Oncoscience最新文献

{"title":"Cytochrome P450 monooxygenase/soluble epoxide hydrolase-mediated eicosanoid pathway in colorectal cancer and obesity-associated colorectal cancer","authors":"Jianan Zhang, Katherine Z. Sanidad, Guodong Zhang","doi":"10.18632/oncoscience.488","DOIUrl":"https://doi.org/10.18632/oncoscience.488","url":null,"abstract":"Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Furthermore, it is well established that obese individuals have high risks of developing CRC, and obesity-associated CRC represents an unmet medical problem in the United States. Using a metabolomics approach, our recent research supports that the cytochrome P450 (CYP) monooxygenase/soluble epoxide hydrolase (sEH)-mediated eicosanoid pathway could play critical roles in the pathogenesis of CRC and obesity-associated CRC. Here in this review, we discuss recent studies about the roles of the CYP/sEH eicosanoid pathway in the pathogenesis of these diseases.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"137 1","pages":"371 - 375"},"PeriodicalIF":0.0,"publicationDate":"2019-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75761972","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 situ analysis of Her2 DNA and RNA in retinoblastoma and adjacent retina","authors":"G. Seigel, D. Shah, Pia Mendoza, E. Szalai, H. Grossniklaus, Yinghui Song, J. Shan","doi":"10.18632/oncoscience.489","DOIUrl":"https://doi.org/10.18632/oncoscience.489","url":null,"abstract":"Retinoblastoma (RB) is an ocular tumor of early childhood. Current treatments attempt to preserve visual function, but may spare chemoresistant tumor cells. One potential therapeutic target for RB is HER2, (ERBB2), expressed in RB in truncated form. In this study, we tested the hypothesis that Her2 DNA and RNA are expressed in RB tumors and adjacent retina. We examined 24 human RB tumors as well as normal-appearing adjacent retinal tissues for Her2 DNA and RNA expression by in situ hybridization. We also examined 28 RB tumors for HER2 protein immunoreactivity. 21/22 RB tumors expressed Her2 DNA and 14/19 tumors expressed Her2 RNA. In 17 paired cases, there were three cases in which Her2 DNA was detected, but not RNA. We also saw Her2 RNA signal in six instances of “normal” adjacent retinal tissue. Heterogeneous HER2 protein expression in specific tumor regions also was confirmed by quantitative HER2 immunohistochemistry. In summary, Her2 DNA and RNA are expressed in many RB tumors, and in some adjacent ocular tissues, with hetereogenous protein expression throughout. These results may provide important insights regarding RB tumor progression, and drug targeting approaches designed to spare the eye, preserve vision and improve quality of life for RB patients.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"76 1","pages":"357 - 366"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85516105","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":"Senescence regulation by nuclear N-WASP: a role in cancer?","authors":"Hui Li, C. Brakebusch","doi":"10.18632/oncoscience.487","DOIUrl":"https://doi.org/10.18632/oncoscience.487","url":null,"abstract":"","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"354 - 356"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79824656","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":"Correction: Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment","authors":"Dana C. Galvan, A. Ayyappan, B. Bryan","doi":"10.18632/oncoscience.491","DOIUrl":"https://doi.org/10.18632/oncoscience.491","url":null,"abstract":"[This corrects the article DOI: 10.18632/oncoscience.472.].","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"21 1","pages":"367 - 367"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87320628","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":"Pomalidomide-induced changes in the pancreatic tumor microenvironment and potential for therapy","authors":"P. Storz","doi":"10.18632/oncoscience.486","DOIUrl":"https://doi.org/10.18632/oncoscience.486","url":null,"abstract":"In pancreatic cancer, standard chemotherapy alone or its combination of with checkpoint inhibitors is largely ineffective, because the tumor microenvironment generates a fibrotic barrier for immunotherapy and for drugs to reach tumor cells. Current most promising efforts are strategies that combine chemotherapy with compounds that alter the tumor microenvironment. Here we discuss treatment with pomalidomide as a method to target immunosuppressive alternatively-activated tumor-associated macrophages, resulting