Constitutive Activation of STAT3 Signaling Regulates hTERT and Promotes Stem Cell-Like Traits in Human Breast Cancer Cells
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{"title"=>"Constitutive activation of STAT3 signaling regulates hTERT and promotes stem cell-like traits in human breast cancer cells", "type"=>"journal", "authors"=>[{"first_name"=>"Seyung S.", "last_name"=>"Chung", "scopus_author_id"=>"55931988300"}, {"first_name"=>"Clement", "last_name"=>"Aroh", "scopus_author_id"=>"56028501600"}, {"first_name"=>"Jaydutt V.", "last_name"=>"Vadgama", "scopus_author_id"=>"7004578978"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84893530696", "sgr"=>"84893530696", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0083971", "pmid"=>"24386318", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pui"=>"372325165"}, "id"=>"a83f1080-df8c-3a0c-9f99-c415f72afe68", "abstract"=>"Mounting clinical data suggest that high telomerase activity is tightly associated with cancer progression and poor outcomes. Constitutively activated STAT3 is found in ∼60% of human malignancies and shows a dismal prognosis. We previously reported that activated STAT3 promoted epithelial-mesenchymal transition (EMT) and cancer stem cell phenotype in human breast cancer. However, little is known how STAT3 is regulated in the cancer stem cell and by which mechanisms STAT3 contributes to poor prognosis in aggressive breast cancer. Here we demonstrate that STAT3 physically interacts with CD44 and NF-kB and activates the catalytic subunit of telomerase (hTERT) in human breast cancer stem cells. STAT3 plays a role as a signal transducing molecule between CD44 and NF-kB. In addition to functioning as a catalytic subunit of telomerase, hTERT has been reported to function as a transcription co-factor which drives EMT and cancer stem cell phenotype in human cancer. We observed that activated hTERT increases CD44 (+) subpopulation, whereas targeted knock-down of hTERT abolished cancer stem cell phenotype. Targeted STAT3 knock-down cells also down-regulated hTERT and decreased CD44 subpopulation. Finally, CD44 knock-down resulted in the abrogation of cancer stem cell phenotype and concurrent down-regulation of pSTAT3 and hTERT. Our study delineates the signaling pathway where STAT3 functions as a modulator for CD44 and hTERT, promoting a cancer stem cell phenotype. The constitutive activation of STAT3 signaling that leads to regulation of hTERT pathway may provide novel therapeutic targets for human breast cancer stem cells.", "link"=>"http://www.mendeley.com/research/constitutive-activation-stat3-signaling-regulates-htert-promotes-stem-celllike-traits-human-breast-c-1", "reader_count"=>25, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>7, "Agricultural and Biological Sciences"=>7, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>5}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1332312"], "description"=>"<p>A: FACS profiles of MCF7_HER2. CD44-FITC was stained for MCF7-HER2 (passage 30) and subjected to FACS profiling. As shown in the figure, MCF7-HER2 possessed 76.72% of CD44 (+) cell population. B. CD44 FACS profiles of MDA-MB-231. CD44-FITC was stained for MDA-MB-231 and subjected FACS profiling. MDA-MB-231 possessed 99.05% of CD44 (+) cell population.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling in selected disciplines", "Oncogenic signaling", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "Cancer detection and diagnosis", "Cancers and neoplasms", "mcf7-her2", "mda-mb-231", "cd44", "cellular"], "article_id"=>889229, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Seyung S. Chung", "Clement Aroh", "Jaydutt V. Vadgama"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083971.g005", "stats"=>{"downloads"=>4, "page_views"=>87, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Both_MCF7_HER2_and_MDA_MB_231_possess_high_CD44_cellular_populations_/889229", "title"=>"Both MCF7-HER2 and MDA-MB-231 possess high CD44 (+) cellular populations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-30 03:24:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1332307"], "description"=>"<p>A: Tumorosphere formation assay. When hTERT was knocked-down, the tumorosphere formation was inhibited <i>in vitro</i>. hTERT knock-down cells were subjected to three dimensional culture condition and were examined for tumor sphere formation after 5 days. B: Quantitative representation of tumorospheres formed in MCF7-HER2 and hTERT knock-down cells. C: Boyden chamber assay. Cell invasiveness was examined by employing Boyden chamber assay. MCF7-HER2 and hTERT knock-down cells were subjected to Boyden chamber assay. Again, less cells invaded the filters when hTERT expression was silenced. D: The cell invasion assay was quantitatively measured in graphic representation.