Oncoscience最新文献

{"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}

{"title":"Nucleostemin: New Stabilizer of ARF","authors":"Bo Cao, Hua Lu","doi":"10.18632/ONCOSCIENCE.282","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.282","url":null,"abstract":"As an essential nucleolar protein for ribosomal assembly and protein production, nucleolar GTPase nucleostemin (NS) is often highly expressed in actively proliferative cells, including stem cells and cancer cells, and therefore thought to play an oncogenic role in various types of human cancers [1]. However, given the heterogeneity of cancer cells, imbalanced expression of NS could trigger distinct events to regulate cell proliferation in different genetic backgrounds. For instance, in wild type p53-harboring osteosarcoma cell line U2OS, increased expression of NS inhibits MDM2 E3 ligase activity toward p53 and thus activates p53, resulting in G1 cell cycle arrest, while knocking down NS also activates p53 indirectly by causing ribosomal stress that induces the interaction of ribosomal protein L5 and L11 with MDM2 and consequently inhibits MDM2 activity toward p53 [2, 3]. \u0000 \u0000Making this NS-engaged regulation more complicated is our recent identification of the alternative reading frame (ARF), an upstream p53 activator in response to oncogenic stress [4], as another NS-binding protein through affinity purification coupled with mass spectrometry [5]. This binding occurs at the N-termini of both NS (amino acid 1–268) and ARF (amino acid 1–65) [5]. Interestingly, although these sites are also required for binding to nucleophosmin (NPM), which was previously shown to prevent ARF from proteosomal degradation by sequestering ARF in the nucleolus [6], NPM and NS do not appear to compete with each other for ARF binding [5]. Instead, NPM and NS are highly likely to form a stable complex with ARF in the nucleolus, working together to protect ARF [5]. However, our data further revealed that NS is not required for NPM to keep ARF in the nucleolus, but responsible for stabilization of nucleoplasmic ARF dissociated from the ARF-NPM complex resulting from depletion of NPM [5]. These findings indicate that abnormal expression of NS, in addition to causing oncogenic effects under certain circumstances and inducing p53 as an counteraction, could also stabilize tumor-suppressor ARF by enhancing the binding of NPM to ARF in the nucleolus and/or by directly interacting with ARF in the nucleoplasm when NPM is absent, providing an alternative surveillance to prevent aberrantly expressed NS-mediated tumor cell proliferation and transformation (Fig. ​(Fig.11). \u0000 \u0000 \u0000 \u0000Figure 1 \u0000 \u0000Nucleostemin regulation of pathways involved in cell cycle arrest and apoptosis \u0000 \u0000 \u0000 \u0000More interestingly, similar to NPM [6], NS is able to bind to ULF and inhibit its E3 ligase activity toward ARF [5], as ULF was identified as an E3 ligase responsible for ARF polyubiquitination and proteosomal degradation in the nucleoplasm, which was inhibited by NPM [6]. Different from NPM, the NS inhibition of ULF appears to occur in the nucleoplasm [5], as NS reduces the interaction between ARF and ULF, inhibiting ULF-mediated ARF polyubiqutination and degradation (Fig. ​(Fig.1).1). Consequently, enforced ex","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"8 1","pages":"940 - 941"},"PeriodicalIF":0.0,"publicationDate":"2015-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90149104","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":"MEF2C and SOCS2 in stemness regulation","authors":"C. Vitali, C. Tripodo, M. Colombo","doi":"10.18632/ONCOSCIENCE.279","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.279","url":null,"abstract":"The physiologic stemness of hematopoietic stem cells (HSC) relies on mechanisms constitutively active under steady state and is fundamental to maintain a lifelong HSC reservoir. On the other side, similar stemness features sustained by partially overlapping molecular circuits, which have recently come into focus, confer aggressive aggressiveness in leukemia clones. \u0000 \u0000Suppressor of Cytokine Signalling 2 (SOCS2) belongs to the SOCS family, comprising eight members (SOCS1–7 and CIS) with similar structures, which are induced upon JAK/STAT activation and function as negative regulators. Recent evidences have demonstrated that SOCS2 is endowed with immunological functions in differentiated cells but no apparent functions were identified in HSC despite its expression in steady state condition. \u0000 \u0000Combining