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Punita Dhawan - One of the best experts on this subject based on the ideXlab platform.
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anti Claudin 1 conjugated to a near infrared fluorophore targets colon cancer in pdox mouse models
Journal of Surgical Research, 2019Co-Authors: Hannah M Hollandsworth, Punita Dhawan, Thinzar M Lwin, Siamak Amirfakhri, Filemoni Filemoni, Surinder K Batra, Robert M Hoffman, Michael BouvetAbstract:Abstract Introduction Claudins are tight-junction proteins, which maintain an epithelial barrier in normal colon cells. Overexpression of Claudin-1 has been implicated for development of colon cancer. We postulated that Claudin-1 may be a useful target in near-infrared imaging and fluorescence-guided surgery. Methods We conjugated Claudin-1 antibody to LI-COR IR800DyeCW (Claudin-1-IRDye800CW). Western blotting of 9 human colon cancer cell lysates was performed. Animal imaging was performed with the LI-COR Pearl Trilogy Fluorescence Imaging System. A dose-response study was carried out with subcutaneous LS174T colon cancer cell line models. Increasing doses of Claudin-1-IRDye800CW via tail vein injection were administered to three groups of mice. Two groups of mice were used as controls (antibody alone, and dye alone). In vivo imaging was performed at 24, 48, and 72 h after administration of the conjugated dye. Orthotopic implantation of patient-derived tumors and cell lines was performed and peritoneal carcinomatosis models were created. After tumor growth, mice were administered Claudin-1-IRDye800CW and imaged in vivo 48 h later. The mice were euthanized and laparotomy was performed to assess internal organs and toxicity. Results Western blotting revealed that all colon cancer cell lysates expressed varying amounts of Claudin-1. All tumors demonstrated strong and specific fluorescence labeling at 800 nm, even with the lowest dose of 12.5 μg of Claudin-1-IRDye800CW. Conclusions Claudin-1 is a useful target for near-infrared antibody-based imaging for visualization of colorectal tumors for future use in fluorescence-guided surgery.
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Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling
Gut, 2013Co-Authors: Jillian L. Pope, Ajaz A. Bhat, Ashok Sharma, Rizwan Ahmad, Moorthy Krishnan, Mary Kay Washington, Robert D. Beauchamp, Amar B. Singh, Punita DhawanAbstract:Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role Claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel villin-Claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal Claudin-1 overexpression). The effect of Claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that Claudin-1 regulates Notch-signalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation. Conclusions Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notch-signalling. An upregulated Claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notch-signalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of Claudin-1 in the regulation of inflammatory bowel diseases and CRC.
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Claudin-1 expression confers resistance to anoikis in colon cancer cells in a Src-dependent manner
Carcinogenesis, 2012Co-Authors: Amar B. Singh, Ashok Sharma, Punita DhawanAbstract:Denial of the appropriate cell-matrix interaction in epithelial cells induces apoptosis and is called 'anoikis'. Cancer cells are resistant to anoikis and it is believed that the resistance to anoikis helps promote tumor malignancy especially metastasis. We and others have demonstrated that the expression of tight junction protein Claudin-1 is highly upregulated in colorectal cancer (CRC) and helps promote tumor progression and metastasis. However, molecular mechanism/s underlying Claudin-1-dependent regulation of CRC progression remains poorly understood. In current study, we have determined that Claudin-1 expression modulates anoikis in colon cancer cells to influence colon cancer invasion and thus metastasis. We have further provided data that Claudin-1 modulates anoikis in a Src-Akt-Bcl-2-dependent manner. Importantly, Claudin-1 physically associates with Src/p-Src in a multiprotein complex that also includes ZO-1, a PDZ-binding tight junction protein. Taken together, our data support the role of Claudin-1 in the regulation of CRC progression and suggest that the regulation of anoikis may serve as a key regulatory mechanism in Claudin-1-dependent regulation of CRC progression. Our findings are of direct clinical relevance and may open new therapeutic opportunity in colon cancer treatment and/or management.
