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1دورية أكاديمية
المؤلفون: Zeeshan Fazal, Ratnakar Singh, Fang Fang, Emmanuel Bikorimana, Hannah Baldwin, Andrea Corbet, Megan Tomlin, Cliff Yerby, Nabil Adra, Costantine Albany, Sarah Lee, Sarah J. Freemantle, Kenneth P Nephew, Brock C Christensen, Michael J. Spinella
المصدر: Epigenetics, Vol 16, Iss 10, Pp 1071-1084 (2021)
مصطلحات موضوعية: cisplatin, testicular germ cell tumour, dna methylation, chemoresistance, Genetics, QH426-470
الوصف: Testicular germ cell tumours (TGCTs) respond well to cisplatin-based therapy. However, cisplatin resistance and poor outcomes do occur. It has been suggested that a shift towards DNA hypermethylation mediates cisplatin resistance in TGCT cells, although there is little direct evidence to support this claim. Here we utilized a series of isogenic cisplatin-resistant cell models and observed a strong association between cisplatin resistance in TGCT cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic and repeat elements. Hypermethylated loci were significantly enriched for repressive DNA segments, CTCF and RAD21 sites and lamina associated domains, suggesting that global nuclear reorganization of chromatin structure occurred in resistant cells. Hypomethylated CpG loci were significantly enriched for EZH2 and SUZ12 binding and H3K27me3 sites. Integrative transcriptome and methylome analyses showed a strong negative correlation between gene promoter and CpG island methylation and gene expression in resistant cells and a weaker positive correlation between gene body methylation and gene expression. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associated with upregulation of polycomb targets and downregulation of tumour suppressor genes. These data support the hypothesis that global remodelling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and chemoresistance of TGCTs and furthers the rationale for hypomethylation therapy for refractory TGCT patients.
وصف الملف: electronic resource
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2دورية أكاديمية
المؤلفون: Shruthi Sriramkumar, Tara X Metcalfe, Tim Lai, Xingyue Zong, Fang Fang, Heather M O'Hagan, Kenneth P Nephew
المصدر: PLoS ONE, Vol 17, Iss 8, p e0271584 (2022)
الوصف: Ovarian cancer (OC) is a lethal gynecological malignancy with a five-year survival rate of only 46%. Development of resistance to platinum-based chemotherapy is a common cause of high mortality rates among OC patients. Tumor and transcriptomic heterogeneity are drivers of platinum resistance in OC. Platinum-based chemotherapy enriches for ovarian cancer stem cells (OCSCs) that are chemoresistant and contribute to disease recurrence and relapse. Studies examining the effect of different treatments on subpopulations of HGSOC cell lines are limited. Having previously demonstrated that combined treatment with an enhancer of zeste homolog 2 inhibitor (EZH2i) and a RAC1 GTPase inhibitor (RAC1i) inhibited survival of OCSCs, we investigated EZH2i and RAC1i combination effects on HGSOC heterogeneity using single cell RNA sequencing. We demonstrated that RAC1i reduced expression of stemness and early secretory marker genes, increased expression of an intermediate secretory marker gene and induced inflammatory gene expression. Importantly, RAC1i alone and in combination with EZH2i significantly reduced oxidative phosphorylation and upregulated Sirtuin signaling pathways. Altogether, we demonstrated that combining a RAC1i with an EZH2i promoted differentiation of subpopulations of HGSOC cells, supporting the future development of epigenetic drug combinations as therapeutic approaches in OC.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1932-6203Test
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3دورية أكاديمية
المؤلفون: Olga Kim, Eun Young Park, David L Klinkebiel, Svetlana D Pack, Yong-Hyun Shin, Zied Abdullaev, Robert E Emerson, Donna M Coffey, Sun Young Kwon, Chad J Creighton, Sanghoon Kwon, Edmund C Chang, Theodore Chiang, Alexander N Yatsenko, Jeremy Chien, Dong-Joo Cheon, Yang Yang-Hartwich, Harikrishna Nakshatri, Kenneth P Nephew, Richard R Behringer, Facundo M Fernández, Chi-Heum Cho, Barbara Vanderhyden, Ronny Drapkin, Robert C Bast, Kathy D Miller, Adam R Karpf, Jaeyeon Kim
المصدر: PLoS Genetics, Vol 16, Iss 6, p e1008808 (2020)
الوصف: Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.
