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Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.
Wu J, Peng D, Zhang Y, Lu Z, Voehler M, Sanders CR, Li J
(2015) Biochem Biophys Res Commun 459: 87-93
MeSH Terms: Amino Acid Motifs, Claudin-1, Claudin-2, Claudin-3, Claudin-5, Claudins, Humans, Nuclear Magnetic Resonance, Biomolecular, Peripheral Nerves, Protein Structure, Secondary, Zonula Occludens-2 Protein
Show Abstract · Added February 5, 2016
Our recent study has shown that cellular junctions in myelin and in the epi-/perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ₁ domain of zonula occludens (ZO₁ or ZO₂) and the C-termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ₁ domain of ZO₂ and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi-/perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ₁ of ZO₂. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ₁, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO₂. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves.
Published by Elsevier Inc.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Modulation of VEGF-induced retinal vascular permeability by peroxisome proliferator-activated receptor-β/δ.
Suarez S, McCollum GW, Bretz CA, Yang R, Capozzi ME, Penn JS
(2014) Invest Ophthalmol Vis Sci 55: 8232-40
MeSH Terms: Analysis of Variance, Animals, Capillary Permeability, Cell Membrane, Cells, Cultured, Claudin-1, Claudin-5, Electric Impedance, Endothelial Cells, Extracellular Signal-Regulated MAP Kinases, Humans, Immunohistochemistry, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Models, Animal, Peroxisome Proliferator-Activated Receptors, Receptors, Vascular Endothelial Growth Factor, Retina, Retinal Vessels, Sulfones, Thiophenes, Vascular Endothelial Growth Factor A
Show Abstract · Added February 19, 2015
PURPOSE - Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability contributes to diabetic macular edema (DME), a serious vision-threatening condition. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) antagonist/reverse agonist, GSK0660, inhibits VEGF-induced human retinal microvascular endothelial cell (HRMEC) proliferation, tubulogenesis, and oxygen-induced retinal vasculopathy in newborn rats. These VEGF-induced HRMEC behaviors and VEGF-induced disruption of endothelial cell junctional complexes may well share molecular signaling events. Thus, we sought to examine the role of PPARβ/δ in VEGF-induced retinal hyperpermeability.
METHODS - Transendothelial electrical resistance (TEER) measurements were performed on HRMEC monolayers to assess permeability. Claudin-1/Claudin-5 localization in HRMEC monolayers was determined by immunocytochemistry. Extracellular signal-regulated protein kinases 1 and 2 (Erk 1/2) phosphorylation, VEGF receptor 1 (VEGFR1) and R2 were assayed by Western blot analysis. Expression of VEGFR1 and R2 was measured by quantitative RT-PCR. Last, retinal vascular permeability was assayed in vivo by Evans blue extravasation.
RESULTS - Human retinal microvascular endothelial cell monolayers treated with VEGF for 24 hours showed decreased TEER values that were completely reversed by the highest concentration of GSK0660 (10 μM) and PPARβ/δ-directed siRNA (20 μM). In HRMEC treated with VEGF, GSK0660 stabilized tight-junctions as evidenced by Claudin-1 staining, reduced phosphorylation of Erk1/2, and reduced VEGFR1/2 expression. Peroxisome proliferator-activated receptor β/δ siRNA had a similar effect on VEGFR expression and Claudin-1, supporting the specificity of GSK0660 in our experiments. Last, GSK0660 significantly inhibited VEGF-induced retinal vascular permeability and reduced retinal VEGFR1and R2 levels in C57BL/6 mice.
CONCLUSIONS - These data suggest a protective effect for PPARβ/δ antagonism against VEGF-induced vascular permeability, possibly through reduced VEGFR expression. Therefore, antagonism/reverse agonism of PPARβ/δ siRNA may represent a novel therapeutic methodology against retinal hyperpermeability and is worthy of future investigation.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
1 Communities
1 Members
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23 MeSH Terms
Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis.
