scholarly journals Prognostic value of TERF1 expression in prostate cancer

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Gabriel Arantes dos Santos ◽  
Nayara Izabel Viana ◽  
Ruan Pimenta ◽  
Vanessa Ribeiro Guimarães ◽  
Juliana Alves de Camargo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Cell Lines ◽  
Normal Tissue ◽  
Receptor Expression ◽  
Telomere Maintenance ◽  
Localized Prostate Cancer ◽  
Cancer Tissue ◽  
Mrna Levels ◽  
Clinical Specimens

Abstract Background Telomere dysfunction is one of the hallmarks of cancer and is crucial to prostate carcinogenesis. TERF1 is a gene essential to telomere maintenance, and its dysfunction has already been associates with several cancers. TERF1 is a target of miR-155, and this microRNA can inhibit its expression and promotes carcinogenesis in breast cancer. We aim to analyze TERF1, in gene and mRNA level, involvement in prostate cancer progression. Results Alterations in TERF1 DNA were evaluated using datasets of primary tumor and castration-resistant tumors (CRPC) deposited in cBioportal. The expression of TERF1 mRNA levels was assessed utilizing TCGA datasets, clinical specimens, and metastatic prostate cancer cell lines (LNCaP, DU145, and PC3). Six percent of localized prostate cancer presents alterations in TERF1 (the majority of that was amplifications). In the CRPC cohort, 26% of samples had TERF1 amplification. Patients with TERF1 alterations had the worst overall survival only on localized cancer cohort (p = 0.0027). In the TCGA cohort, mRNA levels of TERF1 were downregulated in comparison with normal tissue (p = 0.0013) and upregulated in tumors that invade lymph nodes (p = 0.0059). The upregulation of TERF1 is also associated with worst overall survival (p = 0.0028) and disease-free survival (p = 0.0023). There is a positive correlation between TERF1 and androgen receptor expression in cancer tissue (r = 0.53, p < 0.00001) but not on normal tissue (r = − 0.16, p = 0.12). In the clinical specimens, there is no detectable expression of TERF1 and upregulation of miR-155 (p = 0.0348). In cell lines, TERF1 expression was higher in LNCaP and was progressively lower in DU145 and PC3 (p = 0.0327) with no differences in miR-155 expression. Conclusion Amplification/upregulation of TERF1 was associated with the worst prognostic in localized prostate cancer. Our results corroborate that miR-155 regulates TERF1 expression in prostate cancer. TERF1 has the potential to become a biomarker in prostate cancer.

MiR-27a-3p: An AR-modulatory microRNA with a distinct role in prostate cancer progression and therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 193-193
Author(s):  
Foteini Kalofonou ◽  
Ailsa Sita-Lumsden ◽  
Damien Leach ◽  
Claire Fletcher ◽  
Jonathan Waxman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Normal Tissue ◽  
Target Genes ◽  
Tumour Suppressor ◽  
Mrna Levels ◽  
Protein Levels ◽  
Androgen Ablation ◽  
Castrate Resistant

193 Background: Prostate cancer (PCa) is an androgen dependent malignancy. PCa patients initially respond to androgen ablation but eventually the disease becomes castrate resistant. MicroRNAs (miRs) are considered to be master regulators of gene expression and could be potential biomarkers and therapeutic targets for PCa. We previously showed miR-27a-3p to be an androgen receptor (AR)-modulatory oncomiR, with a role in PCa progression. Methods: RNA sequencing was carried out on xenograft tumours treated with an inhibitory antisense oligonucleotide for miR-27a (ASO-27a), or control. Differentially expressed genes were cross-referenced with publicly available patient tissue datasets. ASO-27a was transfected in a panel of PCa cell lines mirroring disease progression, to verify changes in transcriptional and translational levels. Immunohistochemical analysis of encoded proteins was undertaken in a cohort of 46 PCa patients with Gleason 3+4 or 4+3 disease and compared with normal tissue-control. Results: Putative target genes tested included the tumour suppressor HIP2, the oncogenes SRC3, YAP, and PAX3, which can act both as oncogene and tumour suppressor. MRNA or protein levels of the majority of those genes tested were upregulated after ASO-27a treatment of PCa cell lines. In 22Rv1 cells, HIPK2 mRNA levels were significantly upregulated with ASO-27a (p = 0.0137), while protein levels were downregulated . PAX3 mRNA levels were significantly reduced by ASO-27a in 22Rv1 cells (p = 0.0364), while protein levels were significantly increased (p = 0.0112). Immunohistochemically, PAX3 protein was lower in Gleason 7 tumours than in normal tissue, while YAP expression was higher in patients with Gleason 4+3, relative to those with 3+4. SRC3 immunostaining was slightly, but not significantly, higher in patients with 3+4 compared to 4+3. Conclusions: MiR-27a-3p is an AR-modulatory oncomiR in PCa, with potential as a therapeutic target. MiR-27a interaction with its target genes and especially HIPK2, YAP, SRC3 and PAX3 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant disease, through ASO-27a inhibition.