وصف الملف: electronic resource
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4دورية أكاديمية
المؤلفون: Qingchun Cai, Qipeng Fan, Aaron Buechlein, David Miller, Kenneth P Nephew, Sheng Liu, Jun Wan, Yan Xu
المصدر: PLoS ONE, Vol 13, Iss 6, p e0197404 (2018)
الوصف: The cure rate for late stage epithelial ovarian cancer (EOC) has not significantly improved over several decades. New and more effective targets and treatment modalities are urgently needed. RNA-seq analyses of a syngeneic EOC cell pair, representing more and less aggressive tumor cells in vivo were conducted. Bioinformatics analyses of the RNA-seq data and biological signaling and function studies have identified new targets, such as ZIP4 in EOC. Many up-regulated tumor promoting signaling pathways have been identified which are mainly grouped into three cellular activities: 1) cell proliferation and apoptosis resistance; 2) cell skeleton and adhesion changes; and 3) carbohydrate metabolic reprograming. Unexpectedly, lipid metabolism has been the major down-regulated signaling pathway in the more aggressive EOC cells. In addition, we found that hypoxic responsive genes were at the center stage of regulation and detected functional changes were related to cancer stem cell-like activities. Moreover, our genetic, cellular, biochemical, and lipidomic analyses indicated that cells grown in 2D vs. 3D, or attached vs. suspended had dramatic changes. The important clinical implications of peritoneal cavity floating tumor cells are supported by the data proved in this work. Overall, the RNA-seq data provide a landscape of gene expression alterations during tumor progression.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC6013233?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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5دورية أكاديمية
المؤلفون: Eric A Benson, Todd C Skaar, Yunlong Liu, Kenneth P Nephew, Daniela Matei
المصدر: PLoS ONE, Vol 10, Iss 10, p e0141279 (2015)
الوصف: OBJECTIVE:Plasma miRNAs represent potential minimally invasive biomarkers to monitor and predict outcomes from chemotherapy. The primary goal of the current study-consisting of patients with recurrent, platinum-resistant ovarian cancer-was to identify the changes in circulating miRNA concentrations associated with decitabine followed by carboplatin chemotherapy treatment. A secondary goal was to associate clinical response with changes in circulating miRNA concentration. METHODS:We measured miRNA concentrations in plasma samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial that were treated with a low dose of the hypomethylating agent (HMA) decitabine for 5 days followed by carboplatin on day 8. The primary endpoint was to determine chemotherapy-associated changes in plasma miRNA concentrations. The secondary endpoint was to correlate miRNA changes with clinical response as measured by progression free survival (PFS). RESULTS:Seventy-eight miRNA plasma concentrations were measured at baseline (before treatment) and at the end of the first cycle of treatment (day 29). Of these, 10 miRNAs (miR-193a-5p, miR-375, miR-339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p, and miR-148b-5p) displayed fold changes in concentration ranging from -2.9 to 4 (p
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC4612782?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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6دورية أكاديمية
المؤلفون: Frank H C Cheng, Baltazar D Aguda, Je-Chiang Tsai, Marek Kochańczyk, Jora M J Lin, Gary C W Chen, Hung-Cheng Lai, Kenneth P Nephew, Tzy-Wei Hwang, Michael W Y Chan
المصدر: PLoS ONE, Vol 9, Iss 12, p e116050 (2014)
الوصف: Accumulating data indicate that cancer stem cells contribute to tumor chemoresistance and their persistence alters clinical outcome. Our previous study has shown that ovarian cancer may be initiated by ovarian cancer initiating cells (OCIC) characterized by surface antigen CD44 and c-KIT (CD117). It has been experimentally demonstrated that a microRNA, namely miR-193a, targets c-KIT mRNA for degradation and could play a crucial role in ovarian cancer development. How miR-193a is regulated is poorly understood and the emerging picture is complex. To unravel this complexity, we propose a mathematical model to explore how estrogen-mediated up-regulation of another target of miR-193a, namely E2F6, can attenuate the function of miR-193a in two ways, one through a competition of E2F6 and c-KIT transcripts for miR-193a, and second by binding of E2F6 protein, in association with a polycomb complex, to the promoter of miR-193a to down-regulate its transcription. Our model predicts that this bimodal control increases the expression of c-KIT and that the second mode of epigenetic regulation is required to generate a switching behavior in c-KIT and E2F6 expressions. Additional analysis of the TCGA ovarian cancer dataset demonstrates that ovarian cancer patients with low expression of EZH2, a polycomb-group family protein, show positive correlation between E2F6 and c-KIT. We conjecture that a simultaneous EZH2 inhibition and anti-estrogen therapy can constitute an effective combined therapeutic strategy against ovarian cancer.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC4278842?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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7دورية أكاديمية
