bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1729: Mitochondrial necrosis pathway drives tumor progression.
Authors: James Melissa K. , Kitsis Richard N. 
Published: August 2014

Abstract
Necrosis is a prominent feature of aggressive and invasive cancers. Previous clinical/epidemiological studies have suggested an association between the extent of tumor necrosis and poor prognosis and survivorship for some cancers. Evasion of apoptosis is widely accepted as a hallmark of cancer. However, whether necrotic cell death plays no role, limits, or drives carcinogenesis has not been studied in any cancer. Recent work suggests that necrosis may be an actively regulated form of cell death. In contrast to apoptosis where permeabilization of the outer mitochondrial membrane is the defining event, the central event in necrosis is the opening of a pore in the inner mitochondrial membrane termed the mitochondrial permeability transition pore (mPTP). Cyclophilin D, a peptidyl prolyl cis-trans isomerase in the mitochondrial matrix, encoded by the gene ppif, is critical for opening of the mPTP. Stable expression of ppif shRNA was used to deplete cyclophilin D in Met-1 cells, a metastatic breast cancer cell line. We first confirmed that knockdown of ppif in Met-1 cells abrogated necrosis, but not apoptosis. When these cells were transplanted into the mammary glands of wildtype FVB mice, tumors resulting from cells that express ppif shRNA were markedly smaller, with decreased volume and mass, than those derived from cells expressing control shRNA. Reconstitution of ppif knockdown cells with wild type cyclophilin D, but not an enzymatically inactive mutant, rescued tumor volume and mass. As expected, tumors arising from ppif knockdown cells exhibited less necrosis, while rates of apoptosis were unchanged. Moreover, rates of BrdU incorporation were significantly decreased in these tumors. Necrotic cell death is characterized by loss of plasma membrane integrity resulting in a marked inflammatory response. Neutrophils and macrophages recruited to tumors often secrete growth/survival/angiogenic factors that promote tumor growth and metastasis. Consistent with this model, both macrophage and neutrophil recruitment were reduced in tumors derived from ppif knockdown cells. In addition, rates of spontaneous pulmonary metastasis were markedly decreased in mice harboring tumors derived from ppif knockdown cells compared with controls. Our data suggest that, in contrast to apoptotic cell death which limits carcinogenesis, necrotic cell death actually drives disease progression by altering the tumor microenvironment. These findings may have therapeutic implications in that they suggest that inhibition - rather than promotion - of necrotic cell death may provide a novel treatment paradigm for some cancers.
Citation Format: Melissa K. James, Richard N. Kitsis. Mitochondrial necrosis pathway drives tumor progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1729. doi:10.1158/1538-7445.AM2013-1729
Abstract 1743: SOX10 is required for cell cycle regulation and melanomagenesis.
Authors: Cronin Julia C. , Watkins-Chow Dawn E. , Incao Art , Hasskamp Joanne H. , Schönewolf Nicola , Hayward Nicholas K. , Bastian Boris C. , Dummer Reinhard , Loftus Stacie K. , Pavan William J. 
Published: August 2014

Abstract
The transcription factor SOX10 is essential for proper survival and differentiation of neural crest cell lineages, and plays an important role in the establishment and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, however its role in the progression of the disease is not yet understood. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation, and detail the rescue of melanoma in the metabotropic glutamate receptor 1 (Grm1Tg) transgenic mouse by Sox10 haploinsufficiency. Stable SOX10 knockdown in human melanoma cells results in arrested growth, altered cellular morphology, and senescence. Cells with a stable loss of SOX10 are arrested in the G1 phase of the cell cycle with elevated cyclin-dependent kinase inhibitor 1A and 1B (p21 and p27) expression. SOX10 loss also results in hypophosphorylation of retinoblastoma protein (RB) and a reduction in the expression of its binding partner E2F1. Previously, the RB-E2F1 pathway has been shown to play a central role in cell cycle regulation, and here we demonstrate that SOX10 expression is required for the maintenance of the RB-E2F1 pathway to promote melanoma cell growth. One of the main events driving cellular transformation is the dysregulation of the cell cycle, therefore the role that SOX10 has in maintaining this process provides great promise for targeted interventions.
Citation Format: Julia C. Cronin, Dawn E. Watkins-Chow, Art Incao, Joanne H. Hasskamp, Nicola Schönewolf, Nicholas K. Hayward, Boris C. Bastian, Reinhard Dummer, Stacie K. Loftus, William J. Pavan. SOX10 is required for cell cycle regulation and melanomagenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1743. doi:10.1158/1538-7445.AM2013-1743
Abstract 1747: The Pax3:Foxo1a translocation product is a cell cycle-specific modifier of the alveolar rhabdomyosarcoma tumor phenotype.
Authors: Kikuchi Ken , Hettmer Simone , Aslam M. Imran , Michalek Joel E. , Laub Wolfram , Rubin Brian P. , Wagers Amy J. , Keller Charles 
Published: August 2014

