PARVA Promotes Metastasis by Modulating ILK Signalling Pathway in Lung Adenocarcinoma
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{"title"=>"PARVA promotes metastasis by modulating ILK signalling pathway in lung adenocarcinoma", "type"=>"journal", "authors"=>[{"first_name"=>"Ay Huey", "last_name"=>"Huang", "scopus_author_id"=>"55140809200"}, {"first_name"=>"Szu Hua", "last_name"=>"Pan", "scopus_author_id"=>"19639265900"}, {"first_name"=>"Wen Hsin", "last_name"=>"Chang", "scopus_author_id"=>"55253412700"}, {"first_name"=>"Qi Sheng", "last_name"=>"Hong", "scopus_author_id"=>"23094243200"}, {"first_name"=>"Jeremy J.W.", "last_name"=>"Chen", "scopus_author_id"=>"7501892959"}, {"first_name"=>"Sung Liang", "last_name"=>"Yu", "scopus_author_id"=>"7405731475"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84928314017", "pui"=>"604166157", "pmid"=>"25738875", "issn"=>"19326203", "scopus"=>"2-s2.0-84928314017", "doi"=>"10.1371/journal.pone.0118530"}, "id"=>"7884338f-d67e-3378-badc-6380c55765ba", "abstract"=>"α-parvin (PARVA) is known to be involved in the linkage of integrins, regulation of actin cytoskeleton dynamics and cell survival. However, the role that PARVA plays in cancer progression remains unclear. Here, using a lung cancer invasion cell line model and expression microarrays, we identify PARVA as a potential oncogene. The overexpression of PARVA increased cell invasion, colony-forming ability and endothelial cell tube formation. By contrast, knockdown of PARVA inhibited invasion and tube formation in vitro. Overexpression of PARVA also promoted tumorigenicity, angiogenesis and metastasis in in vivo mouse models. To explore the underlying mechanism, we compared the expression microarray profiles of PARVA-overexpressing cells with those of control cells to identify the PARVA-regulated signalling pathways. Pathway analysis showed that eight of the top 10 pathways are involved in invasion, angiogenesis and cell death. Next, to identify the direct downstream signalling pathway of PARVA, 371 significantly PARVA-altered genes were analysed further using a transcription factor target model. Seven of the top 10 PARVA-altered transcription factors shared a common upstream mediator, ILK. Lastly, we found that PARVA forms a complex with SGK1 and ILK to enhance the phosphorylation of ILK, which led to the phosphorylation of Akt and GSK3β. Notably, the inactivation of ILK reversed PARVA-induced invasion. Taken together, our findings imply that PARVA acts as an oncogene by activating ILK, and that this activation is followed by the activation of Akt and inhibition of GSK3β. To our knowledge, this is the first study to characterize the role of PARVA in lung cancer progression.", "link"=>"http://www.mendeley.com/research/parva-promotes-metastasis-modulating-ilk-signalling-pathway-lung-adenocarcinoma", "reader_count"=>3, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "reader_count_by_country"=>{"United Kingdom"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1935343"], "description"=>"<p>(A) The interaction between PARVA and ILK. CL1–0 cells were transiently transfected with the V5-PARVA expression vector. V5-PARVA and endogenous ILK were pulled down using anti-V5 and anti-ILK antibodies, respectively, and analysed by Western blotting with the indicated antibodies. (B) The effect of PARVA on GSK3β activity and c-Jun. CL1–0 and A549 cells were transiently transfected with the PARVA-expressing vector. The phosphorylation and protein expression levels were measured by Western blotting with the indicated antibodies. (C) MMP9 activity was positively regulated by PARVA. A549 cells were transiently transfected with the PARVA-expressing vector or siRNA against PARVA (si-PARVA-2). The activity of MMP9 was detected using a zymography assay. The intensity of the blank zone in the gels represents the activity of MMP9. β-Actin was used as the loading control.