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  • Online Resource  (14)
  • American Association for Cancer Research (AACR)  (14)
  • Ikeda, Hiroshi  (14)
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  • Online Resource  (14)
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  • American Association for Cancer Research (AACR)  (14)
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  • 1
    Online Resource
    Online Resource
    The Monoclonal Antibody nBT062 Conjugated to Cytotoxic Maytansinoids Has Selective Cytotoxicity Against CD138-Positive Multiple Myeloma Cells In vitro and In vivo
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 12 ( 2009-06-15), p. 4028-4037
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 12 ( 2009-06-15), p. 4028-4037
    Abstract: Purpose: We investigated the antitumor effect of murine/human chimeric CD138-specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid derivatives against multiple myeloma (MM) cells in vitro and in vivo. Experimental Design: We examined the growth inhibitory effect of BT062-SPDB-DM4, BT062-SMCC-DM1, and BT062-SPP-DM1 against MM cell lines and primary tumor cells from MM patients. We also examined in vivo activity of these agents in murine MM cell xenograft model of human and severe combined immunodeficient (SCID) mice bearing implant bone chips injected with human MM cells (SCID-hu model). Results: Anti-CD138 immunoconjugates significantly inhibited growth of MM cell lines and primary tumor cells from MM patients without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2-M cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase. Nonconjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that specific binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells. The coculture of MM cells with bone marrow stromal cells protects against dexamethasone-induced death but had no effect on the cytotoxicity of immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo and prolonged host survival in both the xenograft mouse models of human MM and SCID-hu mouse model. Conclusion: These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-2867
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 2
    Online Resource
    Online Resource
    5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells
    American Association for Cancer Research (AACR) ; 2007
    In:  Molecular Cancer Therapeutics Vol. 6, No. 6 ( 2007-06-01), p. 1718-1727
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 6, No. 6 ( 2007-06-01), p. 1718-1727
    Abstract: In this study, we investigated the cytotoxicity of 5-azacytidine, a DNA methyltransferase inhibitor, against multiple myeloma (MM) cells, and characterized DNA damage–related mechanisms of cell death. 5-Azacytidine showed significant cytotoxicity against both conventional therapy-sensitive and therapy-resistant MM cell lines, as well as multidrug-resistant patient-derived MM cells, with IC50 of ∼0.8–3 μmol/L. Conversely, 5-azacytidine was not cytotoxic to peripheral blood mononuclear cells or patient-derived bone marrow stromal cells (BMSC) at these doses. Importantly, 5-azacytidine overcame the survival and growth advantages conferred by exogenous interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or by adherence of MM cells to BMSCs. 5-Azacytidine treatment induced DNA double-strand break (DSB) responses, as evidenced by H2AX, Chk2, and p53 phosphorylations, and apoptosis of MM cells. 5-Azacytidine–induced apoptosis was both caspase dependent and independent, with caspase 8 and caspase 9 cleavage; Mcl-1 cleavage; Bax, Puma, and Noxa up-regulation; as well as release of AIF and EndoG from the mitochondria. Finally, we show that 5-azacytidine–induced DNA DSB responses were mediated predominantly by ATR, and that doxorubicin, as well as bortezomib, synergistically enhanced 5-azacytidine–induced MM cell death. Taken together, these data provide the preclinical rationale for the clinical evaluation of 5-azacytidine, alone and in combination with doxorubicin and bortezomib, to improve patient outcome in MM. [Mol Cancer Ther 2007;6(6):1718–27]
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-07-0010
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Abstract 387: Targeted exome sequences of cancer-related genes in human cancers using amplicon sequencing
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 387-387
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 387-387
