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101. Abstract 3575: The OncoNetwork Consortium: A global collaborative research study on the development and verification of an Ion AmpliSeq RNA gene lung fusion panel

Author

Magdaleno, Susan M., primary, Cheng, Angie, additional, Petraroli, Rosella, additional, Sheils, Orla, additional, Tops, Bastiaan, additional, Corre, Delphine L., additional, Kurth, Henriette, additional, Blons, Helene, additional, Amato, Eliana, additional, Mafficini, Andrea, additional, Rachiglio, Anna Maria, additional, Reimann, Anne, additional, Noppen, Christoph, additional, Ainali, Chrysanthi, additional, Katayama, Jin, additional, Franco, Renato, additional, Feilotter, Harriet, additional, Schageman, Jeoffrey, additional, Cree, Ian, additional, Felton, Andrew, additional, Costa, Jose Luis, additional, Rico, Alain, additional, Scarpa, Aldo, additional, Machado, Jose Carlos, additional, Nishio, Kazuto, additional, Normanno, Nicola, additional, Ligtenberg, Marjolijn, additional, Vaughn, Cecily P., additional, Lacroix, Ludovic, additional, and Laurent-Puig, Pierre, additional

Published
2014
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103. The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer

Author

d'Adhemar, Charles J., primary, Spillane, Cathy D., additional, Gallagher, Michael F., additional, Bates, Mark, additional, Costello, Katie M., additional, Barry-O'Crowley, Jacqui, additional, Haley, Kathryn, additional, Kernan, Niamh, additional, Murphy, Ciara, additional, Smyth, Paul C., additional, O'Byrne, Ken, additional, Pennington, Stephen, additional, Cooke, Aoife A., additional, Ffrench, Brendan, additional, Martin, Cara M., additional, O'Donnell, Dearbhaile, additional, Hennessy, Bryan, additional, Stordal, Britta, additional, Finn, Stephen, additional, McCann, Amanda, additional, Gleeson, Noreen, additional, D'Arcy, Tom, additional, Flood, Brian, additional, O'Neill, Luke A. J., additional, Sheils, Orla, additional, O'Toole, Sharon, additional, and O'Leary, John J., additional

Published
2014
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105. Centrifugo-magnetophoretic particle separation.

Author

Kirby, Dan, Siegrist, Jonathan, Kijanka, Gregor, Zavattoni, Laëtitia, Sheils, Orla, O'Leary, John, Burger, Robert, Ducrée, Jens, Kirby, Dan, Siegrist, Jonathan, Kijanka, Gregor, Zavattoni, Laëtitia, Sheils, Orla, O'Leary, John, Burger, Robert, and Ducrée, Jens

Abstract

There has been a recent surge of research output on magnetophoretic lab-on-a-chip systems due to their prospective use in a range of applications in the life sciences and clinical diagnostics. Manifold applications for batch-mode or continuous-flow magnetophoretic separations of cells, proteins, and nucleic acids are found in bioanalytics, cell biology, and clinical diagnostics. To ensure stable hydrodynamic conditions and thus reproducible separation, state-of-the-art magnetophoretic lab-on-a-chip systems have been based on pressure-driven flow (Gijs in Microfluid Nanofluid 1:22–40, 2004; Pamme and Manz in Anal Chem 76:7250–7256, 2004; Pamme in Lab Chip 7:1644–1659, 2007; Karle et al. in Lab Chip 10:3284–3290, 2010), which involves rather bulky and costly instrumentation. In a flow-based system, suspended particles are following the liquid phase as a result of the Stokes drag, thus being fully exposed to divergent flow lines around obstacles and pump-induced pressure fluctuations. To eventually achieve more stable hydrodynamic conditions, improved control of magnetic particles, a more compact instrumentation footprint, and integration of high-performance upstream sample preparation, this work introduces a novel two-dimensional particle separation principle by combining magnetic deflection with centrifugal sedimentation in a stopped-flow mode (i.e., mere particle sedimentation). The experimental parameters governing our centrifugo-magnetophoretic system are the strength and orientation of the co-rotating magnetic field, the rotationally induced centrifugal field, and the size-dependent Stokes drag of the various particles with respect to the (residual) liquid phase. In this work, the following set of basic functional modes is demonstrated as proof-of-concept: separation of magnetic from non-magnetic particles, routing of magnetic particles based on control of the spin speed, and size separation of various magnetic particles. Finally, a biomimetic application involvi

