rep. 2019; 41(6):3499-3507 [PubMed] Related Publications
Non‑small cell lung carcinomas (NSCLC) are common and are the leading cause of cancer‑associated mortality worldwide. Heptadecanoic acid (C17:0) is an odd‑chain saturated fatty acid. The effect of C17:0 on lung cancer has remained elusive. The present study examined the role of C17:0 in the PC‑9 NSCLC cell line and PC‑9 cells with acquired‑gefitinib resistance (PC‑9/GR) in vitro. Cell proliferation, migration, apoptosis, fatty acid composition and the activation of relevant signaling pathways were assessed. The results indicated that C17:0 significantly inhibited cell proliferation, and migration, while promoting apoptosis in PC‑9 and PC‑9/GR cells. Furthermore, C17:0 enhanced the cytotoxicity of gefitinib to PC‑9 and PC‑9/GR cells. Mechanistical analysis indicated that the activation of the phosphoinositide 3‑kinase/Akt signaling pathway was suppressed in C17:0‑treated PC‑9 and PC‑9/GR cells. Furthermore, the addition of C17:0 led to accumulation of 10‑cis‑heptadecenoic acid in NSCLC cells. Collectively, the present study demonstrated that C17:0 is an effective agent against NSCLC cells in vitro and the results may imply that the intake of C17:1 or C17:0‑rich food may be beneficial during the treatment of NSCLC.

Kerdidani D, Chouvardas P, Arjo AR, et al.
Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma.
Nat Commun. 2019; 10(1):1405 [PubMed] Free Access to Full Article Related Publications
Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

Giannopoulou AF, Velentzas AD, Konstantakou EG, et al.
Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite the initial chemosensitivity, the majority of treated patients will eventually develop chemoresistance, which severely reduces their survival expectancy. Since chromatin regulation genes are more frequently mutated in muscle-invasive bladder cancer, as compared to other epithelial tumors, targeted therapies against chromatin aberrations in chemoresistant clones may prove beneficial for the disease. "Acetyl-chromatin" homeostasis is regulated by the opposing functions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The HDAC/SIRT (super-)family contains 18 members, which are divided in five classes, with each family member being differentially expressed in normal urinary bladder tissues. Since a strong association between irregular HDAC expression/activity and tumorigenesis has been previously demonstrated, we herein attempt to review the accumulated published evidences that implicate HDACs/SIRTs as critical regulators in urothelial bladder cancer. Moreover, the most extensively investigated HDAC inhibitors (HDACis) are also analyzed, and the respective clinical trials are also described. Interestingly, it seems that HDACis should be preferably used in drug-combination therapeutic schemes, including radiation.

Moustaka K, Maleskou E, Lambrianidou A, et al.
Docosahexaenoic Acid Inhibits Proliferation of EoL-1 Leukemia Cells and Induces Cell Cycle Arrest and Cell Differentiation.
Nutrients. 2019; 11(3) [PubMed] Free Access to Full Article Related Publications
Τhe effect of docosahexaenoic acid (DHA, an omega-3 polyunsaturated fatty acid) upon the proliferation of EoL-1 (Eosinophilic leukemia) cell line was assessed, while additional cellular events during the antiproliferative action were recorded. DHA inhibited EoL-1 cells growth dose-dependently by inducing growth arrest at G0/1 phase of the cell cycle. After DHA addition to the cells, the expression of

Zografos E, Anagnostopoulos AK, Papadopoulou A, et al.
Serum Proteomic Signatures of Male Breast Cancer.
Cancer Genomics Proteomics. 2019 Mar-Apr; 16(2):129-137 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To date, the elucidation of serum protein alterations in male breast cancer (MBC) has not been extensively studied, due to the rarity of the disease.
MATERIALS AND METHODS: In the present work, two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) were employed to detect differences in serum protein expression between patients with MBC and healthy controls.
RESULTS: A panel of differentially expressed serum proteins was identified, including proteins involved in the regulation of the cell cycle [e.g. cell division cycle 7-related protein kinase (CDC7)], in mitochondrial function [e.g. mitochondrial aldehyde dehydrogenase (ALDH2) and dimethyladenosine transferase 1 (TFB1M)], in lipid metabolism and transport [e.g. apolipoprotein A-I (APOA1) and E (APOE)], in apoptosis and immune response [e.g. CD5 antigen-like (CD5L), clusterin (CLUS) and C-C motif chemokine 14 (CCL14)], in transcription (e.g. protein SSX3 and signal transducer and activator of transcription 3 (STAT3)], in invasion and metastasis (e.g. alpha-2-HS-glycoprotein (FETUA)], in estrogen synthesis [aromatase (CYP19A1)] and other diverse biological roles [e.g. actin-related protein 2/3 complex subunit 4 (ARPC4), dual specificity mitogen-activated protein kinase kinase 4 (MP2K4), ectoderm-neural cortex protein 1 (ENC1), and matrix metalloproteinase-27 (MMP27)].
CONCLUSION: These findings provide valuable insight into the distinct clinicopathological features of MBC and indicate that select serum proteomic markers may help improve MBC management.