scholarly journals Metastasis free survival (MFS) is a surrogate for overall survival (OS) in localized prostate cancer (CaP)

2016 ◽  
Vol 27 ◽  
pp. vi243 ◽  
Author(s):  
W. Xie ◽  
C. Sweeney ◽  
M. Regan ◽  
M. Nakabayashi ◽  
M. Buyse ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Localized Prostate Cancer ◽  
Free Survival

scholarly journals Expression Profiling of Nuclear Receptors in the NCI60 Cancer Cell Panel Reveals Receptor-Drug and Receptor-Gene Interactions

2010 ◽  
Vol 24 (6) ◽  
pp. 1287-1296 ◽  
Author(s):  
Susan Holbeck ◽  
Jianjun Chang ◽  
Anne M. Best ◽  
Angie L. Bookout ◽  
David J. Mangelsdorf ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Cell Lines ◽  
Nuclear Receptors ◽  
Cancer Cell ◽  
Expression Profiling ◽  
Expression Profiles ◽  
Receptor Gene ◽  
Receptor Expression ◽  
Cancer Drug ◽  
Mrna Levels

Abstract We profiled the expression of the 48 human nuclear receptors (NRs) by quantitative RT-PCR in 51 human cancer cell lines of the NCI60 collection derived from nine different tissues. NR mRNA expression accurately classified melanoma, colon, and renal cancers, whereas lung, breast, prostate, central nervous system, and leukemia cell lines exhibited heterogeneous receptor expression. Importantly, receptor mRNA levels faithfully predicted the growth-inhibitory qualities of receptor ligands in nonendocrine tumors. Correlation analysis using NR expression profiles and drug response information across the cell line panel uncovered a number of new potential receptor-drug interactions, suggesting that in these cases, individual receptor levels may predict response to chemotherapeutic interventions. Similarly, by cross-comparing receptor levels within our expression dataset and relating these profiles to existing microarray gene expression data, we defined interactions among receptors and between receptors and other genes that can now be mechanistically queried. This work supports the strategy of using NR expression profiling to classify various types of cancer, define NR-drug interactions and receptor-gene networks, predict cancer-drug sensitivity, and identify druggable targets that may be pharmacologically manipulated for potential therapeutic intervention.

417 Biochemical disease-free and overall survival of treatments for localized prostate cancer: Cohort study with a 7 year follow-up

2014 ◽  
Vol 13 (1) ◽  
pp. e417
Author(s):  
X. Bonet ◽  
J.F. Suárez ◽  
M. Castells ◽  
A.J. Vicéns ◽  
E. Franco ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Cohort Study ◽  
Localized Prostate Cancer ◽  
Disease Free

scholarly journals Survival and mortality of elderly men with localized prostate cancer managed with primary androgen deprivation therapy or by primary observation

2020 ◽  
Author(s):  
Heikki Seikkula ◽  
Peter J. Boström ◽  
Karri Seppä ◽  
Janne Pitkäniemi ◽  
Nea Malila ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Localized Prostate Cancer ◽  
Curative Treatment ◽  
Entire Study ◽  
Treatment Groups ◽  
Age Cohorts ◽  
Cancer Aggressiveness