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Abstract 2084: Claudin-1 induces resistance to anoikis in Src dependent manner in colon cancer cells
Molecular and Cellular Biology, 2012Co-Authors: Ashok Sharma, Robert D. Beauchamp, Amar B. Singh, Joshua J. Smith, Punita DhawanAbstract:Anoikis, a complete loss of cell anchorage triggers apoptosis in primary human colonic epithelial cells (CEC), is often dysfunctional in metastatic cancer cells. We along with other groups have demonstrated that expression of Claudin-1, a tight junction protein, is markedly increased and mislocalized in colon cancer and helps promote the tumor progression especially metastasis. However the underlying mechanism remains poorly understood. To explore, we examined effect of Claudin-1 expression upon anoikis. Colon cancer cells genetically manipulated (stable overexpression in SW480 cells and RNA-interference based gene silencing in SW620 cells) for Claudin-1 expression were cultured on polyHEMA-coated culture dishes to induce anoikis. Results demonstrated a positive correlation between Claudin-1 expression and resistance to anoikis. We also observed a positive correlation between Claudin-1 expression, Src (L4A1) and Akt phosphorylation (Ser 473) and Bcl-2 expression in the cells subjected to anoikis. Notably, use of PP2, a Src-kinase inhibitor, inhibited Claudin-1-dependent resistance to anoikis (2.5fold) as well as the increases in Akt-phosphorylation and Bcl-2 expression, and thus suggested a causal role of Src-activation in Claudin-1-dependent resistance to anoikis. Our further studies revealed that Claudin-1 associates with Src in a multi-protein complex that also included ZO-1, a PDZ-domain containing tight junction protein, known to associate with Claudin-1and Src. Importantly, Claudin-1 contains a PDZ-binding domain in its c-terminal. Deletion of the c-terminal domain of Claudin-1 resulted in the loss of the physical association between Claudin-1 and Src and a significant loss in Claudin-1-dependent resistance to anoikis. Thus, our findings supported a role of Claudin-1 in the regulation of colon cancer progression through its association with Src and dependent cell signaling. Our further analysis using a large database of colon cancer patient samples (microarray analysis; 260 colon cancer and 10 adjacent normal colon samples) showed a significant and positive correlation between Claudin-1 and Src expression. Taken together, we here report a novel partnering between Claudin-1 and Src proteins in colon cancer cells which has a function implication in the regulation of anoikis in a Claudin-1/Src/PI3-kinase/Bcl-2-dependent manner. Our findings have clinical significance and have the potential to open potential new therapeutic opportunity in colon cancer treatment and/or management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2084. doi:1538-7445.AM2012-2084
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Claudin 1 up regulates the repressor zeb 1 to inhibit e cadherin expression in colon cancer cells
Gastroenterology, 2011Co-Authors: Amar B. Singh, Ashok Sharma, Mary Kay Washington, M Krishnan, Joshua J. Smith, Xi Chen, Steven A Eschrich, Timothy J Yeatman, Daniel R Beauchamp, Punita DhawanAbstract:Background & Aims Expression of the tight junction protein Claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of Claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which Claudin-1 regulates E-cadherin expression and its effects in colon cancer cells. Materials and Methods We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with Claudin-1. We analyzed SW480 colon cancer cells that overexpressed Claudin-1, or SW620 cells in which Claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in Claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples. Results Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates Claudin-1-regulated changes in cell invasion and anoikis. Expression of Claudin-1 correlated with that of ZEB-1 in human colon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of Claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times. Conclusions Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.
Sandra Kuntz - One of the best experts on this subject based on the ideXlab platform.