in a decrease in fibrosis and formation of an immune-responsive environment. The pancreatic tumor microenvironment (TME) is an immunosuppressive, fibrotic barrier. It blocks the delivery of drugs that target tumor cells, but also excludes immune cells and prevents immunotherapy [1]. Major cell types in the TME are different populations of activated fibroblasts, and immune cells, including tumor-associated macrophages (TAMs). Alternatively-activated (M2) macrophages represent approximately 85% of TAMs in the pancreatic tumor microenvironment [2]. In pancreatic ductal adenocarcinoma (PDA) these macrophages regulate two hallmarks of immune escape, the exclusion of cytotoxic T lymphocytes and fibrosis [3, 4]. Both, either targeting immunosuppressive alternativelyactivated TAMs, or their repolarization to inflammatory macrophages, which drive destruction of the tumor stroma and presence of cytotoxic T cells, could be efficient strategies for this cancer [3-5]. Indeed, preclinical data indicate that neutralization of IL-13, a factor that mediates M2 polarization of macrophages, decreases the presence of alternativelyactivated macrophages, as well as fibrosis at pancreatic lesions [4]. In recent work, Bastea et al. now show that pomalidomide, a thalidomide analog that has been developed and tested for hematologic cancers [6], not only induces a decrease in alternatively-activated macrophages, which then results in decreased fibrosis at PanIN lesions and tumors, it also reprograms these populations into tumor suppressive macrophages [7]. Effects of pomalidomide on M2 macrophages are due to downregulation of interferon regulatory factor 4 (IRF4), a transcription factor for M2 macrophage polarization. Through its effects on macrophage populations pomalidomide generates a pro-inflammatory environment by decreasing tissue levels of interleukin 1 receptor antagonist (IL-1ra) and increasing Interleukin 1α (IL-1α), with the net effect of activating interleukin 1 receptor (IL-1R) signaling [7]. It had been shown previously that pancreatic tumors deficient of IL-1α have an immunosuppressive environment due to exclusion of cytotoxic T cells [8]. As expected, due to re-establishing IL-1R signaling, pomalidomide induced presence of activated (IFNγ-positive) CD4+ and CD8+ T cell populations [7]. This is in line with studies showing that in the pancreas shifting M2 to M1 populations orchestrates effective T cell immunotherapy [9]. In addition to its effects on im","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"52 1","pages":"351 - 353"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72573522","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":"CDK12 inactivation across solid tumors: an actionable genetic subtype","authors":"C. H. Marshall, E. Imada, Zhuojun Tang, L. Marchionni, E. Antonarakis","doi":"10.18632/oncoscience.481","DOIUrl":"https://doi.org/10.18632/oncoscience.481","url":null,"abstract":"Inactivating CDK12 alterations have been reported in ovarian and prostate cancers and may have therapeutic implications; however, the prevalence of these mutations across other cancer types is unknown. We searched the cBioPortal and GENIE Project (public release v4.1) databases for cancer types with > 200 sequenced cases, that included patients with metastatic disease, and in which the occurrence of at least monoallelic CDK12 alterations was > 1%. The prevalence of at least monoallelic CDK12 mutations was highest in bladder cancer (3.7%); followed by prostate (3.4%), esophago-gastric (2.1%) and uterine cancers (2.1%). Biallelic CDK12 inactivation was highest in prostate cancer (1.8%), followed by ovarian (1.0%) and bladder cancers (0.5%). These results are the first (to our knowledge) to estimate the prevalence of monoallelic and biallelic CDK12 mutations across multiple cancer types encompassing over 15,000 cases.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"6 1","pages":"312 - 316"},"PeriodicalIF":0.0,"publicationDate":"2019-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73363342","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":"Suppression of vascular endothelial growth factor expression in breast cancer cells by microRNA-125b-mediated attenuation of serum amyloid A activating factor-1 level","authors":"A. Ray, B. Ray","doi":"10.18632/oncoscience.483","DOIUrl":"https://doi.org/10.18632/oncoscience.483","url":null,"abstract":"Increased level of an inflammation-responsive transcription factor called serum amyloid A-activating factor (SAF-1) has been linked to the