Chrysovergis A, Papanikolaou VS, Tsiambas E, et al.
Digital Analysis of BCL2 Expression in Laryngeal Squamous Cell Carcinoma.
Anticancer Res. 2019; 39(3):1253-1257 [PubMed] Related Publications
BACKGROUND: Deregulation of apoptosis is critical regarding the development and progression of malignancies, including laryngeal squamous cell carcinoma (LSCC). B-Cell lymphoma 2 (BCL2) (gene locus:18q21.33), located on the outer mitochondrial membrane, acts mainly as an anti-apoptotic factor suppressing and blocking apoptotic signal transduction.
MATERIALS AND METHODS: Fifty (n=50) primary LSCC tissue sections were used. Immunohistochemistry and digital image analysis were implemented for evaluating BCL2 protein expression levels.
RESULTS: High BCL2 protein expression levels were observed in 21/50 (42%) LSCC tissue sections, whereas the remaining cases (n=29) demonstrated a low expression. Overall, BCL2 expression was associated with grade (p=0.046) and anatomical region of the examined malignancies (transglottic, p=0.047). Interestingly, high BCL2 expression levels were strongly associated with radiotherapy-based only regimens (p=0.01) in corresponding patients.
CONCLUSION: BCL2 overexpression was found to be correlated with an aggressive phenotype (advanced grade of differentiation) in LSCC, also demonstrating a potential selective anatomic localization (transglotic region). Additionally, BCL2 overexpression appears to be a negative regulator for successful radiotherapy implementation by reducing the apoptotic process in patients.

Lee YJ, Kim SY, Lee C
Axl is a novel target of celastrol that inhibits cell proliferation and migration, and increases the cytotoxicity of gefitinib in EGFR mutant non‑small cell lung cancer cells.
Mol Med Rep. 2019; 19(4):3230-3236 [PubMed] Related Publications
Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‑TKI) is an excellent therapeutic agent to treat EGFR mutation‑positive non‑small cell lung cancer (NSCLC). However, the initial response decreases as chemoresistance develops. In the present study, gefitinib‑resistant EGFR mutant NSCLC PC‑9/GR cells were established to examine the characteristics and mechanisms associated with chemoresistance. Axl expression in PC‑9/GR cells was transcriptionally upregulated, since Axl protein and mRNA expression levels were identified to be increased according to western blot analysis and reverse transcription polymerase chain reaction results. The inhibitory effect of celastrol on Axl protein expression level, cell viability and clonogenicity were identified in parental and gefitinib‑resistant PC‑9 cells. In addition, treatment of PC‑9/GR cells with celastrol and gefitinib in combination was demonstrated to synergistically suppress Axl protein expression level, cell proliferation and migration. Taken together, upregulation of Axl expression seems to be associated with chemoresistance of PC‑9/GR cells. Furthermore, celastrol targets Axl to exert its anticancer effects in order to increase the susceptibility of PC‑9/GR cells to gefitinib and overcome chemoresistance.

Leonardi DB, Anselmino N, Brandani JN, et al.
Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.