Abstract Background: Androgen deprivation therapy (ADT) remains a primary treatment for localized prostate cancer (PCa) even though there is no evidence that its use is beneficial in the absence of curative treatment.Methods: Men aged ≥70 years (n = 16534) diagnosed with localized PCa from 1985 to 2014 and managed either with primary observation or ADT in the absence of curative treatment were included. The cases were identified from the population-based Finnish Cancer Registry. We estimated the standardized mortality ratios (SMR) for overall mortality by treatment group. We determined the relative risk (RR) of PCa-specific mortality (PCSM) and other-cause mortality between the two treatment groups. Survival was determined using the life table method. Two age groups (70–79 years and ≥80 years) and three calendar time cohorts (1985–1994, 1995–2004, and 2005–2014) were compared following adjustment of propensity score matching between the treatment groups with four covariates (age, year of diagnosis, educational level, and hospital district). Follow-up continued until death or until December 31, 2015. Results: Patients in the observation group had lower overall SMRs than those in the ADT group in both age cohorts over the entire study period. PCSM was higher in men aged 70–79 years undergoing primary ADT compared to those managed by observation only (RR: 1.70, 95% confidence interval [CI]: 1.29–2.23 [1985–1994]; RR 1.55, 95% CI: 1.35–1.84 [1995–2004]; and RR 2.71, 95% CI: 2.08–3.53 [2005–2014]); p = 0.005 for periodic trend. A similar trend over time was also observed in men aged >80 years; (p for age–period interaction = 0.237). Overall survival was also higher among men in their 70’s managed by observation compared to those undergoing ADT.Conclusions: Primary ADT within four months period from diagnosis is not associated with improved long-term overall survival or decreased PCSM compared to primary conservative management for men with localized PCa. However, this observational study’s conclusions should be weighted with confounding factors related to cancer aggressiveness and comorbidities.

IMMU-12. TUMOR CELL IDO ENHANCES IMMUNE SUPPRESSION AND DECREASES SURVIVAL INDEPENDENT OF TRYPTOPHAN METABOLISM IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi94
Author(s):  
Lijie Zhai ◽  
April Bell ◽  
Erik Ladomersky ◽  
Kristen Lauing ◽  
Lakshmi Bollu ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cell Lines ◽  
Factor H ◽  
Lower Grade ◽  
Complement Factor ◽  
Mrna Levels ◽  
Wild Type ◽  
Human Gbm

Abstract OBJECTIVE Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is an immune checkpoint that’s characterized as a potent immunosuppressive mediator through its ability to metabolize tryptophan and wild-type IDH patient-resected glioblastoma (GBM) expresses IDO in ≥ 95% of cases. Recent findings from our group led us to investigate the alternative hypothesis that IDO possesses immunosuppressive effects that are independent of its associated metabolic activity. METHODS Murine GBM cell lines that overexpress either wild-type or enzyme-null IDO were created for in vivo characterization of IDO enzyme-independent immunosuppressive function. Microarray was conducted to identify human IDO expression-correlated genes, which were further investigated in human GBM cell lines, patient GBM tissues and plasma, as well as the TCGA database. Ex vivo cell co-culture assays and syngeneic mouse orthotopic GBM models were employed to study immunosuppressive mechanisms. RESULTS Here, we demonstrate that non-enzymic IDO activity decreases survival in experimental animals and increases the expression of immunosuppressive complement factor H (CFH) in human GBM. CFH mRNA levels positively correlate with those of IDO and many other immunosuppressive genes in patient resected GBM and can be applied as a prognostic marker in both lower grade gliomas and GBM. Similar to IDO, the increased expression of CFH in patient-resected glioma was positively correlated with an increased signature for regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs). High expression of CFH in tumor cells increases intratumoral Tregs levels and decreases overall survival in mice with GBM, while inducing tumor associated macrophage cell differentiation. CONCLUSIONS Here, we demonstrated that glioblastoma (GBM) cell IDO promotes the accumulation of intratumoral FoxP3+ regulatory T cells (Tregs) and tumor progression while decreasing overall survival - independent of IDO enzyme activity. Our study reveals a targetable non-metabolic IDO-dependent mechanism for future therapeutic intervention in patients with GBM.

scholarly journals Transcriptomic Profiling for the Autophagy Pathway in Colorectal Cancer