Published
2012

106. Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer

Author

Maher, Stephen, Gillham, Charles, Duggan, Shane, Smyth, Paul, Miller, Nicola, Muldoon, Cian, O'Byrne, Kenneth, Sheils, Orla, Hollywood, Donal, Reynolds, John, Maher, Stephen, Gillham, Charles, Duggan, Shane, Smyth, Paul, Miller, Nicola, Muldoon, Cian, O'Byrne, Kenneth, Sheils, Orla, Hollywood, Donal, and Reynolds, John

Abstract

OBJECTIVE: This study explored gene expression differences in predicting response to chemoradiotherapy in esophageal cancer. PURPOSE:: A major pathological response to neoadjuvant chemoradiation is observed in about 40% of esophageal cancer patients and is associated with favorable outcomes. However, patients with tumors of similar histology, differentiation, and stage can have vastly different responses to the same neoadjuvant therapy. This dichotomy may be due to differences in the molecular genetic environment of the tumor cells. BACKGROUND DATA: Diagnostic biopsies were obtained from a training cohort of esophageal cancer patients (13), and extracted RNA was hybridized to genome expression microarrays. The resulting gene expression data was verified by qRT-PCR. In a larger, independent validation cohort (27), we examined differential gene expression by qRT-PCR. The ability of differentially-regulated genes to predict response to therapy was assessed in a multivariate leave-one-out cross-validation model. RESULTS: Although 411 genes were differentially expressed between normal and tumor tissue, only 103 genes were altered between responder and non-responder tumor; and 67 genes differentially expressed >2-fold. These included genes previously reported in esophageal cancer and a number of novel genes. In the validation cohort, 8 of 12 selected genes were significantly different between the response groups. In the predictive model, 5 of 8 genes could predict response to therapy with 95% accuracy in a subset (74%) of patients. CONCLUSIONS: This study has identified a gene microarray pattern and a set of genes associated with response to neoadjuvant chemoradiation in esophageal cancer. The potential of these genes as biomarkers of response to treatment warrants further investigation. Copyright © 2009 by Lippincott Williams & Wilkins.

Published
2009

107. Expanding applications of diagnostic tools

Author

Sheils, Orla

Subjects
Thyroid cancer -- Care and treatment, Thyroid cancer -- Research, Medical tests -- Usage, Biotechnology industry, Business
Abstract

Research in developing new diagnostic tools to identify markers, which indicate progression of thyroid cancer, is discussed.

Published
2006

108. Activated Eosinophils in Association with Enteric Nerves in Inflammatory Bowel Disease

Author

Smyth, Claire M., primary, Akasheh, Nadim, additional, Woods, Sara, additional, Kay, Elaine, additional, Morgan, Ross K., additional, Thornton, Margaret A., additional, O’Grady, Anthony, additional, Cummins, Robert, additional, Sheils, Orla, additional, Smyth, Peter, additional, Gleich, Gerald J., additional, Murray, Frank M., additional, and Costello, Richard W., additional

Published
2013
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109. Abstract 36: The OncoNetwork Consortium: A European Collaborative Research study on the development of an Ion AmpliSeq gene panel targeting hot spots in colon and lung cancers.