analysis of human HSC malignancies and studies on murine HSC under steady state and stress conditions [1], we have recently identified a dual involvement of SOCS2 in the regulation of HSC functions in different contexts and demonstrated a novel regulatory mechanism for SOCS2 expression in HSC. \u0000 \u0000In mice under hematopoietic stress conditions, such as after 5-Fluorouracil-induced myeloablation, hematopoietic cytokines are rapidly produced to sustain bone marrow (BM) recovery. This event induces activation of the JAK-STAT5 pathway consequently upregulating SOCS2. Such negative feedback loop avoids excessive HSC proliferation and eventually the exhaustion of HSC functions. \u0000 \u0000This regulatory function of SOCS2 is completely novel, while the JAK-STAT dependency for its expression is common to the regulatory loop involving other SOCS proteins as well as SOCS2 in other contexts [2]. \u0000 \u0000Also, we uncovered SOCS2 involvement in hematopoietic malignancies. High SOCS2 expression characterized the BM of chronic myeloid leukemia (CML) patients and increased along clone progression toward blast crisis. The highest and widespread SOCS2 expression in BM hematopoietic populations was associated with aggressive acute leukemia subsets, namely acute myeloid (AML) and lymphoblastic leukemias (ALL) with MLL rearrangments and BCR/ABL abnormalities. In AML patients, high SOCS2 was significatively associated with poor prognosis. \u0000 \u0000In AML and ALL patients, high SOCS2 expression also positively correlated with a list of genes that significanly overlapped with leukemic stemness gene signatures [3], suggesting that SOCS2 and hematopoietic stemness can be associated in the context of hematopietic malignancies. Normal HSC and leukemic stem cells (LSC) share some common molecular programs and, conceivably, similar molecular mechanisms could regulate SOCS2 in these populations. \u0000 \u0000Our analysis of public gene expression profiles of AML and ALL excluded that SOCS2 expression could be ascribed only to JAK-STAT pathways activation and suggests that alternative STAT-independent molecular programs should be involved. To our knowledge, this is the first indication of STAT-independent regu","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"31 1","pages":"936 - 937"},"PeriodicalIF":0.0,"publicationDate":"2015-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77602728","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":"Mouse models of radiation-induced glioblastoma","authors":"B. Mukherjee, P. Todorova, S. Burma","doi":"10.18632/ONCOSCIENCE.278","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.278","url":null,"abstract":"Glioblastomas (GBM) are lethal brain tumors that can be triggered by exposure to ionizing radiation (IR), even at low doses from CT scans [1]. High doses of IR are also used to treat GBM, but the irradiated tumors inevitably recur. This raises the possibility that genomic changes induced by radiation may contribute not only to glioma initiation, but also to tumor recurrence. Thus, there is a compelling need for experimental model systems that recapitulate the process of radiation-induced gliomagenesis. Such models could not only help predict GBM-development risks from radiation exposure, but also help identify genetic alterations defining radiation-induced GBM, thereby facilitating the development of rational therapies for treating these recalcitrant tumors. \u0000 \u0000Our study published in the journal Oncogene employed a systematic approach to develop sensitive mouse models that can be used to study radiation-induced gliomagenesis [2]. Ink4a, Ink4b and Arf are key tumor suppressor genes that are deleted in a majority of GBMs [3]. We utilized transgenic mice with brain-restricted deletions of these tumor suppressors, individually and in combination, and examined their susceptibility to IR-induced GBM development. The most deleterious lesion inflicted by IR is the DNA double-strand break (DSB). We have shown previously that accelerated ions (particle radiation) induce complex DSBs that are refractory to repair unlike the simple breaks induced by X-rays (electromagnetic radiation) which are repaired to completion [4]. Therefore, we intra-cranially irradiated these transgenic mice with either X-rays or accelerated Fe ions to understand the process of radiation-induced gliomagenesis, and how this may be influenced by DNA damage complexity. We found that these mice did not develop gliomas spontaneously, but were prone to GBM development after exposure to a single, moderate