    Abstract: Objectives: Next-generation sequencing technologies have revolutionized cancer genomics research by providing a comprehensive method of detecting somatic cancer genome alterations. Platforms for genomic DNA alterations are more common in clinical practice and include whole genome/exome sequencing analysis. These tests are still very expensive, although the costs are coming down substantially. Here, we aimed to determine the efficacy and advantages of targeted exome sequencing of known cancer-related genes in human cancers using amplicon sequencing. Methods: DNA was extracted from 61 human cancer specimens and their corresponding non-cancerous tissues, including oral squamous cell carcinomas (OSCCs) and multiple myelomas (MMs). Forty nanograms of DNA were used for multiplex PCR amplification with an Ion Ampliseq Comprehensive Cancer Panel that offers targeted coverage of all exons in 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers. This platform was designed to be amplification based capture with 15,992 regions (1.6 megabases in total size). Purified DNA libraries were sequenced with 6-8 samples on Ion Proton P1 chip. Sequence reads of tumor and normal samples were aligned to the hg19 genome, and generated BAM files were used to detect somatic mutations (point mutation, insertion and deletion) and copy number variations. Results: Each sample underwent on mean 8.4 million sequencing reads after quality filtering. The mean base coverage depth was 530, and & gt;95% of targeted bases were represented by at least 20 reads. The number of non-synonymous somatic mutations in 47 patients with OSCC ranged from 1 to 21 with a mean of 7.5 (6.4/Mb). The most frequent mutations in OSCC were in TP53 (63.8%), NOTCH1 (25.5%), CDKN2A (19.2%), TAF1L (17.0%), SYNE1 (14.9%) and PIK3CA (8.5%). We also detected a mean of 6.1 (range 3-11) non-synonymous mutations per MM patient. Somatic mutations were found in known MM-associated genes, including TP53 and NRAS. Pathway assessment has shown that somatic aberrations within MM genomes are mainly involved in several important pathways, including cell cycle regulation, RTK-MAPK-PI3K and NF-kB. We found several genetic alterations that may have been associated with the poor prognosis and poor response to chemotherapy of MM patients. Conclusions: This study demonstrates the utility of using a semiconductor-based sequencing to efficiently identify somatic genetic alterations in human cancers. The targeted next-generation sequencing using low amounts of FFPE DNA is a valuable tool for rapid (5 days) and high-throughput genetic testing in research and clinical settings. Citation Format: Yasushi Sasaki, Takafumi Nakagaki, Miyuki Tamura, Hisayo Fukushima, Hiroshi Ikeda, Ryota Koyama, Masashi Idogawa, Takashi Tokino. Targeted exome sequences of cancer-related genes in human cancers using amplicon sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 387. doi:10.1158/1538-7445.AM2017-387
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-387
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
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    Abstract 4424: Molecular diagnostics of drug resistant multiple myeloma cases using targeted next generation sequencing
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4424-4424
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4424-4424
    Abstract: In multiple myeloma (MM), there are two distinct genetic subtypes based on copy number alterations and translocations. About half of all MM cases are a hyperdiploid type, which is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21 and a lower prevalence of primary translocations involving the immunoglobulin heavy chain (IgH) locus at 14q32. The remaining cases are the non-hyperdiploid type, and chromosomes 8, 13, 14, and 16 are frequently lost. Non-hyperdiploid myeloma is strongly association with translocations of IgH alleles with various partner chromosomes, such as t(11;14)(q13;q32), t(4;14)(p16.3; q32), t(14;16)(q32;q23), t(6;14)(p21;q32) or t(14;20) (q32;q11). The copy number alterations in other chromosome regions such as 1q, 6q, 8p, and 16q occur in both subtypes. Overall, non-hyperdiploid MM is associated with worse survival than hyperdiploid MM. In this study, we sequenced all exons of 409 cancer-related genes in matched tumor and normal DNA from 5 non-hyperdiploid MM patients using a next-generation semiconductor sequencing protocol. DNA was extracted from magnetic bead-enriched bone marrow CD138 positive tumor cells from the patients and CD138 negative cells were used as matched normal cells. We detected both point mutations and copy number variations (CNVs). One individual with refractory MM (IgG λ type, ISS stage II) displayed 8 non-synonymous somatic mutations in addition to numbers of CNVs including CCND1 and RB1. We observed 2 point mutations and 3 CNVs, affecting NF-kB pathway genes: IKBKB, CYLD, IKBKE, CD79B and SYK. Although the basis of NF-kB pathway activation is only partially understood, our findings greatly expand the mechanisms by which NF-kB may be activated in this patient. We also detected several gene alterations, which may be associated with poor prognosis and poor response to chemotherapy in patients with refractory MM. Although its value should be further confirmed in larger samples, the targeted next generation sequencing is a valuable tool for high-throughput genetic testing in clinical research. Citation Format: Hiroshi Ikeda, Yasushi Sasaki, Tetsuyuki Igarashi, Yuka Aoki, Toshiaki Hayashi, Tadao Ishida, Takashi Tokino, Yasuhisa Sinomura. Molecular diagnostics of drug resistant multiple myeloma cases using targeted next generation sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4424. doi:10.1158/1538-7445.AM2015-4424
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4424
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
    Online Resource
