Role of Activated Rac1/Cdc42 in Mediating Endothelial Cell Proliferation and Tumor Angiogenesis in Breast Cancer
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{"title"=>"Role of Activated Rac1/Cdc42 in Mediating Endothelial Cell Proliferation and Tumor Angiogenesis in Breast Cancer", "type"=>"journal", "authors"=>[{"first_name"=>"Ji", "last_name"=>"Ma", "scopus_author_id"=>"37661734900"}, {"first_name"=>"Yan", "last_name"=>"Xue", "scopus_author_id"=>"55222745200"}, {"first_name"=>"Wenchao", "last_name"=>"Liu", "scopus_author_id"=>"26659899000"}, {"first_name"=>"Caixia", "last_name"=>"Yue", "scopus_author_id"=>"46462060500"}, {"first_name"=>"Feng", "last_name"=>"Bi", "scopus_author_id"=>"7004320718"}, {"first_name"=>"Junqing", "last_name"=>"Xu", "scopus_author_id"=>"7407007311"}, {"first_name"=>"Jian", "last_name"=>"Zhang", "scopus_author_id"=>"57188635298"}, {"first_name"=>"Yan", "last_name"=>"Li", "scopus_author_id"=>"55261854600"}, {"first_name"=>"Cuiping", "last_name"=>"Zhong", "scopus_author_id"=>"55756745500"}, {"first_name"=>"Yan", "last_name"=>"Chen", "scopus_author_id"=>"55938233500"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"369060441", "sgr"=>"84878650360", "issn"=>"19326203", "pmid"=>"23750283", "scopus"=>"2-s2.0-84878650360", "doi"=>"10.1371/journal.pone.0066275"}, "id"=>"f146a8f6-131c-3c08-b8b9-27aa3dba1f5c", "abstract"=>"Angiogenesis is a well-established target in anti-cancer therapy. Although vascular endothelial growth factor (VEGF)-mediated angiogenesis apparently requires the Rho GTPases Rac1 and Cdc42, the relevant mechanisms are unclear. Here, we determined that activated Rac1/Cdc42 in MCF-7 breast cancer cells could decrease p53 protein levels and increase VEGF secretion to promote proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). However, these effects are reversed after ubiquitin-proteasome breakage. In exploring potential mechanisms for this relationship, we confirmed that activated Rac1/Cdc42 could enhance p53 protein ubiquitination and weaken p53 protein stability to increase VEGF expression. Furthermore, in a xenograft model using nude mice that stably express active Rac1/Cdc42 protein, active Rac1/Cdc42 decreased p53 levels and increased VEGF expression. Additionally, tumor angiogenesis was inhibited, and p53 protein levels were augmented, by intratumoral injection of the ubiquitin-proteasome inhibitor MG132. Finally in 339 human breast cancer tissues, our analyses indicated that Rac1/Cdc42 expression was related to advanced TNM staging, high proliferation index, ER status, and positive invasive features. In particular, our data suggests that high Rac1/Cdc42 expression is correlated with low wt-p53 and high VEGF expression. We conclude that activated Rac1/Cdc42 is a vascular regulator of tumor angiogenesis and that it may reduce stability of the p53 protein to promote VEGF expression by enhancing p53 protein ubiquitin.", "link"=>"http://www.mendeley.com/research/role-activated-rac1cdc42-mediating-endothelial-cell-proliferation-tumor-angiogenesis-breast-cancer", "reader_count"=>17, "reader_count_by_academic_status"=>{"Researcher"=>1, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Master"=>6, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Researcher"=>1, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Master"=>6, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>5}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1073951"], "description"=>"a<p>The Spearman correlation test was used for statistical analyses. <i>P</i> values <0.05 were considered statistically significant.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "Endothelial cells", "oncology", "Cancer treatment", "Antiangiogenesis therapy", "Cancers and neoplasms", "Breast tumors", "Basic cancer research", "histopathologic", "339", "cancer"], "article_id"=>711277, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ji Ma", "Yan Xue", "Wenchao Liu", "Caixia Yue", "Feng Bi", "Junqing Xu", "Jian Zhang", "Yan Li", "Cuiping Zhong", "Yan Chen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066275.t002", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Correlation_of_Rac1_Cdc42_expression_with_clinical_histopathologic_characteristics_in_339_breast_cancer_specimens_/711277", "title"=>"Correlation of Rac1/Cdc42 expression with clinical histopathologic characteristics in 339 breast cancer specimens.