Oncoscience最新文献

{"title":"Circadian-disruption-induced gene expression changes in rodent mammary tissues","authors":"David Z. Kochan, Y. Ilnytskyy, A. Golubov, S. Deibel, R. J. McDonald, O. Kovalchuk","doi":"10.18632/ONCOSCIENCE.292","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.292","url":null,"abstract":"Evidence is mounting that circadian disruption (CD) is a potential carcinogen in breast cancer development. However, despite the growing concern, to our knowledge, no studies have attempted a genome-wide analysis of CD-induced gene expression changes in mammary tissues. Using a rodent model system, a proven photoperiod-shifting paradigm, varying degrees of CD, and Illumina sequencing, we performed an exploratory genome-wide mRNA analysis in mammary tissues. Even though our analysis did not identify any significant patterns in mRNA levels based on the degree of CD, and the majority of groups did not show changes in gene expression on a large-scale, one group (two-week chronic ZT19) displayed 196 differentially expressed genes, 51 of which have been linked to breast cancer. Through gene-specific pathway analysis, the data illustrate that CD may promote breast cancer development through downregulation of DNA repair and p53 signaling pathways, thus promoting genomic instability and cancer development. Although these results have to be interpreted with caution because only a single group illustrated drastic changes in transcript levels, they indicate that chronic CD may directly induce changes in gene expression on a large-scale with potentially malignant consequences.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"9 1","pages":"58 - 70"},"PeriodicalIF":0.0,"publicationDate":"2016-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83561296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum: Kinetochore-microtube attachments in cancer therapy","authors":"D. Del Bufalo, F. Degrassi","doi":"10.18632/oncoscience.291","DOIUrl":"https://doi.org/10.18632/oncoscience.291","url":null,"abstract":"[This corrects the article on p. 902 in vol. 2, PMID: 26697517.].","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"108 1","pages":"49 - 49"},"PeriodicalIF":0.0,"publicationDate":"2016-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79407926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early onset esophageal adenocarcinoma: a distinct molecular entity?","authors":"A. Nistelrooij, Ronald van Marion, K. Biermann, M. Spaander, J. Lanschot, B. Wijnhoven, W. Dinjens, I. Lijnschoten, Marieke C.H. Hogenes","doi":"10.18632/ONCOSCIENCE.290","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.290","url":null,"abstract":"Esophageal adenocarcinoma (EAC) is typically diagnosed in elderly with a median age of 68 years. The incidence of EAC has been rising over the last decades, also among young adults. The aim of the study was to investigate whether early onset EAC is a distinct molecular entity. To identify early onset EACs, the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) was searched. Twenty-eight tumors of patients aged ≤40 years were selected and matched with 27 tumors of patients aged ≥68 years. DNA was isolated from surgically resected specimen and sequenced on the Ion Torrent Personal Genome Machine with the Ion AmpliSeq Cancer Panel. No differences in mutational load between early onset and conventional EACs were observed (P=0.196). The most frequently mutated genes were TP53 (73%) and P16 (16%). Additional mutations in early onset EACs occurred exclusively in: APC, CDH1, CTNNB1, FGFR2, and STK11. In the conventional EACs additional mutations were exclusively identified in: ABL1, FBXW7, GNA11, GNAS, KRAS, MET, SMAD4, and VHL. Additional mutations besides TP53 and P16 seem to occur in different genes related to cell fate pathways for early onset EACs, while the additional mutations in conventional EACs are related to survival pathways.