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  • 1
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    Abstract 2829: Pancreatic tumor microbiome and associated immune responses determine clinical outcomes
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2829-2829
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2829-2829
    Abstract: Most patients diagnosed with pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a very small subset of patients survive longer. The factors that determine the long-term survivorship remain elusive. Recently, studies have shown that bacteria can be found in PDAC which may influence therapy responses. In this study, we aimed to determine if the tumor microbiome, and its associated immune responses, can guide long-term survivorship in resected PDAC patients. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition and immunoprofile in PDAC patients who survived less than 5 years (short term survivors, STS) versus those who survived more than 5 years (long term survivors, LTS) in two independent cohorts of patients from two institutions (MD Anderson Cancer Center and Johns Hopkins University). We found higher alpha-diversity in the tumor microbiome from LTS compared to STS PDAC patients. Additionally, we found greater densities of immune cells in the LTS compared to STS, with significant correlation with alpha-diversity. Taken together, our study demonstrates that the PDAC microbiome composition may influence the host immune response and the natural history of the disease. E.R. and Y.Z. contributed equally to this work. Citation Format: Erick M. Riquelme, Yu Zhang, Liangliang Zhang, Montiel Maria, Zoltan Michelle, Wenli Dong, Pompeyo Quesada, Ismet Sahin, Vidhi Chandra, Anthony San Lucas, Paul Scheet, Hanwen Xu, Samir M. Hanash, Lei Feng, Nadim Ajami, Joseph Petrosino, Christine B. Peterson, Deborah Nejman, Michael P. Kim, Cynthia L. Sears, Laura D. Wood, Anirban Maitra, Ravid Straussman, Matthew Katz, James Robert White, Robert Jenq, Jennifer Wargo, Florencia McAllister. Pancreatic tumor microbiome and associated immune responses determine clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2829.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2829
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 1 ( 2010-01-05), p. 210-215
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 1 ( 2010-01-05), p. 210-215
    Abstract: T-cell activation results from productive T-cell receptor (TCR) engagement by a cognate peptide–MHC (pMHC) complex on the antigen presenting cell (APC) surface, a process leading to the polarization of the T-cell secretory machinery toward the APC interface. We have previously shown that the half-life of the TCR/pMHC interaction and the density of pMHC on the APC are two parameters determining T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate the efficiency of T-cell secretory machinery polarization toward an APC still remains unclear. Here, by using altered peptide ligands conferring different half-lives to the TCR/pMHC interaction, we have tested how this parameter can control T-cell polarization. We observed that only TCR/pMHC interactions with intermediate half-lives can promote the assembly of synapses that lead to T-cell activation. Strikingly, intermediate half-life interactions can be competed out by short half-life interactions, which can efficiently promote T-cell polarization and antagonize T-cell activation that was induced by activating intermediate half-life interactions. However, short TCR/pMHC interactions fail at promoting phosphorylation of signaling molecules at the T-cell–APC contact interface, which are needed for T-cell activation. Our data suggest that although intermediate half-life pMHC ligands promote assembly of activating synapses, this process can be inhibited by short half-life antagonistic pMHC ligands, which promote the assembly of non activating synapses.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0911258107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 3
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    Abstract 767: Oncogenic mutant KRAS modulates EZH2 expression through MEK-ERK and PI3K/AKT signaling in NSCLC: differential effects of different KRAS mutations and increased efficacy of inhibition combined with EZH2 targeted therapy
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 767-767
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 767-767