pathogenesis in human breast cancer. SAF-1 is found to promote vascular endothelial growth factor (VEGF) expression in breast carcinoma cells and boost angiogenesis. In an effort to develop a cellular mechanism to control VEGF expression, we sought to limit SAF-1 activity in breast cancer cells. We report here several targets within the SAF-1 mRNA for binding of microRNA-125b (miR-125b) and we show that VEGF expression is reduced in breast cancer cells when SAF-1 level is reduced with the microRNA action. Within the 3' un-translated region (UTR) of SAF-1 transcript, we have identified four highly conserved miR-125b responsive elements. We show that these miR-125b binding sites mediate repression of SAF-1 by miR-125b. Ectopic expression of miR-125b in nonmetastatic and metastatic breast cancer cells repressed SAF-1-mediated activity on VEGF promoter function and inhibited cancer cell migration and invasion potentials in vitro. Together, these results suggest that termination of SAF-1 function by miR-125b could be developed as a potential anti-VEGF and anti-angiogenic agent, which has high clinical relevance.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"399 1","pages":"337 - 348"},"PeriodicalIF":0.0,"publicationDate":"2019-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80057927","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":"BRG1 and BRM loss selectively impacts RB and P53, respectively: BRG1 and BRM have differential functions in vivo","authors":"Stefanie B. Marquez-Vilendrer, S. Rai, Sarah J B Gramling, Li Lu, D. Reisman","doi":"10.18632/oncoscience.333","DOIUrl":"https://doi.org/10.18632/oncoscience.333","url":null,"abstract":"The SWI/SNF complex is an important regulator of gene expression that functions by interacting with a diverse array of cellular proteins. The catalytic subunits of SWI/SNF, BRG1 and BRM, are frequently lost alone or concomitantly in a range of different cancer types. This loss abrogates SWI/SNF complex function as well as the functions of proteins that are required for SWI/SNF function, such as RB1 and TP53. Yet while both proteins are known to be dependent on SWI/SNF, we found that BRG1, but not BRM, is functionally linked to RB1, such that loss of BRG1 can directly or indirectly inactivate the RB1 pathway. This newly discovered dependence of RB1 on BRG1 is important because it explains why BRG1 loss can blunt the growth-inhibitory effect of tyrosine kinase inhibitors (TKIs). We also observed that selection for Trp53 mutations occurred in Brm-positive tumors but did not occur in Brm-negative tumors. Hence, these data indicate that, during cancer development, Trp53 is functionally dependent on Brm but not Brg1. Our findings show for the first time the key differences in Brm- and Brg1-specific SWI/SNF complexes and help explain why concomitant loss of Brg1 and Brm frequently occurs in cancer, as well as how their loss impacts cancer development.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"39 1","pages":"337 - 350"},"PeriodicalIF":0.0,"publicationDate":"2016-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86602387","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":"Gene enhancer deregulation and epigenetic vulnerability","authors":"Rui Lu, G. Wang","doi":"10.18632/oncoscience.334","DOIUrl":"https://doi.org/10.18632/oncoscience.334","url":null,"abstract":"One major goal of cancer research is to identify tumor-specific mechanisms that sustain cell proliferation or survival and to develop the corresponding therapies that target selectively against tumor. Recent sequencing of primary tumor samples supports that aberration of chromatin modification and epigenetic states plays a central role in oncogenesis. For example, mutation of DNA methyltransferase 3A (DNMT3A, Figure 1) occurs in approximately 20-30% of acute myeloid leukemia (AML) and 5-15% of other hematological malignancies and disorders, making DNMT3A one of the most frequently mutated genes in blood cancer [1]; genes encoding chromatin-remodeling protein complexes are found recurrently mutated or deleted in various tumors. Thus, DNMT3A and ATP-dependent chromatin remodelers appear to function as tumor suppressors, most likely, in a context-dependent manner. However, it remains elusive how alteration of chromatin-modifying machineries contributes to tumorigenesis, and mechanism-based therapeutic approaches are to be developed. Chromatin modifications ensure distinctive cellular identities. Past studies have shed light on several principles in chromatin modifications. One