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"53 1","pages":"42 - 48"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86375115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma","authors":"Jianqing Zhang, Daniel Medina-Cleghorn, L. Bernal-Mizrachi, P. Bracci, A. Hubbard, L. Conde, J. Riby, Daniel K. Nomura, C. Skibola","doi":"10.18632/ONCOSCIENCE.289","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.289","url":null,"abstract":"Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m2; 118%, P < 0.001) compared to those with a BMI < 25 kg/m2. DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"38 1","pages":"31 - 41"},"PeriodicalIF":0.0,"publicationDate":"2016-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81019527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New crossroads for potential therapeutic intervention in cancer - intersections between CDCP1, EGFR family members and downstream signaling pathways","authors":"Yaowu He, B. Harrington, J. Hooper","doi":"10.18632/ONCOSCIENCE.286","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.286","url":null,"abstract":"Signaling pathways regulated by the receptor CDCP1 play central roles in promoting cancer and in mediating resistance to chemo- and targeted-therapies. In this perspective we briefly summarize these findings as well as data demonstrating poorer outcomes for several malignancies that exhibit elevated CDCP1 expression. Promising data from preclinical studies suggest that CDCP1 targeted agents, including therapeutic antibodies, could be useful in the treatment of cancer patients selected on the basis of activation of CDCP1 and its signaling partners including EGFR, HER2, Met and Src.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"5 - 8"},"PeriodicalIF":0.0,"publicationDate":"2016-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82043547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico and experimental analyses predict the therapeutic value of an EZH2 inhibitor GSK343 against hepatocellular carcinoma through the induction of metallothionein genes","authors":"Tsang‐Pai Liu, Yi-Han Hong, K. Tung, Pei-Ming Yang","doi":"10.18632/ONCOSCIENCE.285","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.285","url":null,"abstract":"There are currently no effective molecular targeted therapies for hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27)-specific methyltransferase, has been emerged as novel anticancer target. Our previous study has demonstrated that GSK343, an S-adenosyl-L-methionine (SAM)-competitive inhibitor of EZH2, induces autophagy and enhances drug sensitivity in cancer cells including HCC. In this study, an in silico study was performed and found that EZH2 was overexpressed in cancerous tissues of HCC patients at both gene and protein levels. Microarray analysis and in vitro experiments indicated that the anti-HCC activity of GSK343 was associated with the induction of metallothionein (MT) genes. In addition, the negative association of EZH2 and MT1/MT2A genes in cancer cell lines and tissues was found in public gene expression database. Taken together, our findings suggest that EZH2 inhibitors could be a good therapeutic option for HCC, and induction of MT genes was associated with the anti-HCC activity of EZH2 inhibitors.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"41 1","pages":"9 - 20"},"PeriodicalIF":0.0,"publicationDate":"2016-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88178875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EZH2 inhibition re-sensitizes multidrug resistant B-cell lymphomas to etoposide mediated apoptosis","authors":"M. Smonskey, E. Lasorsa, S. Rosario, J. Kirk, F. Hernandez-Ilizaliturri, L. Ellis","doi":"10.18632/ONCOSCIENCE.288","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.288","url":null,"abstract":"Reactivation of apoptotic pathways is an attractive strategy for patients with treatment-resistant B-cell lymphoma. The tumor suppressor, p53 is central for apoptotic response to multiple DNA damaging agents used to treat aggressive B-cell lymphomas, including etoposide. It has been demonstrated that etoposide induced DNA damage and therapeutic efficacy is enhanced by combination with inhibitors of the histone methyltransferase, enhancer of zeste homolog 2 (EZH2). Further, EZH2 was identified to regulate cell fate decisions in response to DNA damage. Using B-cell lymphoma cell lines resistant to etoposide induced cell death; we show that p53 is dramatically down regulated and MDMX, a negative regulator of p53, is significantly up regulated. However, these cell lines remain responsive to etoposide mediated DNA damage and exhibit cell cycle inhibition and induction of senescence. Furthermore, chemical inhibition of EZH2 directs DNA damage to a predominant p53 dependent apoptotic response associated with loss of MDMX and BCL-XL. These data provide confirmation of EZH2 in determining cell fate following DNA damage and propose a novel therapeutic strategy for patients with aggressive treatment-resistant B-cell lymphoma.