    Online Resource
    BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 19 ( 2009-10-01), p. 7577-7586
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 19 ( 2009-10-01), p. 7577-7586
    Abstract: Several components of the Wnt signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances β-catenin–mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling. [Cancer Res 2009;69(19):7577–86]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-0773
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 6
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    Online Resource
    Abstract 3188: Targeted semiconductor sequencing of 409 cancer-related genes for somatic mutations and copy number variations in multiple myeloma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3188-3188
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3188-3188
    Abstract: Background: 2016's NCCN guideline recommended that induction therapy used conventional chemotherapy such as proteasome inhibitors and Imids in MM. Overall survival is improving by these Novel agents. However, we don't know how to choose these new agents. In the future, we can use next generation sequencer as a tool of drug choosing system. So we reviewed newly diagnosed 11 patients with MM who had received novel agents in our institution.The comprehensive analysis of genetic alterations in tumor by next generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. Method: DNA was extracted from magnetic bead-enriched bone marrow CD138-positive malignant plasma cells from 11 cases of MM, and CD138-negative cells were used as matched non-tumor cells. Forty nanograms of DNA were used for multiplex PCR amplification with an Ion Ampliseq Comprehensive Cancer Panel that offers targeted coverage of all exons in 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers. (covered regions: 95.4% of total). We sequenced 15,992 regions which obtained more than 1.5 megabases of target sequence. Result: Each sample underwent on average 8.3 million sequencing reads after quality filtering. The mean read depths were 539x, and & gt;95% of targeted bases were represented by at least 20 reads. The average number of non-synonymous mutations detected per patient was 5.8 (range 0-11). We also detected copy number variations in which segments of the genome can be duplicated or deleted from sequencing data. We found several genetic alterations that may have been associated with the poor prognosis and poor response to chemotherapy of MM patients. Pathway assessment has shown that somatic aberrations within MM genomes are mainly involved in several important pathways, including cell cycle regulation, RTK-MAPK-PI3K and NF-kB. Conclusion: We performed targeted next-generation sequencing for rapid (2 days), standardized, and cost-effective gene analysis of malignant plasma cells from patients with MM. We can use targeted next-generation sequencing as tool of drug choosing system. Citation Format: Hiroshi Ikeda, Yasushi Sasaki, Kazuya Ishiguro, Tadao Ishida, Yuka Aoki, Takashi Tokino. Targeted semiconductor sequencing of 409 cancer-related genes for somatic mutations and copy number variations in multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3188.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3188
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    detail.hit.zdb_id: 410466-3
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  • 7
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    GLI1 Interferes with the DNA Mismatch Repair System in Pancreatic Cancer through BHLHE41-Mediated Suppression of MLH1
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 24 ( 2013-12-15), p. 7313-7323
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24 ( 2013-12-15), p. 7313-7323
    Abstract: The mismatch repair (MMR) system is indispensable for the fidelity of DNA replication, the impairment of which predisposes to the development and progression of many types of cancers. To date, GLI1 transcription factor, a key molecule of the Hedgehog signaling pathway, has been shown to regulate the expression of several genes crucial for a variety of cancer cell properties in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), but whether GLI1 could control the MMR system was not known. Here, we showed that GLI1 and GLI2 indirectly suppressed the expression of MLH1 in PDAC cells. Through GLI1 target gene screening, we found that GLI1 and GLI2 activated the expression of a basic helix-loop-helix type suppressor BHLHE41/DEC2/SHARP1 through a GLI-binding site in the promoter. Consistent with a previous report that BHLHE41 suppresses the MLH1 promoter activity, we found that the activation of GLI1 led to the BHLHE41-dependent suppression of MLH1, and a double knockdown of GLI1 and GLI2 conversely increased the MLH1 protein in PDAC cells. Using TALEN-based modification of the MLH1 gene, we further showed that GLI1 expression was indeed associated with an increased tolerance to a methylating agent, methylnitrosourea cooperatively with a lower copy number status of MLH1. Finally, GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. On the basis of these results, we propose that GLI1 depresses the MMR activity and might contribute to the development and progression of PDAC. Cancer Res; 73(24); 7313–23. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-2008