Anestis A, Sarantis P, Theocharis S, et al.
Estrogen receptor beta increases sensitivity to enzalutamide in androgen receptor-positive triple-negative breast cancer.
J Cancer Res Clin Oncol. 2019; 145(5):1221-1233 [PubMed] Related Publications
PURPOSE: Androgen receptor (AR) is playing an important role in the progression of a subset of TNBC. We evaluated the impact of ERβ expression along with anti-AR drugs in AR-positive TNBC.
METHODS: ERβ expression was examined in AR-positive TNBC cell line using MTT assay, scratch and Annexin V-FITC assay in the presence or absence of anti-androgens. Protein levels of involved molecules were assessed using Western blot. Receptors' localization was detected by immunofluorescence and their physical association was examined using proximity ligation assay (PLA), which enables the visualization of interacting proteins in fixed cells and tissues.
RESULTS: Transient transfection of ERβ in MDA-MB 453 AR-positive TNBC cell line significantly inhibited cell proliferation, metastatic potential and induced apoptosis. ERβ expression reversed the aggravating role of AR in both indirect and direct ways. Indirectly, ERβ decreased AR activation through the inhibition of PI3K/AKT signaling pathway. Directly, ERβ formed heterodimers with AR in MDA-MB 453 cells and in human tissue samples impeding AR from forming homodimers. Enzalutamide is a more potent anti-androgen in AR + TNBC compared to bicalutamide. ERβ expression increased the sensitivity of MDA-MB 453 cells to anti-androgens and especially to enzalutamide. The administration of enzalutamide enhanced AR:ERβ heterodimers formation increasing the anti-tumor capacity of ERβ.
CONCLUSIONS: Collectively, our results provide evidence for a novel mechanism by which ERβ exerts oncosuppressive effect in AR-positive TBNC through direct and indirect interactions with AR. Moreover, ERβ expression may identify a new subset of TNBC that would respond more favorable to anti-androgens.

Yapijakis C, Papakosta V, Vassiliou S
In Vivo. 2019 Mar-Apr; 33(2):559-562 [PubMed] Free Access to Full Article Related Publications
The association of the high blood pressure D variant of the angiotensin-converting enzyme (ACE) gene with medication-related jaw osteonecrosis (MRONJ) is described in two Greek patients. The first patient, a 73-year-old man, took zolendronate, 4 mg/100 ml IV once per month for two years for prostate cancer and bone metastases. Three months after drug discontinuation, extraction of the first premolar was performed. After the intervention, he suffered from osteonecrosis of the mandible. He presented with hypertension and genetic testing revealed that he was homozygous for the high blood pressure D variant of the ACE gene. The second patient, a 65 years old woman, took denosumab, 120 mg subcutaneously once per month for 6 months for possible bone metastases from breast cancer. Three months after extraction of the first molar, she suffered from MRONJ. He also presented with hypertension and genetic testing revealed that she had the high blood pressure D variant of the ACE gene in a heterozygous state, which moderately predisposes to hypertension. To our knowledge, this is the first report indicating that genetic predisposition to hypertension may increase risk for MRONJ.

Vassiliou AG, Siaterli MZ, Frakolaki E, et al.
L-Dopa decarboxylase interaction with the major signaling regulator ΡΙ3Κ in tissues and cells of neural and peripheral origin.
Biochimie. 2019; 160:76-87 [PubMed] Related Publications
L-Dopa decarboxylase (DDC) catalyzes the decarboxylation of L-Dopa to dopamine and 5-hydroxytryptophan (5-HTP) to serotonin. Although DDC has been purified from a variety of peripheral organs, including the liver, kidney and pancreas, the physiological significance of the peripherally expressed enzyme is not yet fully understood. DDC has been considered as a potential novel biomarker for various types of cancer, however, the role of DDC in the development of hepatocellular carcinoma (HCC) remains to be evaluated. Phosphatidylinositol 3-kinase (PI3K), on the other hand, has been shown to play a key role in the tumorigenesis, proliferation, metastasis, apoptosis, and angiogenesis of HCC by regulating gene expression. We initially identified the interaction of DDC with PI3K by means of the phage display methodology. This association was further confirmed in human hepatocellular carcinoma cell lines, human embryonic kidney cells, human neuroblastoma cells, as well as mouse brain, by the use of specific antibodies raised against DDC and PI3K. Functional aspects of the above interaction were studied upon treatment with the DDC inhibitor carbidopa and the PI3K inhibitor LY294002. Interestingly, our data demonstrate the expression of the neuronal type DDC mRNA in HCC cells. The present investigation provides new evidence on the possible link of DDC with the PI3K pathway, underlining the biological significance of this complex enzyme.

Giannopoulou AF, Konstantakou EG, Velentzas AD, et al.
Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Skin cancer represents the most common human malignancy, and it includes BCC, SCC, and melanoma. Since melanoma is one of the most aggressive types of cancer, we have herein attempted to develop a gene-specific intron retention signature that can distinguish BCC and SCC from melanoma biopsy tumors.
METHODS: Intron retention events were examined through RT-sqPCR protocols, using total RNA preparations derived from BCC, SCC, and melanoma Greek biopsy specimens. Intron-hosted miRNA species and their target transcripts were predicted via the miRbase and miRDB bioinformatics platforms, respectively. Ιntronic ORFs were recognized through the ORF Finder application. Generation and visualization of protein interactomes were achieved by the IntAct and Cytoscape softwares, while tertiary protein structures were produced by using the I-TASSER online server.