</p>", "links"=>[], "tags"=>["transcription factor target model", "PARVA Promotes Metastasis", "expression microarray profiles", "cell tube formation", "actin cytoskeleton dynamics", "vivo mouse models", "lung cancer invasion cell line model", "GSK 3β.", "lung cancer progression", "sgk", "Modulating ILK Signalling Pathway"], "article_id"=>1325714, "categories"=>["Biological Sciences"], "users"=>["Ay-Huey Huang", "Szu-Hua Pan", "Wen-Hsin Chang", "Qi-Sheng Hong", "Jeremy J. W. Chen", "Sung-Liang Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118530.g004", "stats"=>{"downloads"=>1, "page_views"=>72, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PARVA_associates_with_ILK_and_induces_phosphorylation_of_GSK3_946_and_MMP9_activity_/1325714", "title"=>"PARVA associates with ILK and induces phosphorylation of GSK3β and MMP9 activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-04 03:25:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1935323"], "description"=>"<p>(A) PARVA is upregulated in highly invasive CL1–5 lung cancer cells compared with the less invasive CL1–0 cells. PARVA RNA and protein expression levels as determined by expression microarrays (left panel), real-time RT-PCR (middle panel) and Western blotting (right panel). (B) The effects of transient PARVA overexpression on cell invasion. CL1–0, CL1–5 and A549 cells were transiently transfected with the pcDNA3.1/V5-His TOPO-tagged PARVA construct or an empty vector, and the invading cells were evaluated by Boyden chamber assays. (C) The <i>in vitro</i> invasion ability of pooled, stably PARVA-overexpressing cells. CL1–0, CL1–5 and A549 cells were stably transfected with the pcDNA3.1/V5-His TOPO-tagged PARVA construct (PARVA mix) or an empty vector (Mock mix), and their invasive abilities were determined by Boyden chamber assays. (D) The <i>in vitro</i> invasion assay of PARVA-knockdown cells. Endogenous levels of PARVA were transiently silenced by two siRNAs, si-PARVA-1 and si-PARVA-2, in CL1–5 and A549 cells, and were detected using anti-PARVA antibodies. The invasive ability of the cells was analysed by Boyden chamber assays at 48 h after transfection. *, <i>P</i> < 0.05, compared with the mock control cells. The invasion data represent the average of three individual well counts ± SD. α-Tubulin was used as the loading control.</p>", "links"=>[], "tags"=>["transcription factor target model", "PARVA Promotes Metastasis", "expression microarray profiles", "cell tube formation", "actin cytoskeleton dynamics", "vivo mouse models", "lung cancer invasion cell line model", "GSK 3β.", "lung cancer progression", "sgk", "Modulating ILK Signalling Pathway"], "article_id"=>1325699, "categories"=>["Biological Sciences"], "users"=>["Ay-Huey Huang", "Szu-Hua Pan", "Wen-Hsin Chang", "Qi-Sheng Hong", "Jeremy J. W. Chen", "Sung-Liang Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118530.g001", "stats"=>{"downloads"=>0, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PARVA_increases_invasiveness_in_lung_cancer_cells_/1325699", "title"=>"PARVA increases invasiveness in lung cancer cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-04 03:25:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1935345"], "description"=>"<p>(A) The effect of PARVA on the activities of ILK and Akt. CL1–0 and A549 cells were transiently transfected with the PARVA-expressing vector. The phosphorylation and protein expression levels were measured by Western blotting with the indicated antibodies. ILK phosphorylation was measured using anti-pILK Ser246 and anti-pILK Thr173 antibodies. (B) PARVA silencing attenuates ILK phosphorylation at Ser246 and VEGF-A expression. Cells were transfected with scrambled control (si-NC) and PARVA-specific siRNA (si-PARVA-1 and si-PARVA-2). ILK phosphorylation and VEGF-A expression were detected by Western blotting. α-Tubulin was used as the loading control. (C) Silencing ILK blocks PARVA-induced invasion. The expression of ILK was knocked down by introducing siRNAs against ILK (si-ILK-1 and si-ILK-2) in V5-PARVA-overexpressing cells, and the invasive ability of the cells was analysed by Boyden chamber assays. The expression of ILK and VEGF-A was detected by the indicated antibodies. *, <i>P</i> < 0.05, compared with the scrambled control (si-NC). (D) ILK inactivation blocks PARVA-induced invasion. ILK activity was inhibited by an ILK inhibitor, T315. CL1–0 cells were transfected with the PARVA-expressing vector, treated with 0, 0.5 or 0.75 μM T315 and analysed by invasion assay. Cells treated with 0.1% DMSO served as the control vehicle. *, <i>P</i> < 0.05, compared with the PARVA-overexpressing cells treated with DMSO. α-Tubulin was used as the loading control. (E) ILK inhibitor blocks PARVA-mediated phosphorylation of ILK and downstream activity. V5-PARVA-transfected CL1–0 and A549 cells were treated with 1 μM of ILK inhibitor T315 for 24 hrs. Cells treated with 0.1% DMSO served as the vehicle control. Cell lysates were subjected to Western blot with the designated antibodies. <b>*,</b><i>P</i> < 0.05, compared to the DMSO control. α-Tubulin was used as the loading control. (F) PARVA can interact with ILK and SGK1. CL1–0 and A549 cells were transiently transfected with the V5-PARVA construct or an empty vector (mock). PARVA was immunoprecipitated using V5 antibody followed by Western blot with the indicated antibodies. Input lanes were loaded with 1% of cell lysate. α-Tubulin was used as a loading control. The immunoprecipitation experiments were repeated three times. (G) Schematic showing the PARVA enhanced phosphorylation of ILK and activation of Akt and GSK3β signalling. The overexpression of PARVA increases ILK phosphorylation at Ser246, and in turn, phosphorylated ILK activates Akt and inhibits GSK3β activity, leading to the upregulation of the downstream genes AP-1 (c-Jun), VEGF and MMP9, and the promotion of angiogenesis and metastasis.</p>", "links"=>[], "tags"=>["transcription factor target model", "PARVA Promotes Metastasis", "expression microarray profiles", "cell tube formation", "actin cytoskeleton dynamics", "vivo mouse models", "lung cancer invasion cell line model", "GSK 3β.", "lung cancer progression", "sgk", "Modulating ILK Signalling Pathway"], "article_id"=>1325716, "categories"=>["Biological Sciences"], "users"=>["Ay-Huey Huang", "Szu-Hua Pan", "Wen-Hsin Chang", "Qi-Sheng Hong", "Jeremy J. W. Chen", "Sung-Liang Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118530.g005", "stats"=>{"downloads"=>4, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PARVA_induced_invasion_and_VEGF_A_expression_are_mediated_by_ILK_activation_/1325716", "title"=>"PARVA-induced invasion and VEGF-A expression are mediated by ILK activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-04 03:25:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1935347"], "description"=>"<p>* ILK related-transcription factors and target genes</p><p>Transcription factors and target genes in PARVA-induced networks.</p>", "links"=>[], "tags"=>["transcription factor target model", "PARVA Promotes Metastasis", "expression microarray profiles", "cell tube formation", "actin cytoskeleton dynamics", "vivo mouse models", "lung cancer invasion cell line model", "GSK 3β.", "lung cancer progression", "sgk", "Modulating ILK Signalling Pathway"], "article_id"=>1325718, "categories"=>["Biological Sciences"], "users"=>["Ay-Huey Huang", "Szu-Hua Pan", "Wen-Hsin Chang", "Qi-Sheng Hong", "Jeremy J. W. Chen", "Sung-Liang Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118530.t002", "stats"=>{"downloads"=>1, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcription_factors_and_target_genes_in_PARVA_induced_networks_/1325718", "title"=>"Transcription factors and target genes in PARVA-induced networks.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-03-04 03:25:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1935351", "https://ndownloader.figshare.com/files/1935352", "https://ndownloader.figshare.com/files/1935353", "https://ndownloader.figshare.com/files/1935354", "https://ndownloader.figshare.com/files/1935355"], "description"=>"<div><p>α-parvin (PARVA) is known to be involved in the linkage of integrins, regulation of actin cytoskeleton dynamics and cell survival. However, the role that PARVA plays in cancer progression remains unclear. Here, using a lung cancer invasion cell line model and expression microarrays, we identify PARVA as a potential oncogene. The overexpression of PARVA increased cell invasion, colony-forming ability and endothelial cell tube formation. By contrast, knockdown of PARVA inhibited invasion and tube formation <i>in vitro</i>. Overexpression of PARVA also promoted tumorigenicity, angiogenesis and metastasis in <i>in vivo</i> mouse models. To