    Abstract: Background. EZH2 overexpression occurs in lung cancer and is associated with poor outcome. The mechanism(s) driving EZH2 expression in lung cancer are not fully understood and their identification would likely lead to new therapeutic targets in addition to drugs directly inhibiting EZH2 function. In this study, we investigated the mechanisms of EZH2 expression associated with oncogenic KRAS activation and whether pharmacological disruption of MEK-ERK and PI3K/AKT signaling pathways would affect EZH2 expression in a panel of NSCLC cell lines. Moreover, we investigated the efficacy of inhibition of MEK-ERK and PI3K/AKT with combined with direct EZH2 inhibition in KRAS mutant NSCLC cell lines. Methods. NSCLC cell lines were treated with different doses of MEK-ERK inhibitor AZD6244 and PI3K/AKT inhibitor MK2206 and the expression of EZH2, MEK, MAPK and AKT were determined by Western-blotting. We knockdown KRAS expression using small interfering RNA (siRNA). EZH2 expression was correlated with KRAS mutation status in NSCLC tumor samples. Tumor cell inhibition (IC50 values) by AZD6244, MK2206 and drug combination with EZH2 inhibitor 3-deazaneplanocin A (DZNep) (AZD6244+DZNep and MK2206+DZNep) was determined by MTS assay. Results. In NSCLC tissues we found that the expression of EZH2 was higher in tumors with a KRAS G12C mutation compared with the other types of KRAS amino acid substitutions. Knockdown of KRAS down-regulated EZH2 expression in cell lines harboring KRAS G12C and G12D mutations, but not in cells having other types of KRAS mutations. Pharmacological disruption of signaling MEK-ERK pathway with AZD6244 decreased EZH2 expression, and this effect correlated with the type of KRAS mutation, with a higher reduction occurring in NSCLCs harboring KRAS G12C mutation compared with the other types of mutations. By contrast, MK2206 strongly decreased EZH2 expression in NSCLCs with KRAS G12D mutation compared with the other type of KRAS mutations. Interestingly, the combination of MEK-ERK with EZH2 inhibitors enhanced the sensitivity to AZD6244 in KRAS G12C mutant cell lines compared to the other mutations. The combination of PI3K/AKT with EZH2 inhibitors enhanced the sensitivity to MK2206 in NSCLC cell lines with KRAS G12D mutation compared with other types of KRAS mutations.Conclusions. Our findings suggest that: 1. oncogenic KRAS G12C and G12D mutations differentially modulate EZH2 expression through MEK-ERK and PI3K/AKT signaling respectively - indicating the need for specific KRAS mutation guided therapy; 2. Inhibition of MEK-ERK and PI3K/AKT in combination with an EZH2 inhibitor should result in a significant increased sensitivity to MEK-ERK and PI3K/AKT targeted therapy in KRAS mutant lung cancers. (Grant support: 5 R01 CA155196 and P50CA70907) Citation Format: Erick M. Riquelme, Li Shen, Jing Wang, Carmen Behrens, George Simon, Vassiliki Papadimitrakopoulou, John D. Minna, Ignacio I. Wistuba. Oncogenic mutant KRAS modulates EZH2 expression through MEK-ERK and PI3K/AKT signaling in NSCLC: differential effects of different KRAS mutations and increased efficacy of inhibition combined with EZH2 targeted therapy. [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 767. doi:10.1158/1538-7445.AM2015-767
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-767
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
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    Abstract 1714: EZH2Hig h and miR-101Lo w expressions are associated with chemoresistance and shorter survival in patients with lung adenocarcinoma who received adjuvant chemotherapy
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1714-1714
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1714-1714
    Abstract: Background. EZH2 (a histone methyltransferase and part of the polycomb repressive complex-2) has been implicated in neoplastic transformation, tumor progression, and resistance to chemotherapy. Though EZH2 overexpression has been described in non-small cell lung cancer (NSCLC), there have been no functional studies reported. Recently, it has been demonstrated that miR-101 negatively regulates the expression of EZH2. In this study, we investigated the effect of EZH2 and miR-101 expression levels on the outcome of lung adenocarcinoma patients treated with surgery and adjuvant chemotherapy, and analyzed in vitro mechanisms associated with the role in chemoresistance and cell migration of lung adenocarcinoma. Methods. We analyzed EZH2 and miR-101 expression in RNA extracted from 151 lung adenocarcinoma tumors obtained from patients treated with surgery with (n=57) or without (n=94) platinum adjuvant therapy, and compared those data with patients’ overall survival (median follow-up 5.6 years). EZH2 and miR-101 expression levels were tested using Illumina mRNA arrays W6-6 V.3 and Agilent V3 human microRNA, respectively. We knockdown EZH2 expression in adenocarcinoma cell lines using small interfering RNA (siRNA). Cisplatin sensitivity (IC50) was determined by MTS assay. Cell migration was measured using Boyden chamber. Results. We found that, high EZH2 expression (p=0.007) and low miR101 (p=0.01) expression were significantly associated with worse overall survival in lung adenocarcinoma patients who received platinum adjuvant therapy, but not in patients who did not receive such therapy. Similar results (p=0.008) were observed when combined EZH2High/miR-101Low expression was examined. From a panel of 21 adenocarcinoma cell lines with known