Author

Normanno, Nicola, primary, Petraroli, Rosella, additional, Rico, Alain, additional, Kurth, Henriette, additional, Tops, Bastiaan, additional, Amato, Eliana, additional, Mafficini, Andrea, additional, Le Corre, Delphine, additional, Rachiglio, Anna Maria, additional, Reiman, Anne, additional, Sheils, Orla, additional, Noppen, Christoph, additional, Rieber, Nora, additional, Mangion, Jonathan, additional, Ainali, Chrysanthi, additional, Lacroix, Ludovic, additional, Cree, Ian, additional, Ligtenberg, Marjolijn, additional, Felton, Andy, additional, Scarpa, Aldo, additional, and Laurent Puig, Pierre, additional

Published
2013
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110. Pre-Treatment of Platinum Resistant Ovarian Cancer Cells with an MMP-9/MMP-2 Inhibitor Prior to Cisplatin Enhances Cytotoxicity as Determined by High Content Screening

Author

Laios, Alexandros, primary, Mohamed, Bashir, additional, Kelly, Lynne, additional, Flavin, Richard, additional, Finn, Stephen, additional, McEvoy, Lynda, additional, Gallagher, Michael, additional, Martin, Cara, additional, Sheils, Orla, additional, Ring, Martina, additional, Davies, Anthony, additional, Lawson, Margaret, additional, Gleeson, Noreen, additional, D'Arcy, Tom, additional, d'Adhemar, Charles, additional, Norris, Lucy, additional, Langhe, Ream, additional, Saadeh, Feras, additional, O'Leary, John, additional, and O'Toole, Sharon, additional

Published
2013
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112. Tyrosine phosphorylation in the human duodenum

Author

KELLEHER, DERMOT P and SHEILS, ORLA

Subjects
Hepatology, Gastroentrology, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

PUBLISHED, Many growth factor receptors including the epidermal growth factor receptor function through tyrosine kinase activity. The aim of this study was to examine the constitutive level of tyrosine phosphorylation in the normal duodenum and in the hyperproliferative coeliac duodenum. A flow cytometric assay was devised using monoclonal antibody to phosphorylated (but not native) tyrosine residues to determine the levels of tyrosine phosphorylation in both CD3 positive intraepithelial lymphocytes and CD3 negative epithelial cells obtained by EDTA treatment of endoscopically obtained duodenal biopsy specimens. In addition, immunohistochemistry was performed on 18 formalin fixed coeliac duodenal biopsy specimens and eight control specimens. Tyrosine phosphorylation could be detected by flow cytometry on duodenal enterocytes and this expression was up regulated by pretreatment with epidermal growth factor. Tyrosine phosphorylation decreased with progression from the villus to the crypt, however, and was virtually undetectable on crypt enterocytes. Immunohistochemistry of the coeliac duodenum showed virtually absent tyrosine phosphorylation in the crypt. Increased tyrosine phosphorylation was detected in the infiltrating T cells. In conclusion, tyrosine phosphorylation in the duodenum is confined to the non-proliferative villous epithelium and is virtually undetectable in the proliferative crypt compartment. These findings suggest that tyrosine kinase activity is not a significant factor in the regulation of crypt cell proliferation in the human duodenum either in normal subjects or in coeliac disease patients., DK is a Wellcome Senior Fellow in Clinical Science. AL is supported by a grant from the Cancer Research Advancement Board. This work was supported by a grant from the Wellcome Trust.

Published
1995

114. Platelet Adhesion and Degranulation Induce Pro-Survival and Pro-Angiogenic Signalling in Ovarian Cancer Cells

Author

Egan, Karl, primary, Crowley, Darragh, additional, Smyth, Paul, additional, O'Toole, Sharon, additional, Spillane, Cathy, additional, Martin, Cara, additional, Gallagher, Michael, additional, Canney, Aoife, additional, Norris, Lucy, additional, Conlon, Niamh, additional, McEvoy, Lynda, additional, Ffrench, Brendan, additional, Stordal, Britta, additional, Keegan, Helen, additional, Finn, Stephen, additional, McEneaney, Victoria, additional, Laios, Alex, additional, Ducrée, Jens, additional, Dunne, Eimear, additional, Smith, Leila, additional, Berndt, Michael, additional, Sheils, Orla, additional, Kenny, Dermot, additional, and O'Leary, John, additional

Published
2011
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117. Inkjet-like printing of single-cells

Author

Yusof, Azmi, primary, Keegan, Helen, additional, Spillane, Cathy D., additional, Sheils, Orla M., additional, Martin, Cara M., additional, O'Leary, John J., additional, Zengerle, Roland, additional, and Koltay, Peter, additional