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-04 00:21:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1073947"], "description"=>"<p>(A) GST–MCF-7, V12Rac1–MCF-7, and L61Cdc42–MCF-7 cells were incubated, and MG132 was added to select samples for 12 and 24 h, respectively. After incubation, the media were analyzed for VEGF levels using ELISA assay; cell numbers were counted. Data are expressed as the mean ± standard deviation (SD) for three independent experiments. Statistical significance was assessed with one-way ANOVA and Student's t-test. *<i>P</i><0.05, **<i>P</i><0.01, for the GST–MCF-7 group vs V12Rac1– or L61Cdc42–MCF-7 group. #<i>P</i><0.05, ##<i>P</i><0.01, for the MG132-added group vs the no-MG132-added group. (B, C) MCF-7, GST–MCF-7, V12Rac1–MCF-7 and L61Cdc42–MCF-7 cells were incubated, and MG132 was added to select samples for 24 h. After incubation, the cells were analyzed by western blot assay. p53, p21 and β-actin expression was examined. β-actin protein levels were used as a loading control. (D) The immunoprecipitation assay was performed as described in Material and Methods. Total protein was extracted from MCF-7, GST–MCF-7, V12Rac1–MCF-7 and L61Cdc42–MCF-7 cells and subjected to an immunoprecipitation assay. p53 protein expression was examined. β-actin protein levels were used as a loading control.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "Endothelial cells", "oncology", "Cancer treatment", "Antiangiogenesis therapy", "Cancers and neoplasms", "Breast tumors", "Basic cancer research", "mg132", "vegf", "p53", "induced"], "article_id"=>711273, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ji Ma", "Yan Xue", "Wenchao Liu", "Caixia Yue", "Feng Bi", "Junqing Xu", "Jian Zhang", "Yan Li", "Cuiping Zhong", "Yan Chen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066275.g003", "stats"=>{"downloads"=>18, "page_views"=>375, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_MG132_on_VEGF_and_p53_expression_induced_by_active_Rac1_Cdc42_/711273", "title"=>"Effect of MG132 on VEGF and p53 expression induced by active Rac1/Cdc42.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-04 00:21:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1073945"], "description"=>"<p>(A–D) MCF-7 cells were transfected with Rac1/Cdc42 small-interfering RNA (siRac1/Cdc42) or with negative control siRNA and with the plasmid pCEFL-GST-V12Rac1 (V12Rac1), pCEFL-GST-L61Cdc42 (L61Cdc42) or pCEFL-GST-neo using lipofectamine 2000 for 48 h. Protein and RNA were then extracted and subjected to western blot analyses. Total protein was subjected to 15% SDS-PAGE; membranes were incubated with anti-Rac1, anti-Cdc42, anti-p53, anti-VEGF, or anti-β-actin antibody. (E–H) MCF-7 cells were transfected with siRac1/Cdc42 or with p53 siRNA (sip53) and either activated Rac1/Cdc42 plasmid (V12Rac1/L61Cdc42) or wild-type p53 expression plasmid (wt-p53) with lipofectamine 2000 for 48 h. Protein was then extracted and subjected to 15% SDS-PAGE; membranes were incubated with anti-p53, anti-VEGF, or anti-β-actin antibody. The data represent three independent experiments.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "Endothelial cells", "oncology", "Cancer treatment", "Antiangiogenesis therapy", "Cancers and neoplasms", "Breast tumors", "Basic cancer research", "regulates", "p53", "vegf", "mcf-7"], "article_id"=>711271, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ji Ma", "Yan Xue", "Wenchao Liu", "Caixia Yue", "Feng Bi", "Junqing Xu", "Jian Zhang", "Yan Li", "Cuiping Zhong", "Yan Chen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066275.g002", "stats"=>{"downloads"=>4, "page_views"=>215, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rac1_Cdc42_regulates_p53_expression_to_affect_VEGF_expression_in_MCF_7_cells_/711271", "title"=>"Rac1/Cdc42 regulates p53 expression to affect VEGF expression in MCF-7 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-04 00:21:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1073944"], "description"=>"<p>The MTT and tube formation assays were performed as described in Material and Methods. (A) HUVECs were grown to confluence and were then cultured in preconditioned media (derived from GST–MCF-7, V12Rac1–MCF-7 and L61Cdc42–MCF-7 cells pretreated or not with MG132 for 12 h) for 24 h or 48 h; the GST–MCF-7 group was used as a control. (B) HUVECs were plated on Matrigel and incubated with the different preconditioned media for 6 h. Photographs were taken in five random power fields (200 ×). (C) Tube lengths were measured with Image-Pro Plus software. Histograms represent quantification of the HUVEC. The GST–MCF-7 group was used as a control. All data are expressed as mean ± standard deviation (SD) for three independent experiments. Statistical significance was assessed using one-way ANOVA and Student's <i>t</i>-test. *<i>P</i><0.05, **<i>P</i><0.01, for the GST–MCF-7 group vs the V12Rac1– or L61Cdc42– MCF-7 group. #<i>P</i><0.05, ##<i>P</i><0.01, for the MG132-added group vs the no-MG132 group.