Mentis AA, Boziki M, Grigoriadis N, Papavassiliou AG
Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword.
Cell Mol Life Sci. 2019; 76(13):2477-2486 [PubMed] Related Publications
Helicobacter pylori (H. pylori) infection affects an estimated 4.4 billion people globally. Moreover, H. pylori presents the most significant risk factor for gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and it is the first example of bacterial infection linked to carcinogenesis. Here, we contend that H. pylori research, which focuses on a cancer-causing pathogen resident in a relatively accessible organ, the stomach, could constitute an exemplar for microbial-related carcinogenesis in less tractable organs, such as the pancreas and lung. In this context, molecular biological approaches that could reap rewards are reviewed, including: (1) gastric cancer dynamics, particularly the role of stem cells and the heterogeneity of neoplastic cells, which are currently being investigated at the single-cell sequencing level; (2) mechanobiology, and the role of three-dimensional organoids and matrix metalloproteases; and (3) the connection between H. pylori and host pathophysiology and the gut microbiome. In the context of H. pylori's contribution to gastric cancer, several important conundrums remain to be fully elucidated. From among them, this article discusses (1) why H. pylori infection, which causes both gastric and duodenal inflammation, is only linked to gastric cancer; (2) whether a "precision oncomicrobiology" approach could enable a fine-tuning of the expression of only cancer-implicated H. pylori genes while maintaining beneficial H. pylori-mediated factors in extra-gastric tissues; and (3) the feasibility of using antibiotics targeting the microbial DNA damage system, which shares commonalities with mechanisms for human cell replication, as chemopreventives. Additional therapeutic perspectives are also discussed.

Liu P, Xiang Y, Liu X, et al.
Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer.
Molecules. 2019; 24(3) [PubMed] Free Access to Full Article Related Publications
Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a triterpene hydrocarbon compound isolated from plants of various families and genera, elicits anticancer effects in a variety of cancer types. However, whether CuB is a viable treatment option for gefitinib-resistant (GR) NSCLC remains unclear. Here, we investigated the anticancer effects and underlying mechanisms of CuB. We report that CuB inhibited the growth and invasion of GR NSCLC cells and induced apoptosis. The inhibitory effect of CuB occurred through its promotion of the lysosomal degradation of EGFR and the downregulation of the cancerous inhibitor of protein phosphatase 2A/protein phosphatase 2A/Akt (CIP2A/PP2A/Akt) signaling axis. CuB and cisplatin synergistically inhibited tumor growth. A xenograft tumor model indicated that CuB inhibited tumor growth in vivo. Immunohistochemistry results further demonstrated that CuB decreased EGFR and CIP2A levels in vivo. These findings suggested that CuB could suppress the growth and invasion of GR NSCLC cells by inducing the lysosomal degradation of EGFR and by downregulating the CIP2A/PP2A/Akt signaling axis. Thus, CuB may be a new drug candidate for the treatment of GR NSCLC.

Hsu YL, Yen MC, Chang WA, et al.
CXCL17-derived CD11b
Breast Cancer Res. 2019; 21(1):23 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis is the major cause of death from breast cancer. Colonization and adaption of metastatic cells in distant organs is a rate-limiting step of the cancer spreading. The underlying mechanisms responsible for the colonization of breast cancer to lung metastatic niches are not fully understood.
METHODS: Specific gene contributions to lung metastasis were identified by comparing gene profiles of 4T1 tumors metastasizing to various organs via microarray. The oncogenic properties CXCL17 were examined by in vivo spontaneous metastasis mouse model. The chemotactic activity of CXCL17 on CD11b
RESULTS: Here, we demonstrate that breast cancer cells secrete CXCL17, which increases the accumulation of CD11b
CONCLUSION: Our study reveals that MDSCs derived by CXCL17 contribute to the establishment of a lung metastatic niche by PDGF-BB secretion and provide a rationale for development of CXCL17 or PDGF-BB antagonists to inhibit or prevent lung metastasis in cases of breast cancer.