Abstract
BACKGROUND: Rhabdomyosarcoma is the most common soft-tissue sarcoma in childhood, which falls into one of two biologically distinct subtypes, alveolar (aRMS) or embryonal rhabdomyosarcoma. aRMS harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis.
MATERIALS AND METHODS: Primary murine aRMS cultures were obtained from the Myf6Cre, Pax3:Foxo1a, p53 conditional mouse aRMS model, in which eYFP is expressed as a second cistron in the targeted Pax3:Foxo1a-ires-eYFP allele. Limited dilution transplantation experiments were performed using Pax3:Foxo1a knockdown by siRNA of eYFP or control aRMS primary cultures. To elucidate the dynamical function of Pax3:Foxo1a, time-lapse confocal microscopy experiments, cell cycle analysis, quantitative RT-PCR, western blotting, immunohistochemistry and mRNA array were performed using murine aRMS primary cell cultures with or without Pax3:Foxo1a knockdown treated by 6 Gy irradiation, or selected for ploidy using hoechst33342 sorted cell cycle-specific cells.
RESULTS: Pax3:Foxo1a is not required for tumor repopulating ability in mouse limiting-dilution transplantation experiments. The expression level of Pax3:Foxo1a was discovered to be dynamic and varied during the cell cycle in murine aRMS primary cell cultures and human aRMS cell lines. Pax3:Foxo1a is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation in genome-wide expression analysis and quantitative RT-PCR. Radiation resulted in a higher fraction of DNA breaks amongst mitotic cells (as represented by dual pHH3 positive, H2AX positive cells) under conditions of Pax3:Foxo1a expression compared with knockdown, suggesting that Pax3:Foxo1a facilitates G2/M transit, consistent with checkpoint adaptation.
CONCLUSION: We demonstrated that Pax3:Foxo1a does not function in tumor cell maintenance, the expression level of Pax3:Foxo1a is dynamic and varies during the cell cycle, and Pax3:Foxo1a facilitates checkpoint adaptation under stress conditions such as irradiation. Furthermore, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer biology.
Citation Format: Ken Kikuchi, Simone Hettmer, M. Imran Aslam, Joel E. Michalek, Wolfram Laub, Brian P. Rubin, Amy J. Wagers, Charles Keller. The Pax3:Foxo1a translocation product is a cell cycle-specific modifier of the alveolar rhabdomyosarcoma tumor phenotype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1747. doi:10.1158/1538-7445.AM2013-1747
Abstract 1769: Real-time imaging demonstrates cancer cells exposed to UV irradiation either repair their DNA or die.
Authors: Miwa Shinji , Yano Shuya , Hiroshima Yukihiko , Tome Yasunori , Uehara Fuminori , Mii Sumiyuki , Kimura Hiroaki , Hayashi Katsuro , Tsuchiya Hiroyuki , Efimova Elena , Digman Michelle , Gratton Enrico , Hoffman Robert M. 
Published: August 2014