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"361 1","pages":"21 - 30"},"PeriodicalIF":0.0,"publicationDate":"2016-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80260873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PINK1, cancer and neurodegeneration","authors":"C. O’Flanagan, V. Morais, C. O'Neill","doi":"10.18632/ONCOSCIENCE.284","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.284","url":null,"abstract":"Cancer and neurodegeneration are two age-related diseases that arise from aberrant signaling in similar cellular systems, those that balance survival and death. Thus, deregulated molecular processes such as DNA damage repair, intracellular energy balance, and key signal transduction systems, including the PI3-kinase/Akt axis can promote tumorigenesis and induce neurodegeneration [1]. Epidemiological studies support this cross-talk between cancer and neurodegeneration, indicating a reduced risk of certain cancers in patients diagnosed with neurodegenerative diseases such as Parkinson's disease (PD) [2]. In addition, several of the genes discovered to cause inherited PD, including PTEN induced putative kinase 1 (PINK1) have been described to have oncogenic or tumor suppressor properties [3]. \u0000 \u0000In a recent study we focused on the function of PINK1 in cancer cell biology, and discovered a novel function for PINK1 as a positive regulator of cell cycle progression that can promote cancer-associated phenotypes [4]. PINK1 is ubiquitously expressed and was named due to induction by the tumor suppressor PTEN in cancer cells, drawing attention to its putative role in cancer from the first instance. Several mechanistic links between PINK1, PTEN and the PI3-kinase/Akt signaling axis that PTEN inhibits were subsequently highlighted, indicating PINK1 is both regulated by and regulates PI3-kinase/Akt signaling [5]. Interlinked with this, in an as yet undefined manner, PINK1 is best described as a major mitochondrial quality control protein, rudimentary to cell survival due to its regulatory role in the triad of mitochondrial fission, fusion and mitophagy as well as mitochondrial bioenergetics. \u0000 \u0000Although somewhat understudied, the cell cycle and mitochondrial quality control are intrinsically coupled [6]. Mitochondria must divide and undergo fission during mitosis to allow equal distribution of mitochondria to daughter cells, also permitting clearance of damaged mitochondria via mitophagy. Conversely, mitochondrial fusion occurs during the transition from mitosis to G1 following cytokinesis, and can promote stress resistance and cell cycle exit in G0. Our findings show for the first time that regulation of mitochondrial fission to fusion transitions by PINK1 is critical for cell cycle progression at G2/M and G0/G1 checkpoints necessary for cell division, growth and stress resistance, in particular in cancer biology. In line with this, PINK1 deletion reduced proliferation, colony formation, migration and invasive potential in several cell model systems. \u0000 \u0000In further detail, PINK1-deficiency induced multinucleation and cell cycle arrest during G2/M and resulted in a reduced ability to exit the cell cycle following serum withdrawal. This was PINK1 kinase dependent and rescued by re-introduction of human PINK1. The cell cycle changes induced by PINK1 deletion where mechanistically linked to excessive mitochondrial fission, and increased expression and activation ","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"45 1","pages":"1 - 2"},"PeriodicalIF":0.0,"publicationDate":"2016-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82219086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the methylation cycle in cells reprogrammed into a stem cell-like state","authors":"S. Fernández-Arroyo, E. Cuyás, J. Bosch-Barrera, T. Alarcón, J. Joven, J. Menéndez","doi":"10.18632/ONCOSCIENCE.280","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.280","url":null,"abstract":"Generation of induced pluripotent stem (iPS) cells and cancer biogenesis share similar metabolic switches. Most studies have focused on how the establishment of a cancer-like glycolytic phenotype is necessary for the optimal routing of somatic cells for achieving stemness. However, relatively little effort has been dedicated towards elucidating how one-carbon (1C) metabolism is retuned during acquisition of stem cell identity. Here we used ultra-high pressure liquid chromatography coupled to an electrospray ionization source and a triple-quadrupole mass spectrometer [UHPLC-ESI-QqQ-MS/MS] to quantitatively examine the methionine/folate bi-cyclic 1C metabolome during nuclear reprogramming of somatic cells into iPS cells. iPS cells optimize the synthesis of the universal methyl donor S-adenosylmethionine (SAM), apparently augment