Ren J, Shang L, Wang Q, Li J
Ranking Cancer Proteins by Integrating PPI Network and Protein Expression Profiles.
Biomed Res Int. 2019; 2019:3907195 [PubMed] Free Access to Full Article Related Publications
Proteomics, the large-scale analysis of proteins, is contributing greatly to understanding gene function in the postgenomic era. However, disease protein ranking using shotgun proteomics data has not been fully evaluated. In this study, we prioritized disease-related proteins by integrating the protein-protein interaction (PPI) network and protein differential expression profiles from colon and rectal cancer (CRC) or breast cancer (BC) proteomics. We applied Local Ranking (LR) and Global Ranking (GR) methods in network with three kinds of protein sets as a priori knowledge, which were known disease proteins (KDPs) that were collected from the Online Mendelian Inheritance in Man (OMIM) database, differentially expressed proteins (DEPs), and the collection of KDPs and their direct neighborhood with differential expression (eKDPs). The cross-validations showed that GR method outperformed LR method while using eKDPs as the initial training showed significantly higher accuracy compared to using the other two a priori sets. And then we validated the top ranked proteins using RNAi-based loss-of-function screens in the DepMap database. The results showed that 75% of top 20 proteins in CRC are necessary for tumor survival. In summary, the network-based Global Ranking with protein differential expression can efficiently prioritize cancer-related proteins and discover new candidate cancer genes or proteins.

Kalyvianaki K, Panagiotopoulos AA, Malamos P, et al.
Membrane androgen receptors (OXER1, GPRC6A AND ZIP9) in prostate and breast cancer: A comparative study of their expression.
Steroids. 2019; 142:100-108 [PubMed] Related Publications
Accumulating evidence during the last decades revealed that androgens exert membrane-initiated actions leading to the modulation of significant cellular processes, important for cancer cell growth and metastasis (including prostate and breast), that involve signaling via specific kinases. Collectively, many nonclassical, cell surface-initiated androgen actions are mediated by novel membrane androgen receptors (mARs), unrelated to nuclear androgen receptors. Recently, our group identified the G protein coupled oxo-eicosanoid receptor 1 (OXER1) (a receptor of the arachidonic acid metabolite, 5-oxoeicosatetraenoic acid, 5-oxoETE) as a novel mAR involved in the rapid effects of androgens. However, two other membrane proteins, G protein-coupled receptor family C group 6 member A (GPRC6A) and zinc transporter member 9 (ZIP9) have also been portrayed as mARs, related to the extranuclear action of androgens. In the present work, we present a comparative study of in silico pharmacology, gene expression and immunocytochemical data of the three receptors in various prostate and breast cancer cell lines. Furthermore, we analyzed the immunohistochemical expression of these receptors in human tumor and non-tumoral specimens and provide a pattern of expression and intracellular distribution.

Sakai Y, Miyazawa M, Komura T, et al.
Distinct chemotherapy-associated anti-cancer immunity by myeloid cells inhibition in murine pancreatic cancer models.
Cancer Sci. 2019; 110(3):903-912 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti-tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr-1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells. In addition, there were increased numbers of myeloid cells expressing CD11b+ and Gr-1+ in peripheral blood. When mice with PDAC tumors in the intraperitoneal cavity or liver were treated with GEM, numbers of myeloid cells in tumor tissues and in peripheral blood decreased. In contrast, numbers of CD4+ or CD8+ cells increased. In peripheral blood, the numbers of CD8+ cells expressing interferon-gamma (IFN-γ) were higher in GEM-treated mice than in untreated mice. In addition, GEM treatment in combination with myeloid cell depletion further prolonged the survival of PDAC mice. The gene expression profile of peripheral blood in myeloid cell-depleted PDAC mice treated with GEM showed biological processes related to anti-cancer immunity, such as natural killer cell-mediated cytotoxicity, type I IFN signaling, and co-stimulatory signaling for T cell activation. Thus, in PDAC murine models, GEM treatment was associated with an immune response consistent with an anti-cancer effect, and depletion of myeloid-lineage cells played an important role in enhancing anti-cancer immunity associated with GEM treatment.