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Claudin 1 inhibits cell migration and increases intercellular adhesion in triple-negative breast cancer cell line
Molecular Biology Reports, 2020Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Sandra Kuntz, Isabelle Grillier-vuissozAbstract:Triple-negative “Claudin 1 low” subtype represents around 15% of breast cancer and displays poor prognosis. The loss of Claudin 1 is correlated with increased invasiveness and higher recurrence of the disease. Claudin 1 constitutes the backbone of the tight junction and is involved in cell-cell adhesion and migration processes. However, studies showed a controversial role of Claudin 1 in cell migration. In this study, we aimed to clarify the effect of Claudin 1 on migration of mesenchymal triple-negative breast cancer cells (TNBC). We reported that transient over expression of Claudin 1 in MDA-MB-231 and Hs578T “Claudin 1 low” TNBC cells inhibited cell migration using wound healing and transwell migration assays. In order to investigate more specifically the involvement of Claudin 1, we generated stable MDA-MB-231 clones overexpressing Claudin 1. Interestingly, the level of Claudin 1 was correlated to the inhibition of cell migration and to the increase of cell-cell aggregation associated with enhanced formation of β-catenin adherens junction and occludin tight junction. Finally, we reported for the first time the key role of Claudin 1 in the inhibition of cell migration process associated with the disappearance of stress fibers. These data suggest that re-expression of Claudin 1 could be a promising strategy for regulating the migration of TNBC which no longer express Claudin 1.
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Pro-apoptotic effect of Δ2-TGZ in "Claudin-1-low" triple-negative breast cancer cells: involvement of Claudin-1
Breast Cancer Research and Treatment, 2017Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Stéphanie Grandemange, Sébastien Hupont, Michel Boisbrun, Stéphane Flament, Isabelle Grillier-vuissoz, Sandra KuntzAbstract:PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express Claudin-1, a major constituent of tight junction. Patients with these "Claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "Claudin-1-low" TNBC cells, Δ2-TGZ treatment induced Claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of Claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, Claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced Claudin-1 expression in both the cells. In absence of Claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "Claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, Claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that Claudin-1 re-expression could be an interesting therapeutic strategy for "Claudin-1-low" TNBC.
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Pro-apoptotic effect of Δ2-TGZ in "Claudin-1-low" triple-negative breast cancer cells: involvement of Claudin-1.
Breast cancer research and treatment, 2017Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Stéphanie Grandemange, Sébastien Hupont, Michel Boisbrun, Stéphane Flament, Isabelle Grillier-vuissoz, Sandra KuntzAbstract:Purpose 40% of triple-negative breast cancer (TNBC) do not express Claudin-1, a major constituent of tight junction. Patients with these “Claudin-1-low” tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors.
Amar B. Singh - One of the best experts on this subject based on the ideXlab platform.
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Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling
Gut, 2013Co-Authors: Jillian L. Pope, Ajaz A. Bhat, Ashok Sharma, Rizwan Ahmad, Moorthy Krishnan, Mary Kay Washington, Robert D. Beauchamp, Amar B. Singh, Punita DhawanAbstract:Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role Claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel villin-Claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal Claudin-1 overexpression). The effect of Claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that Claudin-1 regulates Notch-signalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation. Conclusions Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notch-signalling. An upregulated Claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notch-signalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of Claudin-1 in the regulation of inflammatory bowel diseases and CRC.
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Claudin-1 expression confers resistance to anoikis in colon cancer cells in a Src-dependent manner
Carcinogenesis, 2012Co-Authors: Amar B. Singh, Ashok Sharma, Punita DhawanAbstract:Denial of the appropriate cell-matrix interaction in epithelial cells induces apoptosis and is called 'anoikis'. Cancer cells are resistant to anoikis and it is believed that the resistance to anoikis helps promote tumor malignancy especially metastasis. We and others have demonstrated that the expression of tight junction protein Claudin-1 is highly upregulated in colorectal cancer (CRC) and helps promote tumor progression and metastasis. However, molecular mechanism/s underlying Claudin-1-dependent regulation of CRC progression remains poorly understood. In current study, we have determined that Claudin-1 expression modulates anoikis in colon cancer cells to influence colon cancer invasion and thus metastasis. We have further provided data that Claudin-1 modulates anoikis in a Src-Akt-Bcl-2-dependent manner. Importantly, Claudin-1 physically associates with Src/p-Src in a multiprotein complex that also includes ZO-1, a PDZ-binding tight junction protein. Taken together, our data support the role of Claudin-1 in the regulation of CRC progression and suggest that the regulation of anoikis may serve as a key regulatory mechanism in Claudin-1-dependent regulation of CRC progression. Our findings are of direct clinical relevance and may open new therapeutic opportunity in colon cancer treatment and/or management.