dose of radiation. Remarkably, we found that Fe ions were at least four-fold more effective than X-rays in inducing these tumors, thereby confirming that complex DSBs triggered by accelerated ions are more harmful than simpler breaks induced by X-rays. This finding has important implications as the use of particle radiation (such as protons and carbon ions) for cancer therapy is steadily increasing. Our work indicates that particle radiation could indeed turn out to be more effective than X-rays for tumor control, but this also raises the specter of increased likelihood of secondary cancers triggered by such radiation. \u0000 \u0000Interestingly, while wild type mice did not develop gliomas upon radiation exposure, loss of Ink4a and Arf was sufficient to render these mice susceptible to IR-induced gliomas; additional loss of Ink4b significantly increased tumor incidence. These observations indicate that Ink4a, Ink4b and Arf act as key barriers to radiation-induced gliomagenesis, and confirms previous results from our laboratory and others implicating Ink4b as an important “backup” tumor suppressor f","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"24 1","pages":"934 - 935"},"PeriodicalIF":0.0,"publicationDate":"2015-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77910257","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":"Ultrasound-stimulated microbubble enhancement of radiation treatments: endothelial cell function and mechanism","authors":"A. Al-Mahrouki, Emily Wong, G. Czarnota","doi":"10.18632/ONCOSCIENCE.277","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.277","url":null,"abstract":"Endothelial cell death caused by novel microbubble-enhanced ultrasound cancer therapy leads to secondary tumour cell death. In order to characterize and optimize these treatments, the molecular mechanisms resulting from the interaction with endothelial cells were investigated here. Endothelial cells (HUVEC) were treated with ultrasound-stimulated microbubbles (US/MB), radiation (XRT), or a combination of US/MB+XRT. Effects on cells were evaluated at 0, 3, 6, and 24 hours after treatment. Experiments took place in the presence of modulators of sphingolipid-based signalling including ceramide, fumonisin B1, monensin, and sphingosine-1-phosphate. Experimental outcomes were evaluated using histology, TUNEL, clonogenic survival methods, immuno-fluorescence, electron microscopy, and endothelial cell blood-vessel-like tube forming assays. Fewer cells survived after treatment using US/MB+XRT compared to either the control or XRT. The functional ability to form tubes was only reduced in the US/ MB+XRT condition in the control, the ceramide, and the sphingosine-1-phosphate treated groups. The combined treatment had no effect on tube forming ability in either the fumonisin B1 or in the monensin exposed groups, since both interfere with ceramide production at different cellular sites. In summary, experimental results supported the role of ceramide signalling as a key element in cell death initiation with treatments using US/MB+XRT to target endothelial cells.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"30 1","pages":"944 - 957"},"PeriodicalIF":0.0,"publicationDate":"2015-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76023593","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":"Identification of new miRNA biomarkers associated with HER2-positive breast cancers","authors":"Hossam Tashkandi, N. Shah, Y. Patel, Hexin Chen","doi":"10.18632/ONCOSCIENCE.275","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.275","url":null,"abstract":"Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in ∼30% breast cancers which are associated with poor prognosis. microRNAs are small non-coding RNA which play an important role in many physiological conditions including cancer. Here we screened and identified many miRNAs which are dysregulated by HER2 overexpression. In line with our quantitative PCR analysis data, in silico analysis of microRNA expression profiles of 1302 breast tumors revealed that miR-146a-5p is up-regulated and miR-181d and miR-195-5p are down-regulated in HER2-positive tumors. Furthermore, the expression levels of these microRNAs can significantly predict patient survival and thus potentially serve as new prognostic markers for HER2-positive breast cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"15 1","pages":"924 - 929"},"PeriodicalIF":0.0,"publicationDate":"2015-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84979991","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}