Published
2011
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122. FOXA1 Is a Potential Oncogene in Anaplastic Thyroid Carcinoma

Author

Nucera, Carmelo, primary, Eeckhoute, Jerome, additional, Finn, Stephen, additional, Carroll, Jason S., additional, Ligon, Azra H., additional, Priolo, Carmen, additional, Fadda, Guido, additional, Toner, Mary, additional, Sheils, Orla, additional, Attard, Marco, additional, Pontecorvi, Alfredo, additional, Nose, Vânia, additional, Loda, Massimo, additional, and Brown, Myles, additional

Published
2009
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123. miR-29b Expression Is Associated With Disease-Free Survival in Patients With Ovarian Serous Carcinoma

Author

Flavin, Richard, primary, Smyth, Paul, additional, Barrett, Ciara, additional, Russell, S., additional, Wen, Hannah, additional, Wei, Jianjun, additional, Laios, Alex, additional, O'Toole, Sharon, additional, Ring, M., additional, Denning, K., additional, Li, J., additional, Aherne, S., additional, Sammarae, D., additional, Aziz, N. A., additional, Alhadi, A., additional, Finn, Sephen P., additional, Loda, M., additional, B, Sheppard, additional, Sheils, Orla, additional, and O'Leary, John J., additional

Published
2009
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125. Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study

Author

Hornig, Mady, primary, Briese, Thomas, additional, Buie, Timothy, additional, Bauman, Margaret L., additional, Lauwers, Gregory, additional, Siemetzki, Ulrike, additional, Hummel, Kimberly, additional, Rota, Paul A., additional, Bellini, William J., additional, O'Leary, John J., additional, Sheils, Orla, additional, Alden, Errol, additional, Pickering, Larry, additional, and Lipkin, W. Ian, additional

Published
2008
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127. Potential role of miR-9 and miR-223 in recurrent ovarian cancer

Author

Laios, Alexandros, primary, O'Toole, Sharon, additional, Flavin, Richard, additional, Martin, Cara, additional, Kelly, Lynne, additional, Ring, Martina, additional, Finn, Stephen P, additional, Barrett, Ciara, additional, Loda, Massimo, additional, Gleeson, Noreen, additional, D'Arcy, Tom, additional, McGuinness, Eamonn, additional, Sheils, Orla, additional, Sheppard, Brian, additional, and O' Leary, John, additional

Published
2008
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128. p16INK4A genetic and epigenetic profiles differ in relation to age and site in head and neck squamous cell carcinomas

Author

O'Regan, Esther M., primary, Toner, Mary E., additional, Finn, Stephen P., additional, Fan, Chun Yang, additional, Ring, Martina, additional, Hagmar, Bjorn, additional, Timon, Conrad, additional, Smyth, Paul, additional, Cahill, Susanne, additional, Flavin, Richard, additional, Sheils, Orla M., additional, and O'Leary, John J., additional

Published
2008
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130. An integrative model for recurrence in ovarian cancer

Author

Laios, Alexandros, primary, O'Toole, Sharon A, additional, Flavin, Richard, additional, Martin, Cara, additional, Ring, Martina, additional, Gleeson, Noreen, additional, D'Arcy, Tom, additional, McGuinness, Eamonn PJ, additional, Sheils, Orla, additional, Sheppard, Brian L, additional, and O' Leary, John J, additional

Published
2008
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136. Human papillomavirus DNA and mRNA prevalence and association with cervical cytological abnormalities in the Irish HIV population.

