Inhibition of Mesothelin as a Novel Strategy for Targeting Cancer Cells
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{"title"=>"Inhibition of mesothelin as a novel strategy for targeting cancer cells", "type"=>"journal", "authors"=>[{"first_name"=>"Kun", "last_name"=>"Wang", "scopus_author_id"=>"57195792170"}, {"first_name"=>"Vidya", "last_name"=>"Bodempudi", "scopus_author_id"=>"23092901200"}, {"first_name"=>"Zhengian", "last_name"=>"Liu", "scopus_author_id"=>"57196426224"}, {"first_name"=>"Emma", "last_name"=>"Borrego-Diaz", "scopus_author_id"=>"6506731059"}, {"first_name"=>"Farnaz", "last_name"=>"Yamoutpoor", "scopus_author_id"=>"26868249700"}, {"first_name"=>"Anna", "last_name"=>"Meyer", "scopus_author_id"=>"55162496900"}, {"first_name"=>"Richard A.", "last_name"=>"Woo", "scopus_author_id"=>"57195801837"}, {"first_name"=>"Weihong", "last_name"=>"Pan", "scopus_author_id"=>"35307918200"}, {"first_name"=>"Arkadiusz Z.", "last_name"=>"Dudek", "scopus_author_id"=>"8516684300"}, {"first_name"=>"Mojtaba S.", "last_name"=>"Olyaee", "scopus_author_id"=>"16234196200"}, {"first_name"=>"Tuba", "last_name"=>"Esfandyari", "scopus_author_id"=>"31667451300"}, {"first_name"=>"Faris", "last_name"=>"Farassati", "scopus_author_id"=>"6508119244"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22485139", "sgr"=>"84859228476", "doi"=>"10.1371/journal.pone.0033214", "scopus"=>"2-s2.0-84859228476", "pui"=>"364556555", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"dc2ebc46-bf24-3d48-8b51-0d51ffc17cbb", "abstract"=>"Mesothelin, a differentiation antigen present in a series of malignancies such as mesothelioma, ovarian, lung and pancreatic cancer, has been studied as a marker for diagnosis and a target for immunotherapy. We, however, were interested in evaluating the effects of direct targeting of Mesothelin on the viability of cancer cells as the first step towards developing a novel therapeutic strategy. We report here that gene specific silencing for Mesothelin by distinct methods (siRNA and microRNA) decreased viability of cancer cells from different origins such as mesothelioma (H2373), ovarian cancer (Skov3 and Ovcar-5) and pancreatic cancer (Miapaca2 and Panc-1). Additionally, the invasiveness of cancer cells was also significantly decreased upon such treatment. We then investigated pro-oncogenic signaling characteristics of cells upon mesothelin-silencing which revealed a significant decrease in phospho-ERK1 and PI3K/AKT activity. The molecular mechanism of reduced invasiveness was connected to the reduced expression of β-Catenin, an important marker of EMT (epithelial-mesenchymal transition). Ero1, a protein involved in clearing unfolded proteins and a member of the ER-Stress (endoplasmic reticulum-stress) pathway was also markedly reduced. Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase. In next step, treatment of ovarian cancer cells (OVca429) with a lentivirus expressing anti-mesothelin microRNA resulted in significant loss of viability, invasiveness, and morphological alterations. Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies.", "link"=>"http://www.mendeley.com/research/inhibition-mesothelin-novel-strategy-targeting-cancer-cells", "reader_count"=>53, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>15, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>5, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>15, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>5, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>21, "Medicine and Dentistry"=>13, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Business, Management and Accounting"=>1, "Chemistry"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>13}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>21}, "Computer Science"=>{"Computer Science"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Unspecified"=>{"Unspecified"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>1, "Switzerland"=>1, "India"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/659169"], "description"=>"<p>(A)Anti-mesothelin siRNA was designed to a middle sequence position in mesothelin mRNA. (B)Once electroporated with anti-mesothelin siRNA, the expression levels of mesothelin was significantly reduced in H2373 cells. Negative control siRNA did not cause such reduction. Lower panel shows the results of band-densitometry comparing the intensity of mesothelin expression upon electroporation of H2373 cells with siRNA. (C)Anti-mesothelin siRNA did not affect the expression levels of β-actin, a house-keeping protein, as an evidence for the specificity of this anti-mesothelin siRNA for its target. (D) Proliferation rate of H2373 cells is significantly (p<0.05) reduced at 48 hours post-electroporation to 40% of the values for negative control treated cells. A rebound to higher proliferation rates is observed due to clearance of siRNA from cells at later time points in harmony with our previous studies. Callout panels show the density of cells in each group of the study at 48 hours post-electroporation. (E) NIH3T3 cells are void of mesothelin and their proliferation rate is not affected by exposure to anti-mesothelin siRNA (mouse). Callout panels show the density of cells at 48 hour post-electroporation.