EZH2 gene/protein expression, we selected 4 cell lines: 2 with high EZH2 (H1993 and HCC1171), and 2 with low EZH2 (HCC461 and HCC193) expression. Knockdown of EZH2 using siRNA reduced cell migration of H1993 and HCC1171 cells (3.7-fold decrease and 1.7-fold, respectively, p & lt;0.05), but not of HCC193 and HCC461 cells. Knockdown of EZH2 significantly decreased (p & lt;0.05) the viability (by MTS assay) of cell lines H1993 and HCC1171 when treated with cisplatin, but not of HCC193 and HCC461 cells. Conclusion. Our in vitro findings suggest that EZH2 overexpression may promote a more malignant phenotype of lung adenocarcinoma, including increased chemoresistance and cell migration capabilities. Expression of EZH2 and miR-101 may represent a predictive marker of worse outcome in lung adenocarcinoma patients treated with surgery and adjuvant platinum chemotherapy. EZH2 is a potential target that regulates the epigenome to overcome drug resistance in lung cancer (Supported in part by grants DoD PROSPECT W81XWH-07-1-0306 and NCI/UT Lung SPORE 5P50CA70907-11, ER, Becas Chile program) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1714. doi:1538-7445.AM2012-1714
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1714
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 5
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    Abstract 651: Revealing the role of lung cancer microbiota in the tumor progression
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 651-651
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 651-651
    Abstract: Lung cancer (LC) remains as the leading cause of death by cancer worldwide. In Chile, LC is the second cause of cancer-related deaths. Recently, studies in melanoma and non-small cell lung cancer (NSCLC) patients have highlighted the role of the gut microbiota as an important host factor in mediating the responses/resistance to immunotherapy, suggesting that bacteria present in the gut may modulate the immune response in these tumors. However, the role of extra-intestinal microbiota; bacteria living outside of the gut, in cancer pathogenesis and the response to anti-cancer therapies remains largely undetermined. Here we characterize the composition of intratumoral microbiota of NSCLC and seek to establish a functional relationship between it and the composition of the immune microenvironment and the clinicopathological characteristics of NSCLC patients. From the first 157 FFPE NSCLC samples, we extracted DNA from all collected samples, obtaining adequate material in quality and quantity to later be submitted for analysis to 16S sequencing. Using 16S rRNA gene sequencing, we assessed the general landscape of the NSCLC tumor microbiome, revealing the presence of large number of bacterial communities in the NSCLC tumor samples on the different histological subtypes analyzed. We have detected differences in alpha diversity in the histological subtypes studied. Even more interesting, we have detected significant differences in lung adenocarcinoma depending on the degree of histological differentiation, observing a decrease in proteobacteria and an enrichment of Bacteroidales, as cell differentiation is lost. Additionally, we identified taxonomic differences between differentiated and undifferentiated tumors. Differentiated tumors show enrichment in Akkermansia muciniphila and while undifferentiated tumors show enrichment in Actinobacter Corynebacterium. Suggesting that these taxa could contribute to maintaining a differentiated state or inducing cell dedifferentiation, respectively. Our results reveal the presence of a large number of bacterial communities in lung cancer samples in the different histological subtypes analyzed. Suggesting that these communities could play a key role in tumor differentiation and progression. Citation Format: Erick M. Riquelme, Ivania Valdes, Carlos Aravena, Ilse Valencia, Barbara Mino, Daniel Carvajal, Alberto Martin. Revealing the role of lung cancer microbiota in the tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 651.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-651
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract 4031: CNG c-myc in mesothelioma
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4031-4031
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4031-4031