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling in selected disciplines", "Oncogenic signaling", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "Cancer detection and diagnosis", "Cancers and neoplasms", "htert", "suppressed", "tumorigenecity", "invasiveness"], "article_id"=>889224, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Seyung S. Chung", "Clement Aroh", "Jaydutt V. Vadgama"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083971.g004", "stats"=>{"downloads"=>0, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcriptional_silencing_of_hTERT_suppressed_the_tumorigenecity_and_invasiveness_in_vitro_/889224", "title"=>"Transcriptional silencing of hTERT suppressed the tumorigenecity and invasiveness <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-30 03:24:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1332304"], "description"=>"<p>Targeted knock-down of STAT3 and chemical inhibition of pSTAT3 both down-regulated hTERT and CD44 expression levels. A: STAT3 shRNA mediated knock-down cells showed decreased expression levels of both hTERT and CD44. Western blot analyses were performed with STAT3 knock-down cells for monitoring hTERT, CD44 and CD24. B: Chemical inhibition of pSTAT3 with stattic also showed the reduced expression levels of hTERT and CE44. Stattic (5 µM) was treated for 24 hours, then proteins expression levels of pSTAT3, hTERT, CD44 and CD24 were examined. C: Western analyses of hTERT knock-down also revealed that CD44 reduction and pSTAT3 inhibition. D: Schematic representation of the interaction of the STAT3 protein with the STRING analysis. Protein-protein interaction database STRING was utilized to search the STAT3 protein interactions.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling in selected disciplines", "Oncogenic signaling", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "Cancer detection and diagnosis", "Cancers and neoplasms", "pstat3", "down-regulated", "htert", "knock-down"], "article_id"=>889222, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Seyung S. Chung", "Clement Aroh", "Jaydutt V. Vadgama"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083971.g003", "stats"=>{"downloads"=>0, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_pSTAT3_down_regulated_hTERT_as_well_as_hTERT_knock_down_down_regulated_CD44_/889222", "title"=>"Inhibition of pSTAT3 down-regulated hTERT as well as hTERT knock-down down-regulated CD44.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-30 03:24:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1332298"], "description"=>"<p>The promoter region of the <b>hTERT</b> gene possessed consensus STAT3-binding sites. Primer sets were designed flanking the putative STAT3-binding sites 1 and 2. Chip assay was performed with the primers. <b>A:</b> Diagram of hTERT promoter with location of consensus STAT3-binding sites 1 and 2 indicated. B: Chip assay was done on the MDA-MB-231 lysates using anti-STAT3 antibody or IgG (control) and protein-A agarose beads as described in Materials and Methods. STAT3 inhibitor stattic was treated for 24 hours and subjected to Chip assay to monitor STAT3 binding to hTERT promoter. Input samples are DNAs amplified from lysates before immunoprecipitation. C: Chip assay was done on the MCF7-HER2 lysates using anti-STAT3 antibody or IgG (control) and protein-A agarose beads.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling in selected disciplines", "Oncogenic signaling", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "Cancer detection and diagnosis", "Cancers and neoplasms", "binds", "htert", "promoter"], "article_id"=>889219, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Seyung S. Chung", "Clement Aroh", "Jaydutt V. Vadgama"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083971.g002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_STAT3_binds_to_the_hTERT_promoter_region_/889219", "title"=>"STAT3 binds to the hTERT promoter region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-30 03:24:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1332297"], "description"=>"<p>A: Immuno-precipitation with STAT3 antibody revealed that NF-kB and CD44 were bound to STAT3 in MDA-MB-231 cell line. STAT3 pull-down was performed in the cytoplasm and nuclear extracts separately. STAT3 was bound CD44 in the cytoplasm and bound to NF-kB in both cytoplasm and nuclear extracts. B: Pull-down assay with STAT3 antibody showed that STAT3 interaction with NF-kB and CD44 held true in MCF7-HER2. C: Real time PCR data showed that hTERT mRNA expressions were up-regulated in pSTAT3 activated cancer cell lines. MCF7 wild type was used as a control for hTERT mRNA expression of 1 fold. D: Western blot analyses: Up-regulation of hTERT expression was associated with pSTAT3 activation in human breast cancer.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling in selected disciplines", "Oncogenic signaling", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "Cancer detection and diagnosis", "Cancers and neoplasms", "binds", "nf-kb", "cd44", "cancer", "telomerase", "transcriptase", "up-regulated", "pstat3", "activated"], "article_id"=>889218, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Seyung S. Chung", "Clement Aroh", "Jaydutt V. Vadgama"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083971.g001", "stats"=>{"downloads"=>6, "page_views"=>337, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_STAT3_binds_NF_kB_and_CD44_in_breast_cancer_and_telomerase_reverse_transcriptase_hTERT_is_up_regulated_in_pSTAT3_activated_breast_cancer_cells_/889218", "title"=>"STAT3 binds NF-kB and CD44 in breast cancer and telomerase reverse transcriptase (hTERT) is up-regulated in pSTAT3 activated breast cancer cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-30 03:24:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1332314"], "description"=>"<p>STAT3 was found to bound CD44 and NF-kB concurrently. STAT3-NF-kB complex translocates into nucleus and binds to hTERT promoter and activated hTERT expression. Activated hTERT enhances CD44 expression in an autocrine manner in breast cancer stem cells.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling in selected disciplines", "Oncogenic signaling", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "Cancer detection and diagnosis", "Cancers and neoplasms", "diagrams", "stat3-htert-cd44", "autocrine", "cancer"], "article_id"=>889231, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Seyung S. Chung", "Clement Aroh", "Jaydutt V. Vadgama"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083971.g007", "stats"=>{"downloads"=>13, "page_views"=>817, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_diagrams_of_STAT3_hTERT_CD44_autocrine_signaling_in_breast_cancer_cells_/889231", "title"=>"Schematic diagrams of STAT3-hTERT-CD44 autocrine signaling in breast cancer cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-30 03:24:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1332313"], "description"=>"<p>A: Tumorosphere formation assay of CD44 knock-down cells. A representative area was pictured from the tumorosphere cultures from MDA-MB-231 control RNA and CD44 transfected cells. B: Quantitative graph was presented for the tumor sphere formation assay of CD44 knock-down cells. C: Western analyses of CD44 shRNA transfected cells. Protein expression levels were examined for hTERT, pSTAT3, CD44 and CD24 from the CD44 knock-down cells. Downstream genes of pSTAT and hTERT levels were presented.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling in selected disciplines", "Oncogenic signaling", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "Cancer detection and diagnosis", "Cancers and neoplasms", "repression", "cd44", "suppressed", "tumorigenecity", "pstat3"], "article_id"=>889230, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Seyung S. Chung", "Clement Aroh", "Jaydutt V. Vadgama"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083971.g006", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcriptional_repression_of_CD44_suppressed_the_tumorigenecity_and_pSTAT3_activation_/889230", "title"=>"Transcriptional repression of CD44 suppressed the tumorigenecity and pSTAT3 activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-30 03:24:36"}

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Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[269, 466, 588, 697, 800, 896, 988, 1076, 1165, 1254, 1340, 1417]}, {"subject_area"=>"/Biology and life sciences/Cell biology", "average_usage"=>[272, 472, 600, 713, 815, 911, 1004, 1094, 1185, 1273, 1358, 1441]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[284, 491, 620, 738, 843, 945, 1043, 1137, 1225, 1315, 1400, 1479, 1555]}, {"subject_area"=>"/Biology and life sciences/Molecular biology", "average_usage"=>[272, 466, 589, 702, 806, 903, 995, 1086, 1176, 1258, 1347, 1422, 1493]}, {"subject_area"=>"/Medicine and health sciences", "average_usage"=>[264, 460, 584, 692, 794, 887, 978, 1067, 1154, 1241, 1328, 1408, 1474]}, {"subject_area"=>"/Medicine and health sciences/Oncology", "average_usage"=>[249, 468, 599, 718, 820, 920, 1008, 1093, 1181, 1281, 1357, 1444, 1517]}]}
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