</p>", "links"=>[], "tags"=>["mesothelin", "proliferation", "mesothelioma"], "article_id"=>329624, "categories"=>["Molecular Biology", "Biochemistry", "Chemistry", "Cancer"], "users"=>["Kun Wang", "Vidya Bodempudi", "Zhengian Liu", "Emma Borrego-Diaz", "Farnaz Yamoutpoor", "Anna Meyer", "Richard A. Woo", "Weihong Pan", "Arkadiusz Z. Dudek", "Mojtaba S. Olyaee", "Tuba Esfandyari", "Faris Farassati"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0033214.g001", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_specific_silencing_of_mesothelin_reduces_proliferation_of_mesothelioma_cells_/329624", "title"=>"Gene specific silencing of mesothelin reduces proliferation of mesothelioma cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 06:59:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/659267"], "description"=>"<p>(A)Mesothelin protein was detected in pancreatic cancer cell lines, Panc1, Miapaca2 and Bxpc3 and ovarian cancer cells Skov3 and Ovcar3. NIH3T3 and Huvec cells which are void of mesothelin were used to prove the specificity of mesothelin antibody. (B)Skov3 cells had reduced proliferation at day 3 post-electroporation with anti-mesothelin siRNA to about 50% of negative control. Callout panels show the density of cell at each time-point. (C–D)Two pancreatic cancer cell lines, Bxpc3 and Miapaca, were tested for the outcome of silencing mesothelin on their proliferation. In both cases a significant loss of proliferation was observed, however for Bxpc3 the decline initiates at later time points as compared with Miapaca cells. For both cells, once again, a rebound to higher proliferation rates is observed at longer time-points due to the clearance of siRNA from cells. Callout panels show the density of cell at each time-point.</p>", "links"=>[], "tags"=>["proliferation", "pancreatic", "ovarian", "cancer"], "article_id"=>329742, "categories"=>["Molecular Biology", "Biochemistry", "Chemistry", "Cancer"], "users"=>["Kun Wang", "Vidya Bodempudi", "Zhengian Liu", "Emma Borrego-Diaz", "Farnaz Yamoutpoor", "Anna Meyer", "Richard A. Woo", "Weihong Pan", "Arkadiusz Z. Dudek", "Mojtaba S. Olyaee", "Tuba Esfandyari", "Faris Farassati"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0033214.g002", "stats"=>{"downloads"=>3, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mesothelin_silencing_reduces_proliferation_rate_of_pancreatic_and_ovarian_cancer_cells_/329742", "title"=>"Mesothelin silencing reduces proliferation rate of pancreatic and ovarian cancer cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 07:00:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/659385"], "description"=>"<p>(A) Once tested in a modified Boyden chamber assay, the invasiveness of H2373 mesothelioma cells is reduced significantly (p<0.05) upon mesothelin silencing. Electroporated cells were introduced to the invasion chambers for this experiment and invaded cells were counted and photographed after 48 hrs. Callout panels represent the density of invaded cells stained with crystal violet. (B–C) Skov3 and Bxpc3 cells both exhibit a significant (p<0.05) decrease in their invasiveness upon mesothelin silencing to values less than 20% of negative control. Callout panels represent the density of invaded cells stained with crystal violet. (D) Silencing mesothelin induces a significant decrease in activation (phosphorylation) of ERK1 (but not ERK2) and phospho-AKT. Additionally, the expression of β-catenin, a known EMT marker, was reduced. Slug, another transcription factor involved in EMT showed a slight increase under this condition. From ER-Stress markers, Ero-1 was decreased while Bip was slightly elevated. (E) Progression of cell cycle is altered by mesothelin silencing mainly by an increase in the percentage of cells in S-phase. The percentage of cells in each phase is shown in upper panel and representative flow cytometry data is offered in the lower panel. G1, S and G2 picks are marked on each graph showing an increase in S phase population of cells.