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "Endothelial cells", "oncology", "Cancer treatment", "Antiangiogenesis therapy", "Cancers and neoplasms", "Breast tumors", "Basic cancer research", "mg132", "huvec", "proliferation", "induced"], "article_id"=>711270, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ji Ma", "Yan Xue", "Wenchao Liu", "Caixia Yue", "Feng Bi", "Junqing Xu", "Jian Zhang", "Yan Li", "Cuiping Zhong", "Yan Chen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066275.g001", "stats"=>{"downloads"=>0, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_MG132_on_HUVEC_proliferation_and_tube_formation_induced_by_active_Rac1_Cdc42_/711270", "title"=>"Effect of MG132 on HUVEC proliferation and tube formation induced by active Rac1/Cdc42.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-04 00:21:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/1073953"], "description"=>"a<p>The Fisher's exact test was used for statistical analyses. <i>P</i> values <0.05 were considered statistically significant.</p>b<p>The Pearson's chi square test was used for statistical analyses.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "Endothelial cells", "oncology", "Cancer treatment", "Antiangiogenesis therapy", "Cancers and neoplasms", "Breast tumors", "Basic cancer research", "339", "cancer"], "article_id"=>711279, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ji Ma", "Yan Xue", "Wenchao Liu", "Caixia Yue", "Feng Bi", "Junqing Xu", "Jian Zhang", "Yan Li", "Cuiping Zhong", "Yan Chen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066275.t001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Statistical_results_of_Rac1_Cdc42_expression_in_339_breast_cancer_specimens_/711279", "title"=>"Statistical results of Rac1/Cdc42 expression in 339 breast cancer specimens.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-04 00:21:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1073952"], "description"=>"a<p>The Spearman correlation test was used for statistical analyses. <i>P</i> values <0.05 were considered statistically significant.</p>b<p>Correlation coefficient (<i>r<sub>s</sub></i>) = −.406.</p>c<p><i>r<sub>s</sub></i>  = .268.</p>d<p><i>r<sub>s</sub></i>  = −.263.</p>e<p><i>r<sub>s</sub></i>  = .224.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "Endothelial cells", "oncology", "Cancer treatment", "Antiangiogenesis therapy", "Cancers and neoplasms", "Breast tumors", "Basic cancer research", "wild-type", "p53", "vegf", "145", "cancer", "specimens", "containing"], "article_id"=>711278, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ji Ma", "Yan Xue", "Wenchao Liu", "Caixia Yue", "Feng Bi", "Junqing Xu", "Jian Zhang", "Yan Li", "Cuiping Zhong", "Yan Chen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066275.t003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Correlation_of_Rac1_Cdc42_expression_with_wild_type_p53_and_VEGF_protein_in_145_breast_cancer_specimens_containing_the_wild_type_p53_protein_/711278", "title"=>"Correlation of Rac1/Cdc42 expression with wild-type p53 and VEGF protein in 145 breast cancer specimens containing the wild-type p53 protein.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-04 00:21:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1073949"], "description"=>"<p>These experiments were described in the Materials and Methods section. Stably transfected cells (MCF-7, GST–MCF-7, V12Rac1–MCF-7, L61Cdc42–MCF-7) were used for xenografts in nude mice. When the tumors reached a volume of 200 mm3, the mice were treated with intratumoral injections of a specific dose of MG132 (10 mg/kg) or PBS. (A, B) Intratumoral vascularization was assessed by VEGF and p53 immunolabeling (400 × power) on paraffin-embedded MCF-7 cell tumor sections. Representative images are shown. Integrated optical density (IOD) values of VEGF and p53 protein expression were evaluated. ImagePro Plus software was used to analyze the IOD values of the positive areas of immunohistochemical staining. The resulting histograms are presented here. A statistical analysis was performed using a one-way ANOVA. The results are presented as mean ± SD for six mice. *<i>P</i><0.05; **<i>P</i><0.01.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "Endothelial cells", "oncology", "Cancer treatment", "Antiangiogenesis therapy", "Cancers and neoplasms", "Breast tumors", "Basic cancer research", "intratumoral", "injections", "mg132", "vascularization", "induced", "mcf-7"], "article_id"=>711275, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ji Ma", "Yan Xue", "Wenchao Liu", "Caixia Yue", "Feng Bi", "Junqing Xu", "Jian Zhang", "Yan Li", "Cuiping Zhong", "Yan Chen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066275.g004", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_intratumoral_injections_of_MG132_on_vascularization_induced_by_active_Rac1_Cdc42_in_MCF_7_cell_xenografts_/711275", "title"=>"Effect of intratumoral injections of MG132 on vascularization induced by active Rac1/Cdc42 in MCF-7 cell xenografts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-04 00:21:15"}

PMC Usage Stats | Further Information

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Relative Metric

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