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Dual Inhibition of Akt/Mammalian Target of Rapamycin Pathway by Nanoparticle Albumin-Bound –Rapamycin and Perifosine Induces Antitumor Activity in Multiple Myeloma
    American Association for Cancer Research (AACR) ; 2010
    In:  Molecular Cancer Therapeutics Vol. 9, No. 4 ( 2010-04-01), p. 963-975
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 9, No. 4 ( 2010-04-01), p. 963-975
    Abstract: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced phosphorylated Akt, resulting in enhanced cytotoxicity in MM.1S cells even in the presence of interleukin-6, insulin-like growth factor-I, or bone marrow stromal cells. Moreover, rapamycin-induced autophagy in MM.1S MM cells, as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin V/propidium iodide analysis and caspase/poly(ADP-ribose) polymerase cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nanoparticle albumin-bound–rapamycin and perifosine. Utilizing the in silico predictive analysis, we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggest that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed/refractory MM. Mol Cancer Ther; 9(4); 963–75. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-09-0763
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 9
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    GLI1 Modulates EMT in Pancreatic Cancer—Letter
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 14 ( 2012-07-15), p. 3702-3703
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 14 ( 2012-07-15), p. 3702-3703
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-0379
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 10
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    Abstract 3895: GLI1 induces the expression of bHLH type transcriptional repressor DEC2 in pancreatic cancer cells
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3895-3895
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3895-3895
    Abstract: Pancreatic ductal adenocarcinoma (PDA), a major histological subtype of pancreatic cancer, is one of most highly lethal tumors because of its local invasion and distant metastasis during the early stage of disease. Therefore, it is desired to uncover the molecular characteristics of this cancer and to develop novel strategies for overcoming its worse prognosis. The activated Hedgehog (Hh) signaling due to the over-expression of Sonic hedgehog (Shh) is crucial for the cellular proliferation and the other malignant phenotypes in a variety of human cancers including PDA. The intracellular Hh signaling is mediated by zinc-finger type of transcriptional factors, GLI1-3, however, little is known about their target genes. Based on these circumstances, we newly established stable PDA cell lines to analyze the target genes of GLI1. We established Panc-1GLI1ER, a derivative of human PDA cell line Panc-1, which stably expresses GLI1 cDNA fused to AF2 domain of Estrogen Receptor (ER), and its control Panc-1ER expressing the fusion gene lacking GLI1. Using Agilent 44K cDNA expression microarray, we analyzed the gene expression status of these cell lines with or without β-estradiol (E2) induction. Genes were classified into eight groups according to its relative expression levels on the early (3hrs) and the late (24hrs) phases of E2 treatment. 277 genes which were up-regulated on the early phase in Panc-1GLI1ER but not Panc-1ER were determined as putative GLI1 direct targets. Among these genes, we isolated several bHLH type transcriptional repressors such as DEC2, HES1, HES5, and HEYL. In this report, we focused on the expression of DEC2 in PDA cells. As well as PTCH, one of the GLI1 direct targets, RT-PCR analysis showed DEC2-up-regulation on the early phase of E2 treatment only in Panc-1GLI1ER. Cyclophosphamide (CHX) treatment did not affect its up-regulation and double knockdown of GLI1 and GLI2 suppressed the endogenous expression in PDA cells, which supports the notion that DEC2 is one of the direct GLI1 target genes. For further investigation, we established tetracycline dependent GLI1 inducible cell lines PANC-1Tet/GLI1 and its control cells PANC-1Tet/Empty. Doxycycline (DOX) elimination from drinking water leads to GLI1 expression in KSN mouse-transplanted PANC-1Tet/GLI1. Immunohistochemical analysis of the tumor revealed that DEC2 was up-regulated by GLI1 induction in vivo. It was reported that HIF1α-DEC2 pathway represses MLH1 gene expression and leads to microsatellite instability. Indeed, immunohistochemical analysis of transplanted PANC-1Tet/GLI1 cells showed repression of MLH1 protein in association with GLI1-dependent DEC2 induction in vivo. There by, Shh-GLI1-DEC2 pathway represses MLH1 expression and could be inducing microsatellite instability in pancreatic carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3895.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3895
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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