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Abstract 2084: Claudin-1 induces resistance to anoikis in Src dependent manner in colon cancer cells
Molecular and Cellular Biology, 2012Co-Authors: Ashok Sharma, Robert D. Beauchamp, Amar B. Singh, Joshua J. Smith, Punita DhawanAbstract:Anoikis, a complete loss of cell anchorage triggers apoptosis in primary human colonic epithelial cells (CEC), is often dysfunctional in metastatic cancer cells. We along with other groups have demonstrated that expression of Claudin-1, a tight junction protein, is markedly increased and mislocalized in colon cancer and helps promote the tumor progression especially metastasis. However the underlying mechanism remains poorly understood. To explore, we examined effect of Claudin-1 expression upon anoikis. Colon cancer cells genetically manipulated (stable overexpression in SW480 cells and RNA-interference based gene silencing in SW620 cells) for Claudin-1 expression were cultured on polyHEMA-coated culture dishes to induce anoikis. Results demonstrated a positive correlation between Claudin-1 expression and resistance to anoikis. We also observed a positive correlation between Claudin-1 expression, Src (L4A1) and Akt phosphorylation (Ser 473) and Bcl-2 expression in the cells subjected to anoikis. Notably, use of PP2, a Src-kinase inhibitor, inhibited Claudin-1-dependent resistance to anoikis (2.5fold) as well as the increases in Akt-phosphorylation and Bcl-2 expression, and thus suggested a causal role of Src-activation in Claudin-1-dependent resistance to anoikis. Our further studies revealed that Claudin-1 associates with Src in a multi-protein complex that also included ZO-1, a PDZ-domain containing tight junction protein, known to associate with Claudin-1and Src. Importantly, Claudin-1 contains a PDZ-binding domain in its c-terminal. Deletion of the c-terminal domain of Claudin-1 resulted in the loss of the physical association between Claudin-1 and Src and a significant loss in Claudin-1-dependent resistance to anoikis. Thus, our findings supported a role of Claudin-1 in the regulation of colon cancer progression through its association with Src and dependent cell signaling. Our further analysis using a large database of colon cancer patient samples (microarray analysis; 260 colon cancer and 10 adjacent normal colon samples) showed a significant and positive correlation between Claudin-1 and Src expression. Taken together, we here report a novel partnering between Claudin-1 and Src proteins in colon cancer cells which has a function implication in the regulation of anoikis in a Claudin-1/Src/PI3-kinase/Bcl-2-dependent manner. Our findings have clinical significance and have the potential to open potential new therapeutic opportunity in colon cancer treatment and/or management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2084. doi:1538-7445.AM2012-2084
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Claudin 1 up regulates the repressor zeb 1 to inhibit e cadherin expression in colon cancer cells
Gastroenterology, 2011Co-Authors: Amar B. Singh, Ashok Sharma, Mary Kay Washington, M Krishnan, Joshua J. Smith, Xi Chen, Steven A Eschrich, Timothy J Yeatman, Daniel R Beauchamp, Punita DhawanAbstract:Background & Aims Expression of the tight junction protein Claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of Claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which Claudin-1 regulates E-cadherin expression and its effects in colon cancer cells. Materials and Methods We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with Claudin-1. We analyzed SW480 colon cancer cells that overexpressed Claudin-1, or SW620 cells in which Claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in Claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples. Results Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates Claudin-1-regulated changes in cell invasion and anoikis. Expression of Claudin-1 correlated with that of ZEB-1 in human colon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of Claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times. Conclusions Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.