2020 ◽  
Vol 21 (19) ◽  
pp. 7101
Author(s):  
Justyna Gil ◽  
Paweł Karpiński ◽  
Maria M. Sąsiadek
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Field Cancerization ◽  
Cancer Tissue ◽  
Mrna Levels ◽  
Targeting Therapy ◽  
Autophagy Pathway ◽  
Using Data

The role of autophagy in colorectal cancer (CRC) pathogenesis appears to be crucial. Autophagy acts both as a tumor suppressor, by removing redundant cellular material, and a tumor-promoting factor, by providing access to components necessary for growth, metabolism, and proliferation. To date, little is known about the expression of genes that play a basal role in the autophagy in CRC. In this study, we aimed to compare the expression levels of 46 genes involved in the autophagy pathway between tumor-adjacent and tumor tissue, employing large RNA sequencing (RNA-seq) and microarray datasets. Additionally, we verified our results using data on 38 CRC cell lines. Gene set enrichment analysis revealed a significant deregulation of autophagy-related gene sets in CRC. The unsupervised clustering of tumors using the mRNA levels of autophagy-related genes revealed the existence of two major clusters: microsatellite instability (MSI)-enriched and -depleted. In cluster 1 (MSI-depleted), ATG9B and LAMP1 genes were the most prominently expressed, whereas cluster 2 (MSI-enriched) was characterized by DRAM1 upregulation. CRC cell lines were also clustered according to MSI-enriched/-depleted subgroups. The moderate deregulation of autophagy-related genes in cancer tissue, as compared to adjacent tissue, suggests a prominent field cancerization or early disruption of autophagy. Genes differentiating these clusters are promising candidates for CRC targeting therapy worthy of further investigation.

scholarly journals NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1861
Author(s):  
Tyler Sheetz ◽  
Joseph Mills ◽  
Anna Tessari ◽  
Megan Pawlikowski ◽  
Ashley E. Braddom ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Therapeutic Option ◽  
The United States ◽  
Mrna Levels ◽  
Advanced Stage ◽  
Castration Resistant Prostate Cancer ◽  
Single Chain

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa.

Survival Advantage From Higher-Dose Radiation Therapy for Clinically Localized Prostate Cancer Treated on the Radiation Therapy Oncology Group Trials

2000 ◽  
Vol 18 (14) ◽  
pp. 2740-2746 ◽  
Author(s):  
Richard Valicenti ◽  
Jiandong Lu ◽  
Miljenko Pilepich ◽  
Sucha Asbell ◽  
David Grignon
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Radiation Therapy ◽  
Radiation Dose ◽  
Radiation Therapy Oncology Group ◽  
Localized Prostate Cancer ◽  
Disease Specific Survival ◽  
Oncology Group ◽  
Dose Radiation ◽  
Disease Specific

PURPOSE: We evaluated the effect of external-beam radiation therapy on disease-specific survival (death from causes related to prostate cancer) and overall survival in men with clinically localized prostate cancer. METHODS: From 1975 to 1992, 1,465 men with clinically localized prostate cancer received radiation therapy on four Radiation Therapy Oncology Group phase III randomized trials and were pooled for this analysis. No one received androgen-deprivation therapy with his initial treatment. All original histology had central pathologic review for grading using the Gleason classification system. Total delivered radiation dose ranged from 60 to 78 Gy (median, 68.4 Gy). The median follow-up time was 8 years. RESULTS: A Cox regression model revealed that Gleason score was an independent predictor of disease-specific survival and overall survival. The 10-year disease-specific survival rates by Gleason score were as follows: score of 2 through 5, 85%; score of 6, 79%; score of 7, 62%; and score of 8 through 10, 43%. Stratifying outcome by this important prognostic factor revealed that higher radiation dose was a significant predictor for improved disease-specific survival and overall survival only for those patients whose cancers had Gleason scores of 8 through 10 (P < .05). After adjusting for clinical T stage, nodal status, and age, treating with a higher radiation dose was associated with a 29% lower relative risk of death from prostate cancer and 27% reduced mortality rate (P < .05). CONCLUSION: These data demonstrate that higher-dose radiation therapy can significantly reduce the risk of dying from prostate cancer in men with clinically localized disease. This survival benefit is restricted to men with poorly differentiated cancers.

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