Panagopoulou M, Karaglani M, Balgkouranidou I, et al.
Circulating cell-free DNA in breast cancer: size profiling, levels, and methylation patterns lead to prognostic and predictive classifiers.
Oncogene. 2019; 38(18):3387-3401 [PubMed] Related Publications
Blood circulating cell-free DNA (ccfDNA) is a suggested biosource of valuable clinical information for cancer, meeting the need for a minimally-invasive advancement in the route of precision medicine. In this paper, we evaluated the prognostic and predictive potential of ccfDNA parameters in early and advanced breast cancer. Groups consisted of 150 and 16 breast cancer patients under adjuvant and neoadjuvant therapy respectively, 34 patients with metastatic disease and 35 healthy volunteers. Direct quantification of ccfDNA in plasma revealed elevated concentrations correlated to the incidence of death, shorter PFS, and non-response to pharmacotherapy in the metastatic but not in the other groups. The methylation status of a panel of cancer-related genes chosen based on previous expression and epigenetic data (KLK10, SOX17, WNT5A, MSH2, GATA3) was assessed by quantitative methylation-specific PCR. All but the GATA3 gene was more frequently methylated in all the patient groups than in healthy individuals (all p < 0.05). The methylation of WNT5A was statistically significantly correlated to greater tumor size and poor prognosis characteristics and in advanced stage disease with shorter OS. In the metastatic group, also SOX17 methylation was significantly correlated to the incidence of death, shorter PFS, and OS. KLK10 methylation was significantly correlated to unfavorable clinicopathological characteristics and relapse, whereas in the adjuvant group to shorter DFI. Methylation of at least 3 or 4 genes was significantly correlated to shorter OS and no pharmacotherapy response, respectively. Classification analysis by a fully automated, machine learning software produced a single-parametric linear model using ccfDNA plasma concentration values, with great discriminating power to predict response to chemotherapy (AUC 0.803, 95% CI [0.606, 1.000]) in the metastatic group. Two more multi-parametric signatures were produced for the metastatic group, predicting survival and disease outcome. Finally, a multiple logistic regression model was constructed, discriminating between patient groups and healthy individuals. Overall, ccfDNA emerged as a highly potent predictive classifier in metastatic breast cancer. Upon prospective clinical evaluation, all the signatures produced could aid accurate prognosis.

Ma G, Zhu J, Liu F, Yang Y
Long Noncoding RNA LINC00460 Promotes the Gefitinib Resistance of Nonsmall Cell Lung Cancer Through Epidermal Growth Factor Receptor by Sponging miR-769-5p.
DNA Cell Biol. 2019; 38(2):176-183 [PubMed] Free Access to Full Article Related Publications
The vital roles of long noncoding RNAs (lncRNAs) in the nonsmall cell lung cancer (NSCLC) tumorigenesis are increasingly important. This work aims to investigate the role of lncRNA LINC00460 in the gefitinib resistance of NSCLC cells and discover its relevant mechanism. Our finding reveals that the expression of lncRNA LINC00460 is upregulated in the gefitinib-resistant NSCLC tissue and cells, and closely correlated with advanced tumor stage and clinical poor prognosis outcome. Gain and loss functional assays are performed in gefitinib-resistant NSCLC cells (A549/GR), stating that LINC00460 facilitates the 50% inhibitive concentration of gefitinib for NSCLC cells, multidrug-resistant-related proteins (P-gp, MRP1, and BCRP), as well as the invasion. In vivo, LINC00460 silencing represses the tumor growth. Bioinformatics prediction tools and luciferase analysis confirm that the upregulated LINC00460 sponged miR-769-5p in NSCLC cells; moreover, epidermal growth factor receptor (EGFR) is identified as a direct target gene of miR-769-5p. Verification experiments confirm that the restoration of EGFR could weaken the sensibility of NSCLC cells toward the gefitinib. In conclusion, our result demonstrates that LINC00460 plays a pivotal role in gefitinib resistance of NSCLC cells by targeting EGFR through sponging miR-769-5p. This finding might serve as a therapeutic target for NSCLC.

Gargalionis AN, Basdra EK, Papavassiliou AG
Polycystins in Colorectal Cancer.
Int J Mol Sci. 2018; 20(1) [PubMed] Free Access to Full Article Related Publications
Cell and extracellular matrix (ECM) biomechanics emerge as a distinct feature during the development and progression of colorectal cancer (CRC). Polycystins are core mechanosensitive protein molecules that mediate mechanotransduction in a variety of epithelial cells. Polycystin-1 (PC1) and polycystin-2 (PC2) are engaged in signal transduction mechanisms and during alterations in calcium influx, which regulate cellular functions such as proliferation, differentiation, orientation, and migration in cancer cells. Recent findings implicate polycystins in the deregulation of such functions and the formation of CRC invasive phenotypes. Polycystins participate in all aspects of the cell's biomechanical network, from the perception of extracellular mechanical cues to focal adhesion protein and nuclear transcriptional complexes. Therefore, polycystins could be employed as novel biomarkers and putative targets of selective treatment in CRC.

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