Pope JL, Ahmad R, Bhat AA, Washington MK, Singh AB, Dhawan P
(2014) Mol Cancer 13: 167
MeSH Terms: Adenomatous Polyposis Coli, Adenomatous Polyposis Coli Protein, Animals, Cell Transformation, Neoplastic, Claudin-1, Colonic Neoplasms, Epithelial Cells, Gene Expression Regulation, Neoplastic, Interleukin-23 Subunit p19, Intestinal Mucosa, Intestines, Mice, Mucin-2
Show Abstract · Added December 8, 2014
BACKGROUND - The tight junction protein Claudin-1, a claudin family member, has been implicated in several gastro-intestinal pathologies including inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this regard, we have demonstrated that claudin-1 expression in colon cancer cells potentiates their tumorigenic ability while in vivo expression of claudin-1 in the intestinal epithelial cells (IECs) promotes Notch-activation, inhibits goblet cell differentiation and renders susceptibility to mucosal inflammation. Notably, a key role of inflammation in colon cancer progression is being appreciated. Therefore, we examined whether inflammation plays an important role in claudin-1-dependent upregulation of colon carcinogenesis.
METHODS - APCmin mice were crossed with Villin-claudin-1 transgenic mice to generate APC-Cldn1 mice. H&E stained colon tissues were assessed for tumor number, size and histological grade. Additionally, microarray and qPCR analyses of colonic tumors were performed to assess molecular changes due to claudin-1 expression. APC-Cldn1 and APCmin controls were assessed for colonic permeability via rectal administration of FITC-dextran, and bacterial translocation via qPCR analysis of 16S rDNA.
RESULTS - Claudin-1 overexpression in APCmin mice significantly increased (~4-fold) colonic tumor growth and size, and decreased survival. Furthermore, transcriptome analysis supported upregulated proliferation, and increased Wnt and Notch-signaling in APC-Cldn1 mice. APC-Cldn1 mice also demonstrated inhibition of mucosal defense genes while expression of pro-inflammatory genes was sharply upregulated, especially the IL-23/IL-17 signaling. We predict that increased Notch/Wnt-signaling underlie the early onset of adenoma formation in APC-Cldn1 mice. An increase in mucosal permeability due to the adenomas and the inherent barrier defect in these mice further facilitate bacterial translocation into the mucosa to induce inflammation, which in turn promote the tumorigenesis.
CONCLUSION - Taken together, these results confirm the role of claudin-1 as a promoter of colon tumorigenesis and further identify the role of the dysregulated antigen-tumor interaction and inflammation in claudin-1-dependent upregulation of colon tumorigenesis.
1 Communities
1 Members
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13 MeSH Terms
Trichostatin-A modulates claudin-1 mRNA stability through the modulation of Hu antigen R and tristetraprolin in colon cancer cells.
Sharma A, Bhat AA, Krishnan M, Singh AB, Dhawan P
(2013) Carcinogenesis 34: 2610-21
MeSH Terms: 3' Untranslated Regions, Base Sequence, Blotting, Western, Breast Neoplasms, Cells, Cultured, Chromatin Immunoprecipitation, Claudin-1, Colonic Neoplasms, ELAV Proteins, Epigenesis, Genetic, Female, Fluorescent Antibody Technique, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Immunoenzyme Techniques, Kidney, Molecular Sequence Data, Mutagenesis, Site-Directed, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tristetraprolin
Show Abstract · Added March 7, 2014
Expression of claudin-1, a tight junction protein, is highly upregulated in colon cancer. We have reported that claudin-1 expression in colon cancer cells is epigenetically regulated as histone deacetylase (HDAC) inhibitors decrease claudin-1 messenger RNA (mRNA) stability and thus expression. In this regard, our data suggested a role of the 3'-untranslated region (UTR) in the regulation of HDAC-dependent regulation of claudin-1 mRNA stability. In the current study, we demonstrate, based on our continued investigation, that the ELAV-like RNA-binding proteins (RBPs), human antigen R (HuR) and tristetraprolin (TTP) associate with the 3'-UTR of claudin-1 mRNA to modulate the latter's stability. Ribonomic and site-directed mutagenesis approaches were used to confirm the binding of HuR and TTP to the 3'-UTR of claudin-1. We further confirmed their roles in the stabilization of claudin-1 mRNA, under conditions of HDAC inhibition. In summary, we report that HuR and TTP are the critical regulators of the posttranscriptional regulation of claudin-1 expression in colon cancer cells. We also demonstrate that inhibition of HDACs by trichostatin treatment decreased the binding of HuR while increasing the binding of TTP to the 3'-UTR of claudin-1. Additionally, we provide data showing transcriptional regulation of claudin-1 expression, through the regulation of transcription factor Sp1. Taken together, we demonstrate epigenetic regulation of claudin-1 expression in colon cancer cells at the transcriptional and posttranscriptional levels.