    Abstract: Background Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis, few treatment options, and an increasing incidence worldwide. There is, therefore, a great need to identify new therapeutic targets and develop more effective therapies for patients with MPM. To better characterize the molecular changes occurring in MPM, we determined genetic and proteomic abnormalities in MPM cell lines and correlated them with those found in MPM tumor tissue specimens. Methods We performed SNP/copy number analysis using Affymetrix SNP 6.0 chips, messenger RNA (mRNA) analysis using Affymetrix U133 plus 2.0 chips, and Reverse Protein Phase Array (RPPA) analysis in 4 mesothelioma cell lines (H28, MSTO-211H, H2052 and H2452) along with the control normal cell line HCT-4012, for comparison. DNA copy number microarray data were analyzed using the Nexus 5.0 software (BioDiscovery Inc.), while mRNA expression array data were analyzed using the GeneSpring GX 11 software (Agilent technologies, Inc.). Additionally, we evaluated copy number gain (CNG) of the c-myc gene and expression of c-myc protein in the mesothelioma cell lines and control cell line by fluorescent in situ hybridization (FISH) and Western blot, respectively. Furthermore, we investigated CGN in MPM tumor tissue specimens by performing FISH using the c-myc probe on tissue microarrays (TMAs) containing 80 MPM samples from different histological subtypes (41 epithelioid, 27 biphasic, 12 sarcomatoid). Results DNA copy number analysis using the Affymetrix chip revealed CNG or amplification of the c-myc oncogenic locus in 3 out of 4 mesothelioma cell lines compared to the control HCT-4012 cell line. In concordance, the mRNA microarray data also showed increased number of transcripts from this locus; more importantly, the RPPA array data showed increased c-myc protein expression in these cell lines compared to control. These results were confirmed by FISH and Western blot analysis, which showed CNG or amplification at this locus and increased levels of the c-myc protein in the mesothelioma cell lines. FISH analysis of TMAs also revealed a relatively high frequency (21%) of CNG (≥4 copies in ≥70% of cells) for the c-myc locus in the MPM tumors. Interestingly, this amplification were seen in either epithelioid (10%) or biphasic (11%) histotype, and none were observed in the sarcomatoid cases. Similarly, within the biphasic cases, we observed that the amplification was present only in the epithelioid component, and not in the sarcomatoid component. Conclusion Our findings suggest that CNG of the c-myc locus is characteristic for MPM tumors of the epithelioid histotype or of the epitheloid component of biphasic histotype, and suggest that c-myc CNG could have a role in pathogenesis of this disease; however, further studies are needed to clarify the role of c-myc in MPM development and progression. Supported by grant US DoD W81XWH-07-1-0306. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4031. doi:10.1158/1538-7445.AM2011-4031
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-4031
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    Abstract 2332: Oncogenic mutant KRAS modulates EZH2 expression through MEK-ERK signaling by remodeling gene expression in NSCLC
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2332-2332
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2332-2332
    Abstract: Abstract: Background. EZH2 overexpression occurs in lung cancer and is associated with a poor outcome. The mechanisms driving EZH2 expression in lung cancer are not fully understood. In this study, we investigated whether pharmacological disruption of signaling MEK-ERK pathway would affect EZH2 expression in a panel of NSCLC cell lines with and without KRAS mutation. Moreover, we analyzed the transcriptome expression following knockdown of EZH2 expression in NSCLC cell lines with different types of KRAS mutations. Methods. NSCLC cell lines were treated with different doses of MEK inhibitor AZD6244 (0, 0.5 and 1μM) and the expressions of EZH2, MEK and MAPK were determined by Western-blots. Cell lines were transfected with gene-specific EZH2 siRNA and control siRNA. Gene expression profiling was performed using the Illumina Human HT-12 v 4.0 platform. Functional pathway analysis was conducted using the software Ingenuity Pathways Analysis. Result. We found that pharmacological disruption of signaling MEK-ERK pathways with AZD6244 decreases the expression of MAPK p44/42 and phospho-MAPK p44/42 in all NSCLC cell lines analyzed wild-type and of KRAS mutant status. However, after AZD6244 treatment, EZH2 expression in NSCLC cell lines varied according to the KRAS mutation status: strong reduction only in NSCLC cell lines harboring GtoC mutation, a partial reduction in cells with GtoS and GtoR mutation, and no change in cell lines with GtoD or GtoV mutation and with wild-type KRAS. The gene expression analysis revealed that 3,235 genes were similarly regulated for mutant KRAS GtoC, GtoD and GtoV in NSCLC following EZH2 knockdown compared with KRAS wild-type (P & lt; 0.05). Functional pathways analysis showed that EZH2 knockdown modulated differentially pathways commonly activated in cancer as growth factor signaling, molecular mechanism of cancer and cellular growth, proliferation and development, between cell lines that harbor mutant KRAS GtoC, GtoD or GtoV compared with KRAS wild-type. Conclusion. Our findings suggest that oncogenic mutant KRAS GtoC, GtoS and GtoR modulate EZH2 expression through MEK-ERK signaling contributing to changes of the expression of genes frequently altered in cancer (Grant support: 5 R01 CA155196 and P50CA70907) Citation Format: Erick M. Riquelme, Li Shen, Jing Wang, Carmen Behrens, John D. Minna, Ignacio I. Wistuba. Oncogenic mutant KRAS modulates EZH2 expression through MEK-ERK signaling by remodeling gene expression in NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2332. doi:10.1158/1538-7445.AM2014-2332