Author

Loy, Aisling, McInerney, Jamie, Pilkington, Loretto, Keegan, Helen, Delamere, Sandra, Martin, Cara M, Sheils, Orla, O'Leary, John J, and Mulcahy, Fiona

Subjects
PAPILLOMAVIRUS disease diagnosis, HIV infection complications, HIV infection epidemiology, DNA, PAP test, PAPILLOMAVIRUS diseases, PAPILLOMAVIRUSES, RNA, MEDICAL triage, CERVIX uteri tumors, DISEASE prevalence, CROSS-sectional method, CD4 lymphocyte count, CERVICAL intraepithelial neoplasia, DIAGNOSIS
Abstract

The complex interplay between HIV and human papillomavirus and its link to cervical dysplasia is poorly understood. This is the first study to assess the prevalence of oncogenic human papillomavirus mRNA in HIV-positive women, its relationship to HIV and its potential use in the triage of cervical cancer screening in HIV-positive women. In this cross-sectional study, we included 321 HIV-positive women. In all, 28.7% had abnormal cervical cytology, 51.1% were human papillomavirus DNA-positive and 21.8% tested positive for human papillomavirus mRNA. Women with a CD4 count of <200 × 10(6)/L were more likely to test positive for human papillomavirus DNA and mRNA. Virally suppressed women were less likely to be human papillomavirus DNA-positive; however, the same did not hold true for human papillomavirus mRNA. We found the human papillomavirus mRNA screening to be more specific when screening for low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion than human papillomavirus DNA at 84.53% compared to 57.36%. However, the sensitivity was less at 51.59% versus 91.07% for human papillomavirus DNA. It may be possible in the future to use human papillomavirus mRNA/DNA testing within a triage algorithm for the screening and management of cervical cancer in the HIV-positive patient. [ABSTRACT FROM AUTHOR]

Published
2015
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137. Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion.

Author

Cooke, Niamh M., Spillane, Cathy D., Sheils, Orla, O'Leary, John, and Kenny, Dermot

Subjects
OVARIAN cancer treatment, OVARIAN cancer patients, ASPIRIN, CELL communication, CELL lines, METASTASIS
Abstract

Background: Platelet-cancer cell interactions play a key role in successful haematogenous metastasis. Disseminated malignancy is the leading cause of death among ovarian cancer patients. It is unknown why different ovarian cancers have different metastatic phenotypes. To investigate if platelet-cancer cell interactions play a role, we characterized the response of ovarian cancer cell lines to platelets both functionally and at a molecular level. Methods: Cell lines 59 M and SK-OV-3 were used as in vitro model systems of metastatic ovarian cancer. Platelet cloaking of each cell line was quantified by flow cytometry. Matrigel invasion chamber assays were used to assess the invasive capacity of the cell lines. The induction of an EMT was assessed by morphology analysis and by gene expression analysis of a panel of 11 EMT markers using TaqMan RT-PCR. Results: SK-OV-3 cells adhered to and activated more platelets than 59 M cells (p = 0.0333). Platelets significantly promoted the ability of only SK-OV-3 cells to invade (p = 0.0001). Morphology and transcritpome analysis indicated that platelets induce an epithelial-to-mesenchymal transition phenotype in both cells lines, with a more exaggerated response in SK-OV-3 cells. Next, we investigated if antiplatelet agents could abrogate the platelet-induced aggressive phenotype in SK-OV-3 cells. Both aspirin (p = 0.05) and 2-methylthioadenosine 5'-monophosphate triethylammonium salt hydrate (P2Y12 inhibitor; p = 0.01) significantly decreased their invasion capacity, and effectively reverted invasion to levels comparable to SK-OV-3 cells alone. Conclusion: While there is increasing evidence for the cancer-protective effect of aspirin, this study suggests P2Y12 inhibition may also play a role. Understanding these complex interactions between platelets and cancer cells could ultimately allow the establishment of therapies tailored to inhibiting metastasis, thus significantly reducing cancer morbidity. [ABSTRACT FROM AUTHOR]

Published
2015
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138. Ligation of TLR7 on CD19+CD1dhi B cells suppresses allergic lung inflammation via regulatory T cells.

Author

Khan, Adnan R., Amu, Sylvie, Saunders, Sean P., Hams, Emily, Blackshields, Gordon, Leonard, Martin O., Weaver, Casey T., Sparwasser, Tim, Sheils, Orla, and Fallon, Padraic G.