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2 Members
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24 MeSH Terms
Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling.
Pope JL, Bhat AA, Sharma A, Ahmad R, Krishnan M, Washington MK, Beauchamp RD, Singh AB, Dhawan P
(2014) Gut 63: 622-34
MeSH Terms: Animals, Apoptosis, Cell Differentiation, Cell Proliferation, Claudin-1, Colitis, Colon, Dextran Sulfate, Disease Models, Animal, Homeostasis, Intestinal Mucosa, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Receptors, Notch, Signal Transduction
Show Abstract · Added January 20, 2014
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.
1 Communities
7 Members
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17 MeSH Terms
Rab25 regulates integrin expression in polarized colonic epithelial cells.
Krishnan M, Lapierre LA, Knowles BC, Goldenring JR
(2013) Mol Biol Cell 24: 818-31
MeSH Terms: Adenovirus E1A Proteins, Caco-2 Cells, Cell Line, Tumor, Cell Movement, Cell Polarity, Claudin-1, Epithelial Cells, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Integrin alpha2, Integrin alpha5, Integrin alpha5beta1, Integrin beta1, Integrins, Intestinal Mucosa, Microvilli, Neoplasm Invasiveness, Proto-Oncogene Proteins, RNA Interference, rab GTP-Binding Proteins
Show Abstract · Added October 7, 2013
Rab25 is a tumor suppressor for colon cancer in humans and mice. To identify elements of intestinal polarity regulated by Rab25, we developed Caco2-BBE cell lines stably expressing short hairpin RNA for Rab25 and lines rescuing Rab25 knockdown with reexpression of rabbit Rab25. Rab25 knockdown decreased α2-, α5-, and β1-integrin expression. We observed colocalization and direct association of Rab25 with α5β1-integrins. Rab25 knockdown also up-regulated claudin-1 expression, increased transepithelial resistance, and increased invasive behavior. Rab25-knockdown cells showed disorganized brush border microvilli with decreases in villin expression. All of these changes were reversed by reintroduction of rabbit Rab25. Rab25 knockdown altered the expression of 29 gene transcripts, including the loss of α5-integrin transcripts. Rab25 loss decreased expression of one transcription factor, ETV4, and overexpression of ETV4 in Rab25-knockdown cells reversed losses of α5β1-integrin. The results suggest that Rab25 controls intestinal cell polarity through the regulation of gene expression.
1 Communities
2 Members
0 Resources
22 MeSH Terms
Claudin-1 expression confers resistance to anoikis in colon cancer cells in a Src-dependent manner.
Singh AB, Sharma A, Dhawan P
(2012) Carcinogenesis 33: 2538-47
MeSH Terms: Anoikis, Cell Line, Tumor, Claudin-1, Colonic Neoplasms, Humans, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, src-Family Kinases
Show Abstract · Added March 7, 2014
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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2 Members
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8 MeSH Terms
Caudal homeobox protein Cdx-2 cooperates with Wnt pathway to regulate claudin-1 expression in colon cancer cells.