Abstract
The DNA repair protein 53BP1 is re-localized in foci after DNA damage. In this study, we imaged the real-time response of 53BP1 linked to GFP to DNA damage induced by UV irradiation. Inhibition of proliferation by UV irradiation was analyzed by a clonogenic assay. The relocalization of GFP fused to the chromatin-binding domain of 53BP1 was imaged after UV irradiation of MiaPaca-2 53BP1-GFP human pancreatic cancer cells. The clonogenic assay demonstrated that UVC dose-dependently inhibited cell proliferation, while UVA and UVB showed little effect. During live-cell imaging, 53BP1-GFP foci formation was observed within 30 min after UVC irradiation. High-dose UVC also induced apoptosis within 24 h after irradiation. The cells treated with UVC irradiation appear to have two different fates: DNA repair or apoptosis. A fraction of the cells underwent apoptosis, and the other fraction repaired their DNA as evidenced by 53BP1 focus formation. The present study demonstrates that some cells may repair their DNA successfully and others can not. This has important implication for UV-based photodynamic therapy.
Citation Format: Shinji Miwa, Shuya Yano, Yukihiko Hiroshima, Yasunori Tome, Fuminori Uehara, Sumiyuki Mii, Hiroaki Kimura, Katsuro Hayashi, Hiroyuki Tsuchiya, Elena Efimova, Michelle Digman, Enrico Gratton, Robert M. Hoffman. Real-time imaging demonstrates cancer cells exposed to UV irradiation either repair their DNA or die. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1769. doi:10.1158/1538-7445.AM2013-1769
Abstract 177: Inhibition of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway for chemoprevention of hepatocellular carcinoma.
Authors: Wei Lan , Hoshida Yujin , Bain Gretchen , Swaney Jamie , Lauwers Gregory Y. , Schaefer Esperance A. , Yamada Suguru , Lanuti Michael , Chung Raymond T. , Tanabe Kenneth K. , Fuchs Bryan C. 
Published: August 2014

Abstract
Background: Hepatocellular carcinoma (HCC) is increasing in incidence both in the United States and worldwide. Due to the limited treatment options for HCC, prevention in high-risk patients with cirrhosis has been proposed as an alternative strategy. Aberrant activation of the autotoxin-lysophosphatidic acid (ATX-LPA) pathway, an upstream activator of RhoA signaling, has been associated with fibrosis in several organs. Here, we hypothesized that inhibition of the ATX-LPA pathway in fibrotic liver would reduce progression to cirrhosis and HCC occurrence. Methods: Rats were treated weekly with 50 mg/kg diethylnitrosamine (DEN) to induce sequential development of fibrosis, cirrhosis and HCC. After establishment of liver fibrosis (8 weeks), rats were treated daily by oral gavage with either vehicle control, 5 mg/kg AM063 (an ATX inhibitor) or 30 mg/kg AM095 (a LPA receptor 1 (LPA1) antagonist). At the end of the study, rats were sacrificed, livers were sectioned and stained to analyze disease progression, and tumor nodules were counted. In addition, the effect of LPA on RhoA signaling was investigated in hepatic stellate cell lines (TWNT4 and LX-2). Results: Gene set enrichment analysis revealed that a RhoA activation gene signature, which was associated with poor prognosis in human cirrhosis patients, increased in DEN-injured rat livers. Several members of this gene signature, including pro-fibrogenic connective tissue growth factor (CTGF), were reduced after treatment with either AM063 or AM095. In addition, both AM063 and AM095 significantly (p &lt; 0.01) prevented the development of HCC tumor nodules in DEN-injured livers from a median of 16 in controls to a median of 8 and 6 in AM063 and AM095-treated rats, respectively. Interestingly, the extent of fibrosis in DEN-injured rat livers as measured by Ishak score also significantly (p &lt; 0.01) decreased from a median of 6 in controls to a median of 4 in both AM063 and AM095-treated rats. Examination of hepatic stellate cell lines revealed that LPA increased RhoA-mediated CTGF expression, which was inhibited by AM095. Conclusions: We have identified the ATX-LPA pathway as a major mediator of liver fibrosis progression. Further, AM063 and AM095 are potential chemoprevention strategies for HCC.
Citation Format: Lan Wei, Yujin Hoshida, Gretchen Bain, Jamie Swaney, Gregory Y. Lauwers, Esperance A. Schaefer, Suguru Yamada, Michael Lanuti, Raymond T. Chung, Kenneth K. Tanabe, Bryan C. Fuchs. Inhibition of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway for chemoprevention of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 177. doi:10.1158/1538-7445.AM2013-177
Abstract 1776: Lymphomas associated with aberrant DNA rearrangements are suppressed by Mre11 mutation.
Authors: Smith Cheryl J. , Xie Jeffrey , Ferguson David O. , Sekiguchi JoAnn M. 
Published: August 2014