important property is reversibility. Epigenomic states are reset in response to developmental or environmental cues such as differentiation. Epigenetic changes are mediated by antagonizing enzymes that ‘write’ or ‘erase’ specific chromatin modification, exemplified by DNA methyltransferase or demethylase, and histone acetyltransferase (HAT) or deacetylase (HDAC). Second, epigenetic states can be relatively stable over cell divisions. Such ‘inheritance’ is partly owing to self-recruitment of modifying enzymes to promote self-propagation. Furthermore, different chromatin modifications that fall into the same gene-active or gene-repressive category often cooperate forming a selfreinforcement network. For example, methylated DNA is ‘read’ by MeCP2, which recruits HDACs to deacetylate histones (Figure 1). Due to the epigenetic crosstalk via antagonizing and reinforcing networks, one would Editorial","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"11 1","pages":"299 - 301"},"PeriodicalIF":0.0,"publicationDate":"2016-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81830707","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":"Adaptive survival mechanism to glucose restrictions","authors":"N. Djouder","doi":"10.18632/oncoscience.332","DOIUrl":"https://doi.org/10.18632/oncoscience.332","url":null,"abstract":"Glucose is partly metabolized through the glucose sensing hexosamine biosynthetic pathway (HBP) leading to the formation of an end product called acetylated amino sugar nucleotide uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAC serves as a donor substrate during O-GlcNAcylation (O-linked β-N-acetylglucosamine or O-GlcNAc) [1]. Serine or threonine residues of nuclear and cytoplasmic proteins are directly O-GlcNAcylated, competing with phosphorylation. O-GlcNAcylation is catalyzed by one unique enzyme called O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). O-GlcNAcylation is cleaved and removed by another one enzyme called N-acetyl-β-D-glucosaminidase (OGA) [1]. The existence of single and unique enzymes (OGT and OGA) acting on various different substrates suggest that enzyme activity can be modulated by binding partners in response to glucose levels [1]. O-GlcNAcylation levels are very dynamic and cycles rapidly, fluctuating in response to glucose concentrations influencing cell signaling pathways [1]. O-GlcNAcylation is thus relevant to various chronic human diseases such as diabetes, cardiovascular and neurodegenerative disorders and cancer. For example, OGT promotes aneuploidy, regulates cell-cycling via HCF-1 cleavage, and participates in regulatory links between metabolic changes and carcinogenesis [2]. Changes in OGA or OGT activity and hence, in O-GlcNAcylation levels may occur in human breast cancer and hepatocellular carcinoma (HCC) tissues [1]. The oncoprotein c-MYC is also O-GlcNAcylated. c-MYC protein is very unstable; its levels and activity are regulated by ubiquitination and proteasomal degradation, initiated by its phosphorylation at Thr-58 by GSK3β. Thr-58 is an OGT target which regulates c-MYC stability. O-GlcNAcylation at Thr-58 stabilizes c-MYC, promoting tumorigenesis [1]. Unconventional prefoldin RPB5 interactor (URI) binds and modulates OGT activity in response to glucose concentrations. In presence of glucose, URI, OGT and protein phosphatase 1 gamma (PP1γ) form a heterotrimeric complex. Glucose deprivation induces anaplerotic reactions, increasing ATP/cAMP levels, thereby activating PKA which in turn, phosphorylates URI at Ser-371. Phosphorylated URI frees PP1γ from the heterotrimeric complex and, URI becomes a potent inhibitor of OGT [1]. PKA reportedly forms a mitochondrial complex with PP1 catalytic units and the pro-apoptotic Bcl-2-associated death promoter (BAD) that influences glucose homeostasis [3]. Thus, URI/OGT/PP1γ complex may integrate glucose metabolism, possibly through a mitochondrial supra-molecular complex including PKA and BAD [3,4]. Abnormal glucose metabolism and BAD requirement in glucose deprivation-induced death is reported in Bad knockout and non-phosphorylatable BAD(3SA) knockin mice [3,5]. BAD is thus an apoptotic sentinel that monitors glucose signaling. Notably, OGT overexpression in a transgenic mouse model yields a type 2 diabetes (T2D) phenotype with insulin resist","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"16 1","pages":"302 - 303"},"PeriodicalIF":0.0,"publicationDate":"2016-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84351843","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}