المؤلفون: Seungyoon Nam, Hyojung Ryu, Won-joon Son, Yon Hui Kim, Kyung Tae Kim, Curt Balch, Kenneth P Nephew, Jinhyuk Lee
المصدر: PLoS ONE, Vol 9, Iss 10, p e109745 (2014)
الوصف: RNA interference (RNAi), mediated by small non-coding RNAs (e.g., miRNAs, siRNAs), influences diverse cellular functions. Highly complementary miRNA-target RNA (or siRNA-target RNA) duplexes are recognized by an Argonaute family protein (Ago2), and recent observations indicate that the concentration of Mg2+ ions influences miRNA targeting of specific mRNAs, thereby modulating miRNA-mRNA networks. In the present report, we studied the thermodynamic effects of differential [Mg2+] on slicing (RNA silencing cycle) through molecular dynamics simulation analysis, and its subsequent statistical analysis. Those analyses revealed different structural conformations of the RNA duplex in Ago2, depending on Mg2+ concentration. We also demonstrate that cation effects on Ago2 structural flexibility are critical to its catalytic/functional activity, with low [Mg2+] favoring greater Ago2 flexibility (e.g., greater entropy) and less miRNA/mRNA duplex stability, thus favoring slicing. The latter finding was supported by a negative correlation between expression of an Mg2+ influx channel, TRPM7, and one miRNA's (miR-378) ability to downregulate its mRNA target, TMEM245. These results imply that thermodynamics could be applied to siRNA-based therapeutic strategies, using highly complementary binding targets, because Ago2 is also involved in RNAi slicing by exogenous siRNAs. However, the efficacy of a siRNA-based approach will differ, to some extent, based on the Mg2+ concentration even within the same disease type; therefore, different siRNA-based approaches might be considered for patient-to-patient needs.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC4201462?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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8دورية أكاديمية
المؤلفون: James W Antoon, Elizabeth C Martin, Rongye Lai, Virgilo A Salvo, Yan Tang, Ashley M Nitzchke, Steven Elliott, Seung Yoon Nam, Wei Xiong, Lyndsay V Rhodes, Bridgette Collins-Burow, Odile David, Guandi Wang, Bin Shan, Barbara S Beckman, Kenneth P Nephew, Matthew E Burow
المصدر: PLoS ONE, Vol 8, Iss 8, p e69291 (2013)
الوصف: Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(-), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC3739787?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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9دورية أكاديمية
المؤلفون: Gianpiero Di Leva, Claudia Piovan, Pierluigi Gasparini, Apollinaire Ngankeu, Cristian Taccioli, Daniel Briskin, Douglas G Cheung, Brad Bolon, Laura Anderlucci, Hansjuerg Alder, Gerard Nuovo, Meng Li, Marilena V Iorio, Marco Galasso, Ramasamy Santhanam, Guido Marcucci, Danilo Perrotti, Kimerly A Powell, Anna Bratasz, Michela Garofalo, Kenneth P Nephew, Carlo M Croce
المصدر: PLoS Genetics, Vol 9, Iss 3, p e1003311 (2013)
الوصف: MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC3591271?pdf=renderTest; https://doaj.org/toc/1553-7390Test; https://doaj.org/toc/1553-7404Test
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10دورية أكاديمية
المؤلفون: Syreeta L Tilghman, Melyssa R Bratton, H Chris Segar, Elizabeth C Martin, Lyndsay V Rhodes, Meng Li, John A McLachlan, Thomas E Wiese, Kenneth P Nephew, Matthew E Burow
المصدر: PLoS ONE, Vol 7, Iss 3, p e32754 (2012)
الوصف: Several environmental agents termed "endocrine disrupting compounds" or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs). Of the ncRNAs, microRNAs have emerged as a target of estrogen signaling. Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells.To investigate the cellular effects of DDT and BPA, we used the human MCF-7 breast cancer cell line, which is ER (+) and hormone sensitive. Our results show that DDT and BPA potentiate ER transcriptional activity, resulting in an increased expression of receptor target genes, including progesterone receptor, bcl-2, and trefoil factor 1. Interestingly, a differential increase in expression of Jun and Fas by BPA but not DDT or estrogen was observed. In addition to ER responsive mRNAs, we investigated the ability of DDT and BPA to alter the miRNA profiles in MCF-7 cells. While the EDCs and estrogen similarly altered the expression of multiple microRNAs in MCF-7 cells, including miR-21, differential patterns of microRNA expression were induced by DDT and BPA compared to estrogen.We have shown, for the first time, that BPA and DDT, two well known EDCs, alter the expression profiles of microRNA in MCF-7 breast cancer cells. A better understanding of the molecular mechanisms of these compounds could provide important insight into the role of EDCs in human disease, including breast cancer.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC3293845?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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