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Abstract 4331: Characterization of targeted overexpression of Claudin-1 transgenic mice
Tumor Biology, 2011Co-Authors: Jillian L. Pope, Ajaz A. Bhat, Moorthy Krishnan, Robert D. Beauchamp, Amar B. Singh, Punita DhawanAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Disruption of cell-cell junctions and changes in the expression of junctional proteins is a critical event in the progression of cancer. We have previously reported a tumor stage specific increase in the expression of a tight junction protein, Claudin-1, in colorectal cancer and its association with tumor-growth and metastasis. Furthermore, our studies have shown that in colon cancer cells, Claudin-1 expression is regulated by a complex interaction between APC, Smad4 and β-catenin, three important regulators of colorectal carcinogenesis. We wanted to investigate the consequence of overexpression of Claudin -1 in vivo specifically in the colon. We have generated a transgenic mouse model in which Claudin-1 is expressed under the control of the villin promoter. The villin promoter is expressed in the adult intestinal epithelium and has been frequently used for intestinal-specific overexpression of several genes of interest. Western blot analysis demonstrated a robust expression of Claudin-1 in the colon, small intestine and cecum of transgenic mice while low levels of expression were present in wild type mice. These results are confirmed with immunohistochemistry analysis where Claudin-1 was largely expressed on the membrane in the same tissues. Colonic permeability was assayed using FITC-dextran, however, there was no significant difference between the flux of FITC-dextran in wild-type and transgenic mice. Real-Time PCR analysis for inflammatory cytokine expression showed a decrease in IL-10 mRNA in transgenic mice compared to that of wild-type mice. Further, treatment with Dextran Sodium Sulfate (DSS) to induce colitis showed a significant decrease in body weight of Claudin-1 transgenic mice as compared to wild type mice on DSS. An increase in disease severity was observed in transgenic mice as determined by histology scoring, as well as a significant difference in the ratio of colon weight to colon length. Claudin-1 expression in transgenic mice is localized to the membrane, where it maintains its normal function. Further experiments with this model include combined treatment with DSS and AOM to examine the effect of Claudin -1 overexpression in inflammation-induced-tumorigenesis as well as performing crosses with sporadic models of tumorigenesis involving mutations in the APC gene, to examine the role of Claudin-1 upregulation in tumor formation and progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4331. doi:10.1158/1538-7445.AM2011-4331
Marine Geoffroy - One of the best experts on this subject based on the ideXlab platform.
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Claudin 1 inhibits cell migration and increases intercellular adhesion in triple-negative breast cancer cell line
Molecular Biology Reports, 2020Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Sandra Kuntz, Isabelle Grillier-vuissozAbstract:Triple-negative “Claudin 1 low” subtype represents around 15% of breast cancer and displays poor prognosis. The loss of Claudin 1 is correlated with increased invasiveness and higher recurrence of the disease. Claudin 1 constitutes the backbone of the tight junction and is involved in cell-cell adhesion and migration processes. However, studies showed a controversial role of Claudin 1 in cell migration. In this study, we aimed to clarify the effect of Claudin 1 on migration of mesenchymal triple-negative breast cancer cells (TNBC). We reported that transient over expression of Claudin 1 in MDA-MB-231 and Hs578T “Claudin 1 low” TNBC cells inhibited cell migration using wound healing and transwell migration assays. In order to investigate more specifically the involvement of Claudin 1, we generated stable MDA-MB-231 clones overexpressing Claudin 1. Interestingly, the level of Claudin 1 was correlated to the inhibition of cell migration and to the increase of cell-cell aggregation associated with enhanced formation of β-catenin adherens junction and occludin tight junction. Finally, we reported for the first time the key role of Claudin 1 in the inhibition of cell migration process associated with the disappearance of stress fibers. These data suggest that re-expression of Claudin 1 could be a promising strategy for regulating the migration of TNBC which no longer express Claudin 1.