explore the underlying mechanism, we compared the expression microarray profiles of PARVA-overexpressing cells with those of control cells to identify the PARVA-regulated signalling pathways. Pathway analysis showed that eight of the top 10 pathways are involved in invasion, angiogenesis and cell death. Next, to identify the direct downstream signalling pathway of PARVA, 371 significantly PARVA-altered genes were analysed further using a transcription factor target model. Seven of the top 10 PARVA-altered transcription factors shared a common upstream mediator, ILK. Lastly, we found that PARVA forms a complex with SGK1 and ILK to enhance the phosphorylation of ILK, which led to the phosphorylation of Akt and GSK3β. Notably, the inactivation of ILK reversed PARVA-induced invasion. Taken together, our findings imply that PARVA acts as an oncogene by activating ILK, and that this activation is followed by the activation of Akt and inhibition of GSK3β. To our knowledge, this is the first study to characterize the role of PARVA in lung cancer progression.</p></div>", "links"=>[], "tags"=>["transcription factor target model", "PARVA Promotes Metastasis", "expression microarray profiles", "cell tube formation", "actin cytoskeleton dynamics", "vivo mouse models", "lung cancer invasion cell line model", "GSK 3β.", "lung cancer progression", "sgk", "Modulating ILK Signalling Pathway"], "article_id"=>1325722, "categories"=>["Biological Sciences"], "users"=>["Ay-Huey Huang", "Szu-Hua Pan", "Wen-Hsin Chang", "Qi-Sheng Hong", "Jeremy J. W. Chen", "Sung-Liang Yu"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0118530.s001", "https://dx.doi.org/10.1371/journal.pone.0118530.s002", "https://dx.doi.org/10.1371/journal.pone.0118530.s003", "https://dx.doi.org/10.1371/journal.pone.0118530.s004", "https://dx.doi.org/10.1371/journal.pone.0118530.s005"], "stats"=>{"downloads"=>39, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PARVA_Promotes_Metastasis_by_Modulating_ILK_Signalling_Pathway_in_Lung_Adenocarcinoma_/1325722", "title"=>"PARVA Promotes Metastasis by Modulating ILK Signalling Pathway in Lung Adenocarcinoma", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-03-04 03:25:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1935331"], "description"=>"<p>(A) PARVA increases clonogenesis <i>in vitro</i>, as measured by colony-forming assays. Both the mixed populations of mock-transfected cells (mock mix) and PARVA-transfected cells (PARVA mix) were derived from CL1–0 cells. Eighty cells were seeded for the anchorage-dependent assays (left panel) and 500 cells were seeded for the anchorage-independent assays (right panel). Colonies with a diameter >0.5 mm were counted using an inverted microscope. Each value of bar is presented as the average of six wells. <b>*</b>, <i>P</i> < 0.05, compared with the mock control. (B) PARVA increases tumorigenesis <i>in vivo</i>. One million mock-transfected (mock mix) and PARVA-overexpressing (PARVA mix) cells were injected subcutaneously into NOD/SCID mice. The tumour volume was measured every 3 or 4 days and was calculated using the following formula: <i>V = A</i> (length) × <i>B</i><sup>2</sup>/2 (width) (left panel). Tumour weight was measured in the excised tumours (right panel). Tumour volume and weight are presented as the average values of six individual mice ± SEM. A representative image of tumours excised from mock and pooled PARVA-overexpressing mice is shown in the right panel. Scale bar: 5 mm. <b>*</b>, <i>P</i> < 0.05, compared with the mock control group. (C) A representative example of lungs in the mouse metastasis model. Mock mix and PARVA mix stable clones were implanted (orthotopic injection) into the left lobe of the lung of NOD/SCID mice. After 4 weeks, the mice were sacrificed, and the lungs were stained with Bouin solution and photographed. Scale bar: 10 mm.