Abstract

B cells have been described as having the capacity to regulate cellular immune responses and suppress inflammatory processes. One such regulatory B-cell population is defined as IL-10-producing CD19+CD1dhi cells. Previous work has identified an expansion of these cells in mice infected with the helminth, Schistosoma mansoni. Here, microarray analysis of CD19+CD1dhi B cells from mice infected with S. mansoni demonstrated significantly increased Tlr7 expression, while CD19+CD1dhi B cells from uninfected mice also demonstrated elevated Tlr7 expression. Using IL-10 reporter, Il10−/− and Tlr7−/- mice, we formally demonstrate that TLR7 ligation of CD19+CD1dhi B cells increases their capacity to produce IL-10. In a mouse model of allergic lung inflammation, the adoptive transfer of TLR7-elicited CD19+CD1dhi B cells reduced airway inflammation and associated airway hyperresponsiveness. Using DEREG mice to deplete FoxP3+ T regulatory cells in allergen-sensitized mice, we show that that TLR7-elicited CD19+CD1dhi B cells suppress airway hyperresponsiveness via a T regulatory cell dependent mechanism. These studies identify that TLR7 stimulation leads to the expansion of IL-10-producing CD19+CD1dhi B cells, which can suppress allergic lung inflammation via T regulatory cells. [ABSTRACT FROM AUTHOR]

Published
2015
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139. Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model

Author

Cahill, Susanne, primary, Smyth, Paul, additional, Finn, Stephen P, additional, Denning, Karen, additional, Flavin, Richard, additional, O'Regan, Esther M, additional, Li, Jinghuan, additional, Potratz, Astrid, additional, Guenther, Simone M, additional, Henfrey, Richard, additional, O'Leary, John J, additional, and Sheils, Orla, additional

Published
2006
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145. The In-situ Polymerase Chain Reaction.

Author

O'Leary, John J., Martin, Cara, and Sheils, Orla

Subjects
POLYMERASE chain reaction, MOLECULAR biology, DNA, GENES, BIOMOLECULES, FORMALDEHYDE
Abstract

This article studies the in-situ polymerase chain reaction (PCR) in molecular biology. The technique, conventionally performed in a tube, permits the amplification of single copy mammalian/viral targets (either DNA or RNA) in fresh/frozen and archival paraffin-wax-embedded material. All the in-cell PCR techniques attempt to create double-stranded or singlestranded DNA/cDNA amplicons within the cell, which can either be detected directly or following an In-situ hybridisation step. Fixation of cells with formaldehyde fixatives provides a number of drawbacks. Formaldehyde is not easily removed from tissues after tissue processing.

Published
2003

148. The role of secreted frizzled-related protein 2 expression in prostate cancer.

Author

O'Hurley, Gillian, Perry, Antoinette S, O'Grady, Anthony, Loftus, Barbara, Smyth, Paul, O'Leary, John J, Sheils, Orla, Fitzpatrick, John M, Hewitt, Stephen M, Lawler, Mark, and Kay, Elaine W

Subjects
PROSTATE cancer, CARCINOMA, BENIGN prostatic hyperplasia, CELL morphology, TUMOR growth
Abstract

O'Hurley G, Perry A S, O'Grady A, Loftus B, Smyth P, O'Leary J J, Sheils O, Fitzpatrick J M, Hewitt S M, Lawler M & Kay E W (2011) Histopathology 59, 1240-1248 The role of secreted frizzled-related protein 2 expression in prostate cancer Aims: Improved prostate cancer (PCa)-specific biomarkers are urgently required to distinguish between indolent and aggressive disease, in order to avoid overtreatment. In this study, we investigated the prostatic tissue expression of secreted frizzled-related protein (SFRP)-2. Methods and results: Following immunohistochemical analysis on PCa tissue microarrays with samples from 216 patients, strong/moderate SFRP-2 expression was observed in epithelial cells of benign prostatic hyperplasia, and negative/weak SFRP-2 expression was observed in the majority of tumour epithelia. However, among Gleason grade 5 carcinomas, 40% showed strong/moderate SFRP-2 expression and 60% showed negative SFRP-2 expression in epithelial cells. Further microscopic evaluation of Gleason grade 5 tumours revealed different morphological patterns, corresponding with differential SFRP-2 expression. The first subgroup (referred to as Type A) appeared to have a morphologically solid growth pattern, whereas the second subgroup (referred to as Type B) appeared to have a more diffuse pattern. Furthermore, 100% (4/4) of Type A patients experienced biochemical recurrence, as compared with 0% (0/6) of Type B patients. Conclusions: These results imply: (i) that there is a loss of SFRP-2 expression from benign to malignant prostate glands; and (ii) differential SFRP-2 expression among two possible subgroups of Gleason grade 5 tumours. [ABSTRACT FROM AUTHOR]