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Pro-apoptotic effect of Δ2-TGZ in "Claudin-1-low" triple-negative breast cancer cells: involvement of Claudin-1
Breast Cancer Research and Treatment, 2017Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Stéphanie Grandemange, Sébastien Hupont, Michel Boisbrun, Stéphane Flament, Isabelle Grillier-vuissoz, Sandra KuntzAbstract:PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express Claudin-1, a major constituent of tight junction. Patients with these "Claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "Claudin-1-low" TNBC cells, Δ2-TGZ treatment induced Claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of Claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, Claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced Claudin-1 expression in both the cells. In absence of Claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "Claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, Claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that Claudin-1 re-expression could be an interesting therapeutic strategy for "Claudin-1-low" TNBC.
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Pro-apoptotic effect of Δ2-TGZ in "Claudin-1-low" triple-negative breast cancer cells: involvement of Claudin-1.
Breast cancer research and treatment, 2017Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Stéphanie Grandemange, Sébastien Hupont, Michel Boisbrun, Stéphane Flament, Isabelle Grillier-vuissoz, Sandra KuntzAbstract:Purpose 40% of triple-negative breast cancer (TNBC) do not express Claudin-1, a major constituent of tight junction. Patients with these “Claudin-1-low” tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors.
Isabelle Grillier-vuissoz - One of the best experts on this subject based on the ideXlab platform.
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Claudin 1 inhibits cell migration and increases intercellular adhesion in triple-negative breast cancer cell line
Molecular Biology Reports, 2020Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Sandra Kuntz, Isabelle Grillier-vuissozAbstract:Triple-negative “Claudin 1 low” subtype represents around 15% of breast cancer and displays poor prognosis. The loss of Claudin 1 is correlated with increased invasiveness and higher recurrence of the disease. Claudin 1 constitutes the backbone of the tight junction and is involved in cell-cell adhesion and migration processes. However, studies showed a controversial role of Claudin 1 in cell migration. In this study, we aimed to clarify the effect of Claudin 1 on migration of mesenchymal triple-negative breast cancer cells (TNBC). We reported that transient over expression of Claudin 1 in MDA-MB-231 and Hs578T “Claudin 1 low” TNBC cells inhibited cell migration using wound healing and transwell migration assays. In order to investigate more specifically the involvement of Claudin 1, we generated stable MDA-MB-231 clones overexpressing Claudin 1. Interestingly, the level of Claudin 1 was correlated to the inhibition of cell migration and to the increase of cell-cell aggregation associated with enhanced formation of β-catenin adherens junction and occludin tight junction. Finally, we reported for the first time the key role of Claudin 1 in the inhibition of cell migration process associated with the disappearance of stress fibers. These data suggest that re-expression of Claudin 1 could be a promising strategy for regulating the migration of TNBC which no longer express Claudin 1.
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Pro-apoptotic effect of Δ2-TGZ in "Claudin-1-low" triple-negative breast cancer cells: involvement of Claudin-1
Breast Cancer Research and Treatment, 2017Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Stéphanie Grandemange, Sébastien Hupont, Michel Boisbrun, Stéphane Flament, Isabelle Grillier-vuissoz, Sandra KuntzAbstract:PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express Claudin-1, a major constituent of tight junction. Patients with these "Claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "Claudin-1-low" TNBC cells, Δ2-TGZ treatment induced Claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of Claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, Claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced Claudin-1 expression in both the cells. In absence of Claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "Claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, Claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that Claudin-1 re-expression could be an interesting therapeutic strategy for "Claudin-1-low" TNBC.
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Pro-apoptotic effect of Δ2-TGZ in "Claudin-1-low" triple-negative breast cancer cells: involvement of Claudin-1.
Breast cancer research and treatment, 2017Co-Authors: Marine Geoffroy, Alexandra Kleinclauss, Stéphanie Grandemange, Sébastien Hupont, Michel Boisbrun, Stéphane Flament, Isabelle Grillier-vuissoz, Sandra KuntzAbstract:Purpose 40% of triple-negative breast cancer (TNBC) do not express Claudin-1, a major constituent of tight junction. Patients with these “Claudin-1-low” tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors.