Promoter Methylation-Mediated Silencing of β-Catenin Enhances Invasiveness of Non-Small Cell Lung Cancer and Predicts Adverse Prognosis
Publication Date
November 14, 2014
Journal
PLoS ONE
Authors
Yuan Miao, Liang Wang, Xiupeng Zhang, Xiaohan Xu, et al
Volume
9
Issue
11
Pages
e112258
DOI
https://dx.plos.org/10.1371/journal.pone.0112258
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0112258
Web of Science
000345558500041
Scopus
84911499062
Mendeley
http://www.mendeley.com/research/promoter-methylationmediated-silencing-%CE%B2catenin-enhances-invasiveness-nonsmall-cell-lung-cancer-pred
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Mendeley | Further Information

{"title"=>"Promoter methylation-mediated silencing of β-catenin enhances invasiveness of non-small cell lung cancer and predicts adverse prognosis", "type"=>"journal", "authors"=>[{"first_name"=>"Yuan", "last_name"=>"Miao", "scopus_author_id"=>"35277557900"}, {"first_name"=>"Liang", "last_name"=>"Wang", "scopus_author_id"=>"57075008700"}, {"first_name"=>"Xiupeng", "last_name"=>"Zhang", "scopus_author_id"=>"37562330800"}, {"first_name"=>"Xiaohan", "last_name"=>"Xu", "scopus_author_id"=>"56422706300"}, {"first_name"=>"Guiyang", "last_name"=>"Jiang", "scopus_author_id"=>"12041986400"}, {"first_name"=>"Chuifeng", "last_name"=>"Fan", "scopus_author_id"=>"7402656597"}, {"first_name"=>"Yang", "last_name"=>"Liu", "scopus_author_id"=>"55742253500"}, {"first_name"=>"Xuyong", "last_name"=>"Lin", "scopus_author_id"=>"35210878000"}, {"first_name"=>"Juanhan", "last_name"=>"Yu", "scopus_author_id"=>"8655083600"}, {"first_name"=>"Yong", "last_name"=>"Zhang", "scopus_author_id"=>"55954398900"}, {"first_name"=>"Enhua", "last_name"=>"Wang", "scopus_author_id"=>"7403414327"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"600506553", "doi"=>"10.1371/journal.pone.0112258", "sgr"=>"84911499062", "scopus"=>"2-s2.0-84911499062", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"25396757"}, "id"=>"c08ed369-f175-3767-87d2-4a49d62518a1", "abstract"=>"β-Catenin plays dual role in adhesion complex formation and the Wnt signaling pathway. Although β-catenin expression appears to be upregulated and Wnt signaling pathway is activated in the majority of cancers, its expression level seems to be lost in non-small cell lung cancer (NSCLC). We previously reported that the promoter of β-catenin was hypermethylated in two NSCLC cell lines. In the current study, we expanded our analysis for the methylation status of β-catenin promoter region and its protein expression in seven NSCLC cell lines and a series of 143 cases of primary human lung cancer with adjacent non-neoplastic tissues. Quantitative methylation specific PCR (qMSP) analysis showed methylation of β-catenin promoter region in five NSCLC cell lines, with increased β-catenin protein levels upon 5'-Aza-2'-deoxycytidine (5-aza-dC) treatment. The methylation status in SPC (methylated) and A549 (unmethylated) was confirmed by bisulfite sequencing PCR. 5-Aza-dC treatment inhibited invasiveness of SPC but not A549. Immunofluorescence analysis showed membranous β-catenin expression was lost in SPC and could be re-established by 5-aza-dC, while Wnt3a treatment led to nuclear translocation of β-catenin in both SPC and A549. Dual-luciferase assays indicated that 5-aza-dC treatment caused no significant increase in Wnt signaling activity compared with Wnt3a treatment. The effect of demethylation agent in SPC can be reversed by β-catenin depletion but not E-cadherin depletion which indicated that the methylation mediated β-catenin silencing might enhance NSCLC invasion and metastasis in an E-cadherin independent manner. Subsequent immunohistochemistry results further confirmed that β-catenin promoter hypermethylation correlated with loss of immunoreactive protein expression, positive lymph node metastasis, high TNM stage and poor prognosis. The present study implicates β-catenin promoter hypermethylation in the mechanism of epigenetic changes underlying NSCLC metastasis and progression, thus indicating the potential of β-catenin as a novel epigenetic target for the treatment of NSCLC patients.", "link"=>"http://www.mendeley.com/research/promoter-methylationmediated-silencing-%CE%B2catenin-enhances-invasiveness-nonsmall-cell-lung-cancer-pred", "reader_count"=>11, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>1, "Professor"=>2, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>1, "Professor"=>2, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_subject_area"=>{"Environmental Science"=>2, "Agricultural and Biological Sciences"=>5, "Medicine and Dentistry"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Environmental Science"=>{"Environmental Science"=>2}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1795001"], "description"=>"<p>After knockdown of β-catenin (A) or E-cadherin (C), protein expression of SPC and A549 cell lines were examined 48 h after 5-aza-dC treatment using the indicated antibodies. (B, D) Graphs show the quantification of protein expression after 5-aza-dC treatment