Published
2011
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150. hsa_circ_0001275 Is One of a Number of circRNAs Dysregulated in Enzalutamide Resistant Prostate Cancer and Confers Enzalutamide Resistance In Vitro.

Author

Lim, Marvin C. J., Baird, Anne-Marie, Greene, John, McNevin, Ciara, Ronan, Karine, Podlesniy, Petar, Sheils, Orla, Gray, Steven G., McDermott, Ray S., and Finn, Stephen P.

Subjects
CIRCULAR RNA, IN vitro studies, REVERSE transcriptase polymerase chain reaction, ANTIANDROGENS, GENE expression profiling, ENZYME-linked immunosorbent assay, DESCRIPTIVE statistics, TUMOR markers, CELL lines, POLYMERASE chain reaction, DRUG resistance in cancer cells, PROSTATE tumors
Abstract

Simple Summary: Although newer generations of androgen deprivation therapy such as enzalutamide are providing hope, it is clinically challenging to deliver effective therapy to individuals with metastatic castrate-resistant prostate cancer. Between 20–40% of patients have intrinsic resistance to therapy and all patients will ultimately experience disease progression due to acquired resistance, which is a significant clinical dilemma. The aim of our study was to evaluate the role of circular RNAs (circRNAs) in enzalutamide-resistant prostate cancer as part of the effort to identify useful biomarkers for patient selection and potential new therapeutic targets. We confirmed that hsa_circ_0001275 was highly upregulated in an enzalutamide resistant cell line and demonstrated that its overexpression resulted in increased enzalutamide resistance. Our data showed that hsa_circ_0001275 was not expressed abundantly in patient plasma samples, however, a trend of expression was evident which paralleled disease activity indicating a possible association with enzalutamide resistance. Overall, we have provided evidence that hsa_circ_0001275 promotes enzalutamide resistance and thus may serve as a potential therapeutic target. Background: Enzalutamide is part of the treatment regimen for metastatic castration-resistant prostate cancer (MCRPC). However, both intrinsic and acquired resistance to the drug remain substantial clinical quandaries. circRNAs, a novel type of non-coding RNA, have been identified in a number of cancers including prostate cancer and have been associated with cancer development and progression. circRNAs have shown great potential as clinically useful blood-based 'liquid biopsies' and as therapeutic targets in prostate cancer. The aim of this study was to examine the role of circRNA transcripts in enzalutamide-resistant prostate cancer cells and assess their utility as biomarkers. Methods: An isogenic cell line model of enzalutamide resistance was subjected to circRNA microarray profiling. Several differentially expressed circRNAs, along with their putative parental genes were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). circRNAs of interest were stably overexpressed in the control cell line and drug sensitivity was assessed using an ELISA-based proliferation assay. The candidate circRNA, hsa_circ_0001275, was measured in patient plasma samples using RT-droplet digital PCR (RT-ddPCR). Results: hsa_circ_0001275 and its parental gene, PLCL2, were significantly up-regulated in strongly resistant clones vs. control (p < 0.05). Overexpression of hsa_circ_0001275 in the control cell line resulted in increased resistance to enzalutamide (p < 0.05). While RT-ddPCR analysis of hsa_circ_0001275 expression in plasma samples of 44 clinical trial participants showed a trend that mirrored the stages of disease activity (as defined by PSA level), the association did not reach statistical significance. Conclusions: Our data suggest that increased levels of hsa_circ_0001275 contribute to enzalutamide resistance. hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance. [ABSTRACT FROM AUTHOR]

Published
2021
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