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2332
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 8
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    Abstract 4643: EZH2 promote a malignant phenotype in lung adenocarcinoma and VEGF/VEGFR2 pathways mediates regulation of EZH2 through E2F3/HIF-1α and downregulation of miR-101.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4643-4643
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4643-4643
    Abstract: Background. EZH2 overexpression has been described in a wide variety of tumors, including lung cancer. EZH2 has been implicated in neoplastic transformation, tumor progression and activation of angiogenesis. The mechanisms associated with the regulation of EZH2 expression in lung cancer cells are mostly unknown. In this study, we investigated the role of EZH2 in cell proliferation/migration and response to chemotherapy in lung adenocarcinoma (LADCa) cell lines. Moreover, we studied the mechanisms of EZH2 regulation associated to the VEGF/VEGFR2 pathway expression. Methods. LADCa cell lines were inhibited pharmacologically with different doses of DZNep (0, 2.5 and 5μM) and by knockdown of EZH2 by siRNA. EZH2, H3K27me3 and PARP-C expressions were determined by Western-blots (WB). Cisplatin and carboplatin sensitivity (IC50) and proliferation were determined by MTS assay. Cell migration was measured using Boyden chamber assay. After stimulation of cell lines with VEGF-A, EZH2, VEGFR-2, E2F3 and HIF-1α expression were determined using WBs, and EZH2 and miR-101 expressions were determined by quantitative PCR. To study the role of VEGFR-2 and HIF-1α in the regulation of EZH2, we examined the effect of knockdown VEGFR-2 and HIF-1α by siRNA. Results. We found that inhibition with DZNep and knockdown by siRNA decreased the expression of EZH2, reduced H3K27me3 level, and increased PARP-C levels in LADCa cell lines. Treatment with DZNep and knockdown of EZH2 significantly increased sensitivity to cisplatin and carboplatin (p & lt;0.05) by MTS assay of LADCa cell lines. Knockdown of EZH2 reduced significantly cell proliferation and migration of LADCa cell lines (p & lt;0.05). VEGF stimulation induced expression of EZH2 and H3K27me3 levels. Concomitantly, we found that stimulation with VEGF induced expression of E2F3 and HIF-1α, and downregulation of miR-101. This phenomenon was observed only in LADCa cell lines expressing VEGFR-2, and not in cell lines with low or lack of expression of VEGFR-2. The increased expression of EZH2, E2F3 and HIF-1α, and the down-regulation of miR-101 in response to VEGF, were reduced by knocking down VEGFR-2 and to a lesser degree by knocking down HIF-1α in LADCa. Conclusion. Our in vitro findings suggest that EZH2 overexpression may promote a more malignant phenotype of lung adenocarcinoma. The pharmacologic inhibition with DZNep and knockdown of EZH2 by siRNA increased sensitivity of LADCa cell lines to cisplatin and carboplatin, and reduced cell migration capabilities. Our results suggest that VEGF/VEGFR-2 axis plays a role in the regulation of EZH2 through E2F3/HIF-1α and miR-101 regulations. EZH2 is a potential therapeutic target in lung cancer that regulates the epigenome to overcome drug resistance. (Supported in part by grants DoD PROSPECT W81XWH-07-1-0306, NCI/UT Lung SPORE 5P50CA70907-11, and Becas Chile) Citation Format: Erick M. Riquelme, Carmen Berhens, Milind Suraokar, Ignacio I. Wistuba. EZH2 promote a malignant phenotype in lung adenocarcinoma and VEGF/VEGFR2 pathways mediates regulation of EZH2 through E2F3/HIF-1α and downregulation of miR-101. [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 4643. doi:10.1158/1538-7445.AM2013-4643
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4643
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    Author Correction: Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells
    Springer Science and Business Media LLC ; 2023
    In:  Nature Communications Vol. 14, No. 1 ( 2023-02-03)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-02-03)
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-023-36369-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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    Author Correction: Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells
    Springer Science and Business Media LLC ; 2022
    In:  Nature Communications Vol. 13, No. 1 ( 2022-10-31)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-10-31)
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-022-34311-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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