the ability of the redox balance regulator NADPH in SAM biosynthesis, and greatly increase their methylation potential by triggering a high SAM:S-adenosylhomocysteine (SAH) ratio. Activation of the methylation cycle in iPS cells efficiently prevents the elevation of homocysteine (Hcy), which could alter global DNA methylation and induce mitochondrial toxicity, oxidative stress and inflammation. In this regard, the methyl donor choline is also strikingly accumulated in iPS cells, suggesting perhaps an overactive intersection of the de novo synthesis of choline with the methionine-Hcy cycle. Activation of methylogenesis and maintenance of an optimal SAM:Hcy ratio might represent an essential function of 1C metabolism to provide a labile pool of methyl groups and NADPH-dependent redox products required for successfully establishing and maintaining an embryonic-like DNA methylation imprint in stem cell states.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"188 1","pages":"958 - 967"},"PeriodicalIF":0.0,"publicationDate":"2016-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79739782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Replication stress in MLL-rearrangements","authors":"M. Milyavsky, B. Gole, L. Wiesmüller","doi":"10.18632/ONCOSCIENCE.281","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.281","url":null,"abstract":"Hematopoietic stem cells (HSC) are the only cells capable of self-renewal throughout the individual's lifetime and generate the whole spectrum of blood cells. Therefore genome aberrations in HSC can result in hematopoiesis failure or leukemic transformation. Chromosomal translocations, inversions, amplifications and complex rearrangements at the 11q human genomic locus encoding mixed lineage leukemia gene (MLL) are the hallmark of several blood malignancies including infant, therapy-induced, donor - and de novo leukemias. The vast majority of these 11q aberrations fall within a 7.3kb MLL breakpoint cluster region (MLLbcr) with a particular hotspot at the intron11-exon12 boundary [1]. Intriguingly, a large variety of genotoxic, cytotoxic and biological stimuli were connected with MLLbcr breakage pointing to the existence of several DNA cleavage and repair mechanisms acting at this locus [1, 2]. From the broad spectrum of stimuli triggering cleavage in concert with diverse mutagenic outcomes at the locus it is tempting to seek for a common molecular process engaged. \u0000 \u0000Based on our and others’ experimental evidences, we postulate that replication stress in HSC can be responsible for MLL rearrangements (Figure ​(Figure1).1). Thus, our data revealed MLLbcr breakage upon mere replication blockage via DNA polymerase inhibition or upon exposure to the nucleoside analog 5-fluorouracil [2]. Induction of HSC's specific replication stress can be linked to many agents and conditions implicated in MLL leukemias. Normally, quiescence of HSC with only rare replication cycles accompanied by low metabolic activity and ROS levels contributes to minimize the mutational load under homeostatic conditions [3, 4]. In contrast, forcing HSC into excessive cycling by chronic stimulation with physiological triggers mimicking inflammation, bleeding or cytopenia provokes a robust DDR that drives both HSC death and mutagenesis of the survivors. Thus, Walter et al. [4] detected DDR markers associated with replication fork stalling and collapse such as DNA breaks and nuclear γ H2AX, 53BP1 and FANCD2 foci upon enforced HSC exit from quiescence. Transplantation induces rapid cycling of normally dormant HSC that can be exacerbated by donor immunosuppression, damaged microenvironment and altered cytokine profile. Signs of endogenous DNA damage upon serial transplantation of HSC are well documented in both humans and mice with evidence for altered DNA replication dynamics, chromosome gaps and breaks indicative of replication stress [3, 5]. We suggest that exhaustion or failure of replication stress-associated high fidelity repair pathways under transplantation challenge can be implicated in donor cell-derived acute leukemia with MLL translocations in patients who received HSC transplant [6]. Given the fact that replication stress in HSC is associated with aging [3] one can hypothesize that MLL rearrangements, particularly amplifications often associated with complex rearrangements [","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"12 1","pages":"938 - 939"},"PeriodicalIF":0.0,"publicationDate":"2015-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84362861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}