and siRNA transfection. GAPDH was used as a control. (E) Representative images of cells on the bottom of the Transwell membranes show the changes in invasive cell numbers (×400, Scale bar = 50 µm). (F) Number of cells invading onto the lower surface of the filter was counted, each carried out in triplicate. (Bars represent SD. *<i>P</i><0.05, compared to the control). (G) Dual-luciferase assay results show that both 5-aza-dC treatment and β-catenin depletion resulted in no significant changes in Wnt signaling activities compared with Wnt3a treated cells. Each of the experiments was repeated in triplicate. (H) Immunofluorescent staining showing that the membranous β-catenin is enhanced by 5-aza-dC treatment only in SPC cell line, but not in A549 cell line. Depletion of β-catenin attenuates membranous β-catenin in both SPC and A549 cell lines, but depletion of E-cadherin has no effect on membranous expression of β-catenin in either SPC or A549 cell line. Treatment with 5-aza-dC slightly altered the amounts of membranous β-catenin expression after β-catenin or E-cadherin depletion in SPC cell line but not in A549 cell line. (Scale bar = 20 µm, β-catenin antibody was replaced by normal mouse IgG as a negative control).</p>", "links"=>[], "tags"=>["Wnt 3a treatment", "Subsequent immunohistochemistry results", "methylation status", "NSCLC cell lines", "immunoreactive protein expression", "549. Immunofluorescence analysis", "spc", "promoter", "lymph node metastasis", "catenin", "bisulfite sequencing PCR", "tnm"], "article_id"=>1241999, "categories"=>["Biological Sciences"], "users"=>["Yuan Miao", "Liang Wang", "Xiupeng Zhang", "Xiaohan Xu", "Guiyang Jiang", "Chuifeng Fan", "Yang Liu", "Xuyong Lin", "Juanhan Yu", "Yong Zhang", "Enhua Wang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112258.g003", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_5_aza_dC_treatment_with_946_catenin_and_or_E_cadherin_depletion_/1241999", "title"=>"Effect of 5-aza-dC treatment with β-catenin and/or E-cadherin depletion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-14 02:54:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1794996"], "description"=>"<p>(A) Protein levels of β-catenin after 5-aza-dC treatment (7 µM) in NSCLC cell lines. (B) Quantification of protein expression after 5-aza-dC treatment. (C) Representative images of cells on the bottom of the Transwell membranes show the changes in invasive cell numbers (×400, Scale bar = 50 µm). (D) Number of cells invading onto the lower surface of the filter was counted, each carried out in triplicate. (Bars represent SD. *<i>P</i><0.05, compared to the control). (E) Dual-luciferase assay results show that 5-aza-dC treatment resulted in no significant changes in Wnt signaling activities compared with Wnt3a treated cells. Each of the experiments was repeated in triplicate. (D) Immunofluorescent staining showing that β-catenin is primarily localized at the membrane in SPC and A549 cell lines. Treatment with 5-aza-dC altered the amounts of membranous β-catenin expression. However, β-catenin was translocated into the nucleus following Wnt3a treatment (Scale bar = 20 µm, β-catenin antibody was replaced by normal mouse IgG as a negative control).</p>", "links"=>[], "tags"=>["Wnt 3a treatment", "Subsequent immunohistochemistry results", "methylation status", "NSCLC cell lines", "immunoreactive protein expression", "549. Immunofluorescence analysis", "spc", "promoter", "lymph node metastasis", "catenin", "bisulfite sequencing PCR", "tnm"], "article_id"=>1241995, "categories"=>["Biological Sciences"], "users"=>["Yuan Miao", "Liang Wang", "Xiupeng Zhang", "Xiaohan Xu", "Guiyang Jiang", "Chuifeng Fan", "Yang Liu", "Xuyong Lin", "Juanhan Yu", "Yong Zhang", "Enhua Wang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112258.g002", "stats"=>{"downloads"=>2, "page_views"=>115, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_5_aza_dC_treatment_in_SPC_and_A549_/1241995", "title"=>"Effects of 5-aza-dC treatment in SPC and A549.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-14 02:54:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1795016", "https://ndownloader.figshare.com/files/1795017"], "description"=>"<div><p>β-Catenin plays dual role in adhesion complex formation and the Wnt signaling pathway. Although β-catenin expression appears to be upregulated and Wnt signaling pathway is activated in the majority of cancers, its expression level seems to be lost in non-small cell lung cancer (NSCLC). We previously reported that the promoter of β-catenin was hypermethylated in two NSCLC cell lines. In the current study, we expanded our analysis for the methylation status of β-catenin promoter region and its protein expression in seven NSCLC cell lines and a series of 143 cases of primary human lung cancer with adjacent non-neoplastic tissues. Quantitative methylation specific PCR (qMSP) analysis showed methylation of β-catenin promoter region in five NSCLC cell lines, with increased β-catenin protein levels upon 5′-Aza-2′-deoxycytidine (5-aza-dC) treatment. The methylation status in SPC (methylated) and A549 (unmethylated) was confirmed by bisulfite sequencing PCR. 5-Aza-dC treatment inhibited invasiveness of SPC but not A549. Immunofluorescence analysis showed membranous β-catenin expression was lost in SPC and could be re-established by 5-aza-dC, while Wnt3a treatment led to nuclear translocation of β-catenin in both SPC and A549. Dual-luciferase assays indicated that 5-aza-dC treatment caused no significant increase in Wnt signaling activity compared with Wnt3a treatment. The effect of demethylation agent in SPC can be reversed by β-catenin depletion but not E-cadherin depletion which indicated that the methylation mediated β-catenin silencing might enhance NSCLC invasion and metastasis in an E-cadherin independent manner. Subsequent immunohistochemistry results further confirmed that β-catenin promoter hypermethylation correlated with loss of immunoreactive protein expression, positive lymph node metastasis, high TNM stage and poor prognosis. The present study implicates β-catenin promoter hypermethylation in the mechanism of epigenetic changes underlying NSCLC metastasis and progression, thus indicating the potential of β-catenin as a novel epigenetic target for the treatment of NSCLC patients.</p></div>", "links"=>[], "tags"=>["Wnt 3a treatment", "Subsequent immunohistochemistry results", "methylation status", "NSCLC cell lines", "immunoreactive protein expression", "549. Immunofluorescence analysis", "spc", "promoter", "lymph node metastasis", "catenin", "bisulfite sequencing PCR", "tnm"], "article_id"=>1242012, "categories"=>["Biological Sciences"], "users"=>["Yuan Miao", "Liang Wang", "Xiupeng Zhang", "Xiaohan Xu", "Guiyang Jiang", "Chuifeng Fan", "Yang Liu", "Xuyong Lin", "Juanhan Yu", "Yong Zhang", "Enhua Wang"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0112258.s001", "https://dx.doi.org/10.1371/journal.pone.0112258.s002"], "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Promoter_Methylation_Mediated_Silencing_of_946_Catenin_Enhances_Invasiveness_of_Non_Small_Cell_Lung_Cancer_and_Predicts_Adverse_Prognosis_/1242012", "title"=>"Promoter Methylation-Mediated Silencing of β-Catenin Enhances Invasiveness of Non-Small Cell Lung Cancer and Predicts Adverse Prognosis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-11-14 02:54:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1795012"], "description"=>"<p>Association between β-catenin gene methylation and clinicopathological features.</p>", "links"=>[], "tags"=>["Wnt 3a treatment", "Subsequent immunohistochemistry results", "methylation status", "NSCLC cell lines", "immunoreactive protein expression", "549. Immunofluorescence analysis", "spc", "promoter", "lymph node metastasis", "catenin", "bisulfite sequencing PCR", "tnm"], "article_id"=>1242009, "categories"=>["Biological Sciences"], "users"=>["Yuan Miao", "Liang Wang", "Xiupeng Zhang", "Xiaohan Xu", "Guiyang Jiang", "Chuifeng Fan", "Yang Liu", "Xuyong Lin", "Juanhan Yu", "Yong Zhang", "Enhua Wang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112258.t002", "stats"=>{"downloads"=>3, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_between_946_catenin_gene_methylation_and_clinicopathological_features_/1242009", "title"=>"Association between β-catenin gene methylation and clinicopathological features.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-11-14 02:54:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1795010"], "description"=>"<p>(A) β-catenin expression in normal lung epithelium with strong membranous staining. Membranous β-catenin expression was lost in lung squamous cell carcinoma (B) and lung adenocarcinoma (C). Scale bar = 20 µm. (D) Quantitative methylation results of q-MSP. Data represent mean±SD. The Mann-Whitney U-test was used to determine the statistical significance. **<i>P</i><0.001. (E) Survival curves of patients with or without β-catenin promoter methylation. Mantel's log-rank test was used to determine statistical significance.</p>", "links"=>[], "tags"=>["Wnt 3a treatment", "Subsequent immunohistochemistry results", "methylation status", "NSCLC cell lines", "immunoreactive protein expression", "549. Immunofluorescence analysis", "spc", "promoter", "lymph node metastasis", "catenin", "bisulfite sequencing PCR", "tnm"], "article_id"=>1242007, "categories"=>["Biological Sciences"], "users"=>["Yuan Miao", "Liang Wang", "Xiupeng Zhang", "Xiaohan Xu", "Guiyang Jiang", "Chuifeng Fan", "Yang Liu", "Xuyong Lin", "Juanhan Yu", "Yong Zhang", "Enhua Wang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112258.g004", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_946_catenin_expression_and_promoter_methylation_in_normal_lung_tissues_and_lung_cancer_tissues_/1242007", "title"=>"β-catenin expression and promoter methylation in normal lung tissues and lung cancer tissues.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-14 02:54:00"}
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Relative Metric

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