Bhat AA, Sharma A, Pope J, Krishnan M, Washington MK, Singh AB, Dhawan P
(2012) PLoS One 7: e37174
MeSH Terms: Base Sequence, Binding Sites, CDX2 Transcription Factor, Cell Line, Tumor, Claudin-1, Colorectal Neoplasms, DNA, GATA4 Transcription Factor, Gene Expression Regulation, Homeodomain Proteins, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Transcription, Genetic, Wnt Proteins
Show Abstract · Added June 28, 2013
Dysregulation of tight junctions (TJs) is often associated with human diseases including carcinogenesis and recent studies support role of TJ integral proteins in the regulation of Epithelial-to-Mesenchymal Transition (EMT). In this regard, expression of claudin-1, a key constituent of TJs, is highly increased in colon cancer and is causally associated with the tumor growth and progression. However, mechanism/s underlying regulation of claudin-1 expression in intestinal epithelial cells remains poorly understood. In our studies, we have identified putative binding sites for intestinal transcription factors Cdx1, -2 and GATA4 in the 5'-flanking region of the claudin-1 gene. Our further studies using full length and/or deletion mutant constructs in two different human colon cancer cell lines, SW480 and HCT116, showed key role of Cdx1, Cdx2 and GATA4 in the regulation of claudin-1 mRNA expression. However, overexpression of Cdx2 had the most potent effect upon claudin-1 mRNA expression and promoter activity. Also, in colon cancer patient samples, we observed a significant and parallel correlation between claudin-1 and Cdx2 expressions. Chromatin immunoprecipitation (ChIP) assay confirmed the Cdx2 binding with claudin-1 promoter in vivo. Using Cdx2 deletion mutant constructs, we further mapped the Cdx2 C-terminus domain to be important in the regulation of claudin-1 promoter activity. Interestingly, co-expression of activated β-catenin further induced the Cdx2-dependent upregulation of claudin-1 promoter activity while expression of the dominant negative (dn)-TCF-4 abrogated this activation. Taken together, we conclude that homeodomain transcription factors Cdx1, Cdx2 and GATA4 regulate claudin-1 gene expression in human colon cancer cells. Moreover, a functional crosstalk between Wnt-signaling and transcriptional activation related to caudal-related homeobox (Cdx) proteins and GATA-proteins is demonstrated in the regulation of claudin-1 promoter-activation.
0 Communities
5 Members
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15 MeSH Terms
Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells.
Singh AB, Sharma A, Smith JJ, Krishnan M, Chen X, Eschrich S, Washington MK, Yeatman TJ, Beauchamp RD, Dhawan P
(2011) Gastroenterology 141: 2140-53
MeSH Terms: Anoikis, Cadherins, Cell Line, Tumor, Claudin-1, Colonic Neoplasms, Disease Progression, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Immunoblotting, Membrane Proteins, Microarray Analysis, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription Factors, Up-Regulation, Zinc Finger E-box-Binding Homeobox 1
Show Abstract · Added June 14, 2013
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.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
3 Members
0 Resources
18 MeSH Terms
HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability.
Krishnan M, Singh AB, Smith JJ, Sharma A, Chen X, Eschrich S, Yeatman TJ, Beauchamp RD, Dhawan P
(2010) Oncogene 29: 305-12
MeSH Terms: 3' Untranslated Regions, Butyrates, Cell Line, Tumor, Cell Movement, Claudin-1, Colonic Neoplasms, Gene Expression Regulation, Neoplastic, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Immunoblotting, Membrane Proteins, RNA Interference, RNA Stability, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Transcription, Genetic
Show Abstract · Added June 14, 2013
Expression and cellular distribution of claudin-1, a tight junction protein, is dysregulated in colon cancer and its overexpression in colon cancer cells induced dedifferentiation and increased invasion. However, the molecular mechanism(s) underlying dysregulated claudin-1 expression in colon cancer remains poorly understood. Histone deacetylase (HDAC)-dependent histone acetylation is an important mechanism of the regulation of cancer-related genes and inhibition of HDACs induces epithelial differentiation and decreased invasion. Therefore, in this study, we examined the role of HDAC-dependent epigenetic regulation of claudin-1 in colon cancer. In this study, we show that sodium butyrate and Trichostatin A (TSA), two structurally different and widely used HDAC inhibitors, inhibited claudin-1 expression in multiple colon cancer cell lines. Further studies revealed modulation of claudin-1 mRNA stability by its 3'-UTR as the major mechanism underlying HDAC-dependent claudin-1 expression. In addition, overexpression of claudin-1 abrogated the TSA-induced inhibition of invasion in colon cancer cells suggesting functional crosstalk. Analysis of mRNA expression in colon cancer patients, showed a similar pattern of increase in claudin-1 and HDAC-2 mRNA expression throughout all stages of colon cancer. Inhibition of claudin-1 expression by HDAC-2-specific small interfering RNA further supported the role of HDAC-2 in this regulation. Taken together, we report a novel post-transcriptional regulation of claudin-1 expression in colon cancer cells and further show a functional correlation between claudin-1 expression and TSA-mediated regulation of invasion. As HDAC inhibitors are considered to be promising anticancer drugs, these new findings will have implications in both laboratory and clinical settings.
1 Communities
2 Members
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18 MeSH Terms