Abstract
Many translocations associated with spontaneous human lymphoid malignancies are mediated by short regions of sequence homology (microhomology) at the breakpoints. The hallmark features of this error prone pathway are deletions of flanking sequence and short homologies of 1-25 bases at the junctions that serve to align the DNA ends prior to joining. In addition to its importance in the etiology of human cancers, microhomology-mediated joining or alternative NHEJ (aNHEJ) also appears to play a significant role in therapy-induced oncogenic translocations.
Studies have provided compelling evidence that the DNA end-binding complex composed of Mre11 (nuclease), Rad50 (tetherer) and Nbs1 (signaler)–MRN–functions in the context of the aNHEJ pathway. In addition, in vivo and cell based studies have identified that deficiencies in components of the MRN complex reduce aNHEJ activity. However, it is not known whether the MRN complex participates in the generation of aNHEJ catalyzed translocations that can predispose to cancer. Therefore, our studies seek to better understand the contribution of Mre11/MRN to the aNHEJ pathway and thus, in generation of translocations.
We have obtained mice harboring an Mre11 conditionally targeted null allele as well as an Mre11 knock-in mutation that abrogates nuclease activity. We have included mutant mice in this study that succumb to early onset Pro-B lymphomas associated with clonal translocations containing microhomologies of 2-8 nucleotides. Thus, the spontaneously arising tumors in this mutant background represent a valuable in vivo system to assess the involvement of Mre11/MRN in aNHEJ mediated translocations.
We have determined that Mre11/MRN inactivation in the B-cell lineage suppresses Pro-B lymphoma in this mutant background. In future experiments we are investigating the impact of Mre11/MRN inactivation on various cancer phenotypes. Together, these studies will provide insights into the mechanisms underlying human lymphoma and may ultimately provide insights into targets for improved treatment of lymphoid malignancies.
Citation Format: Cheryl J. Smith, Jeffrey Xie, David O. Ferguson, JoAnn M. Sekiguchi. Lymphomas associated with aberrant DNA rearrangements are suppressed by Mre11 mutation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1776. doi:10.1158/1538-7445.AM2013-1776
Abstract 1782: Regulation of ATM-dependent DNA damage signaling in human breast cancer cells by the RhoGEF Net1A .
Authors: Oh Wonkyung , Frost Jeffrey A. 
Published: August 2014

Abstract
The Neuroepithelioma transforming gene 1 (Net1) is a RhoGEF that is frequently overexpressed in human cancer, including breast cancer. We have previously reported that DNA damage activates Net1 to control p38 MAPK signaling and protect cells from ionizing radiation (IR) induced apoptosis. However, others have shown that Net1 activation contributes to cell death by activating a RhoB-Bim signaling pathway. Thus, the role of Net1 in controlling IR responses and cell survival is controversial. Here we show that the Net1A isoform is uniquely important for DNA double-strand break (DSB)-induced signaling and DNA repair. SiRNA-mediated knockdown of Net1A in human breast cancer cells reduced IR-stimulated ATM activation and signaling to its substrates Chk2 and H2AX. In addition, suppression of Net1A expression adversely affected cell survival after IR. We also observed that Net1A overexpression significantly reduced γH2AX foci formation after IR, which required the unique N-terminal region of Net1A. Importantly, this effect did not require Rho GTPase activation by Net1A, and was not recapitulated by overexpression of RhoA or RhoB. Using comet assays, we found that Net1A depletion substantially slowed DNA DSB repair in response to IR. Intriguingly, knockdown of Net1A promoted non-homologous end joining (NHEJ) in the absence of DNA damage, and Net1A was found to co-immunoprecipitate with the DNA-PK complex in an IR-regulated manner. Taken together, these data suggest a model in which Net1A functions as a non-catalytic binding protein to control DNA damage response signaling and DNA repair to affect cell survival after IR.
Citation Format: Wonkyung Oh, Jeffrey A. Frost. Regulation of ATM-dependent DNA damage signaling in human breast cancer cells by the RhoGEF Net1A . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1782. doi:10.1158/1538-7445.AM2013-1782
Abstract 1790: Mutagenic effects of inorganic particulate matter on Raji and HepG2 cell lines exposed to ultraviolet radiation.
Authors: Xiao Michael , El-Naggar Atif , Helsing Albert V. , Lynch Philip M. , Alegre Melissa M. , Robison Richard A. , O'Neill Kim L. 
Published: August 2014

Abstract
Epidemiological studies have correlated exposure to ultraviolet-irradiated particulate matter with cardiovascular, respiratory, and malignant lung diseases. This study investigated the DNA damage induced by two major inorganic particulate matter compounds found in diesel exhaust, ammonium nitrate and ammonium sulfate on Burkitt's lymphoma (Raji) and hepatocellular carcinoma (HepG2) cell lines. We found a dose-dependent positive correlation of accumulated DNA damage in concentrations of ammonium nitrate and ammonium sulfate (25 μg/ml, 50 μg/ml, 100 μg/ml, 200 μg/ml, 400 μg/ml) with ultraviolet exposure (250 J/m2, 400 J/m2, 600 J/m2, 850 J/m2), as measured by the Comet Assay in both cell lines. There was a significant difference between the treated ammonium nitrate samples and negative control samples in Raji and HepG2 (p &lt; 0.001). Apoptosis was shown in Raji and HepG2 cells when exposed to high concentrations of ammonium nitrate (200 μg/ml, 400 μg/ml) for 1 hour in samples without ultraviolet exposure, as assessed by the Comet Assay. However, the quantity of apoptotic cells greatly diminished after ultraviolet exposure at these concentrations. To further investigate and clarify the underlying mechanisms, we used Annexin V to quantify apoptosis. Flow Cytometry confirmed the results shown by the Comet Assay; ultraviolet exposure diminished apoptosis in ammonium nitrate-induced DNA damage in both Raji and HepG2. Ammonium sulfate induced DNA damage with or without ultraviolet influence was minimal as assessed by the Comet Assay in both cell lines, with a significant difference (p &lt; 0.05) between the treated and negative control samples. These results indicate that the inorganic particulate compound, ammonium nitrate, induced DNA strand breaks at all concentrations and apoptosis at high concentrations in Raji and HepG2 cells, with ultraviolet radiation preventing apoptosis at high concentrations. We hypothesize that ultraviolet radiation inhibits an essential cellular mechanism, possibly involving p53, thereby explaining this phenomenon. Further studies are necessary to characterize the roles of apoptosis inhibition in DNA damage caused by inorganic particulate matter.
Citation Format: Michael Xiao, Atif El-Naggar, Albert V. Helsing, Philip M. Lynch, Melissa M. Alegre, Richard A. Robison, Kim L. O'Neill. Mutagenic effects of inorganic particulate matter on Raji and HepG2 cell lines exposed to ultraviolet radiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1790. doi:10.1158/1538-7445.AM2013-1790
Abstract 1793: ADAR1 regulates ARHGAP26 expression by RNA editing through destruction of the miR-30b-3p and miR-573 target sites.
Authors: Wang Qiong , Guo Zhendong , Zhang Weina , Wang Li 
Published: August 2014

Abstract
Rho GTPase activating protein 26 (ARHGAP26) is a putative tumor suppressor gene. It was observed to negatively regulate the small GTP-binding protein RhoA and be down-regulated in myeloid malignancies and metastatic brain cancers. Herein, we demonstrated that ARHGAP26 transcript undergoes extensive A-to-I RNA editing catalyzed by ADAR1 in its 3’-UTR. Either knocking down of ADAR1 by silencing or overexpression by ADAR1 expression vector decreased or increased the expression level of ARHGAP26 gene. Furthermore, luciferase assay showed that miR-30b-3p and miR-573 targeted the ARHGAP26, but the RNA editing abolished the effect of miR-30b-3p or miR-573. In addition, we observed that the level of the A-to-I RNA editing on ARHGAP26 transcript decreased significantly in human brain cancer tissues comparing to their controls, which contributes to the down-regulation of the ARHGAP26 expression in human cancer tissues. These data suggested that ADAR1 regulated the expression of ARHGAP26 gene by A-to-I RNA editing through destruction of the existing miR-30b-3p and miR-573 target sites. It implied that down-regulation of tumor suppressors through RNA editing is one crucial way to explain how dyregulation of RNA editing involves in tumorigenesis.
Citation Format: Qiong Wang, Zhendong Guo, Weina Zhang, Li Wang. ADAR1 regulates ARHGAP26 expression by RNA editing through destruction of the miR-30b-3p and miR-573 target sites. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1793. doi:10.1158/1538-7445.AM2013-1793
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.