</p>", "links"=>[], "tags"=>["mesothelin", "cancer", "pro-oncogenic", "signaling", "pathways"], "article_id"=>329859, "categories"=>["Molecular Biology", "Biochemistry", "Chemistry", "Cancer"], "users"=>["Kun Wang", "Vidya Bodempudi", "Zhengian Liu", "Emma Borrego-Diaz", "Farnaz Yamoutpoor", "Anna Meyer", "Richard A. Woo", "Weihong Pan", "Arkadiusz Z. Dudek", "Mojtaba S. Olyaee", "Tuba Esfandyari", "Faris Farassati"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0033214.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_effects_of_silencing_mesothelin_on_cancer_cell_invasiveness_pro_oncogenic_cell_signaling_pathways_and_cell_cycle_progression_/329859", "title"=>"The effects of silencing mesothelin on cancer cell invasiveness, pro-oncogenic cell signaling pathways and cell cycle progression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 07:00:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/659636"], "description"=>"<p>(A) Ovca429 cell were infected with MSLNmiR3 or Negative Control virus at MOI∼30. Cell proliferation was assessed at the indicated time-points. (B) Photographs of Ovca429 cells expressing EmGFP post-infection at the indicated time-points. 10× objective was used for taking pictures at day 10 and 20× was used at day 20 in order to focus on morphological changes of cells. (C) Left panel: Three-day post infection, Ovca429 cells were transferred and cultured in Boyden assay invasion chambers for 21 hrs. Cells were washed, fixed, and cell nuclei were stained by DAPI. Representative fields from each group were then counted for the number of nuclei and averages were calculated and compared (p<0.05). Numbers of cells invaded for the negative control virus was considered as 100%. Right panel: Photographs of invaded cells nuclei in MSLNmiR3 and negative control virus treated groups. The bar shows 100 µM in length.</p>", "links"=>[], "tags"=>["msln", "confers", "inhibited", "proliferation"], "article_id"=>330110, "categories"=>["Molecular Biology", "Biochemistry", "Chemistry", "Cancer"], "users"=>["Kun Wang", "Vidya Bodempudi", "Zhengian Liu", "Emma Borrego-Diaz", "Farnaz Yamoutpoor", "Anna Meyer", "Richard A. Woo", "Weihong Pan", "Arkadiusz Z. Dudek", "Mojtaba S. Olyaee", "Tuba Esfandyari", "Faris Farassati"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0033214.g005", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Silencing_MSLN_confers_inhibited_cell_proliferation_and_invasion_/330110", "title"=>"Silencing MSLN confers inhibited cell proliferation and invasion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 07:02:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/659496"], "description"=>"<p>(A) Upper panel: miRNA mimics (miR) target full length human MSLN gene. The arrow represents the relative position of miRs across MSLN gene sequence. The exact miR sequences are explained in the Experimental Procedure. Middle panel: Expression plasmids encoding scrambled miR or miR targeting MSLN were electroporated (voltage: 1170 V, width: 30 ms, and pulses: 1. Neon Electroporation System, Invitrogen, CA) into human ovarian cancer Ovcar-5 cells and cultured for 48 hrs. EmGFP expression which indicates proper orientation and expression of each miR was determined by FACS. Lower panel: MSLN protein levels were determined by Western blot following electroporation of cells with miRs. (B) Upper panel: Schematic representation of lentiviral genome encoding miR3 against MSLN or scrambled miR. Middle panel: Ovca429 cells were infected by lentiviral particles carrying scrambled miR (Neg. Ctrl) or miR3 against MSLN (MSLNmiR3) at MOI∼30 for 3 days. Expression of MSLN was determined by FACS. The far right panel is infected with negative control virus without staining for MSLN but stained with secondary antibody. Lower panel: The equal expression of EmGFP proves entrance and activity of the negative control and MSLNmiR3 viruses.</p>", "links"=>[], "tags"=>["suppress", "msln", "ovarian", "cancer"], "article_id"=>329967, "categories"=>["Molecular Biology", "Biochemistry", "Chemistry", "Cancer"], "users"=>["Kun Wang", "Vidya Bodempudi", "Zhengian Liu", "Emma Borrego-Diaz", "Farnaz Yamoutpoor", "Anna Meyer", "Richard A. Woo", "Weihong Pan", "Arkadiusz Z. Dudek", "Mojtaba S. Olyaee", "Tuba Esfandyari", "Faris Farassati"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0033214.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MiRs_suppress_MSLN_expression_in_human_ovarian_cancer_cells_/329967", "title"=>"MiRs suppress MSLN expression in human ovarian cancer cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 07:01:24"}

PMC Usage Stats | Further Information

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Relative Metric

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