</p>", "links"=>[], "tags"=>["transcription factor target model", "PARVA Promotes Metastasis", "expression microarray profiles", "cell tube formation", "actin cytoskeleton dynamics", "vivo mouse models", "lung cancer invasion cell line model", "GSK 3β.", "lung cancer progression", "sgk", "Modulating ILK Signalling Pathway"], "article_id"=>1325707, "categories"=>["Biological Sciences"], "users"=>["Ay-Huey Huang", "Szu-Hua Pan", "Wen-Hsin Chang", "Qi-Sheng Hong", "Jeremy J. W. Chen", "Sung-Liang Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118530.g002", "stats"=>{"downloads"=>2, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PARVA_increases_tumorigenicity_and_metastasis_in_lung_cancer_in_vitro_and_in_vivo_/1325707", "title"=>"PARVA increases tumorigenicity and metastasis in lung cancer <i>in vitro</i> and <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-04 03:25:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1935340"], "description"=>"<p>(A) The effects of PARVA on angiogenesis <i>in vivo</i>. Mock and PARVA-overexpressing transfectants derived from CL1–0 cells were inoculated into NOD/SCID mice as mentioned in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118530#pone.0118530.g002\" target=\"_blank\">Fig. 2B</a>. The resulting tumours were sectioned and stained with an anti-CD31 antibody. A representative immunohistochemistry image is shown in the right panel. The microvessel density (MVD) for each group represents the mean value of three individual immunohistochemistry slides from three different mice. Each slide represents the average value of microvessel numbers of five fields (left panel). The arrowheads indicate CD31<sup>+</sup> vessels. Scale bar: 10 μm. *, <i>P</i> < 0.05, compared with the mock control groups. (B) Induction of tube formation by PARVA. Endothelial cells were treated for 4 h with serum-free culture medium from mock or stably pooled PARVA-overexpressing CL1–0 transfectants, and the branch points and tube lengths were counted using the angiogenesis module of MetaXpress. Each experiment was performed in triplicate. A representative image of the tube formation assay is shown in the lower panel. Scale bar: 10 μm. *, <i>P</i> < 0.05, compared with the mock control groups. (C) Reduction in tube formation induced by PARVA silencing. Endothelial cells were treated with the serum-free culture medium from the scrambled control (si-NC) and PARVA-silenced A549 transfectants (si-PARVA-1 and si-PARVA-2), and the rate of tube formation was determined as described in (C). *, <i>P</i> < 0.05, compared with the scrambled control (si-NC). (D) Induction of VEGF-A by PARVA. The cellular and secreted forms of VEGF-A were detected in the mock and stably PARVA-overexpressing CL1–0 transfectants by Western blotting. β-Actin was used as the loading control. (E) Reduction in VEGF-A expression by PARVA silencing. The VEGF-A expression of the scrambled control (si-NC) and PARVA-silenced A549 transfectants (si-PARVA-2) was detected by Western blotting. β-Actin was used as the loading control. Western blot experiments were repeated at least three times.</p>", "links"=>[], "tags"=>["transcription factor target model", "PARVA Promotes Metastasis", "expression microarray profiles", "cell tube formation", "actin cytoskeleton dynamics", "vivo mouse models", "lung cancer invasion cell line model", "GSK 3β.", "lung cancer progression", "sgk", "Modulating ILK Signalling Pathway"], "article_id"=>1325711, "categories"=>["Biological Sciences"], "users"=>["Ay-Huey Huang", "Szu-Hua Pan", "Wen-Hsin Chang", "Qi-Sheng Hong", "Jeremy J. W. Chen", "Sung-Liang Yu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118530.g003", "stats"=>{"downloads"=>1, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PARVA_promotes_tube_formation_in_vitro_and_angiogenesis_in_vivo_/1325711", "title"=>"PARVA promotes tube formation <i>in vitro</i> and angiogenesis <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-04 03:25:18"}

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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Net::HTTPInternalServerError

Source
Counter
Time
2019-04-06 02:38:24 UTC
Target URL
http://counter-101.soma.plos.org/api/v1.0/stats/doi/10.1371%2Fjournal.pone.0118530
Trace

/app/models/concerns/networkable.rb:21:in `get_result'
/app/models/source.rb:165:in `get_data'
/app/models/retrieval_status.rb:47:in `perform_get_data'
/app/jobs/source_job.rb:52:in `block (2 levels) in perform'
/app/jobs/source_job.rb:51:in `block in perform'
/app/jobs/source_job.rb:35:in `each'
/app/jobs/source_job.rb:35:in `perform'