Publications by authors named "Nicolas Jonckheere"

44 Publications

Mg Transporters in Digestive Cancers.

Nutrients 2021 Jan 13;13(1). Epub 2021 Jan 13.

Université de Picardie Jules Verne, UFR des Sciences, UR-UPJV 4667, F-80000 Amiens, France.

Despite magnesium (Mg) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg homeostasis is regulated by Mg transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg transporters' expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg transporters in the regulation of cancer cell fates and oncogenic signaling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu13010210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828344PMC
January 2021

Unsupervised Hierarchical Clustering of Pancreatic Adenocarcinoma Dataset from TCGA Defines a Mucin Expression Profile that Impacts Overall Survival.

Cancers (Basel) 2020 11 9;12(11). Epub 2020 Nov 9.

Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France.

Mucins are commonly associated with pancreatic ductal adenocarcinoma (PDAC) that is a deadly disease because of the lack of early diagnosis and efficient therapies. There are 22 mucin genes encoding large -glycoproteins divided into two major subgroups: membrane-bound and secreted mucins. We investigated mucin expression and their impact on patient survival in the PDAC dataset from The Cancer Genome Atlas (PAAD-TCGA). We observed a statistically significant increased messenger RNA (mRNA) relative level of most of the membrane-bound mucins (), secreted mucins (), and atypical mucins () compared to normal pancreas. We show that mRNA levels are associated with poorer survival in the high-expression group compared to the low-expression group. Using unsupervised clustering analysis of mucin gene expression patterns, we identified two major clusters of patients. Cluster #1 harbors a higher expression of and atypical /, whereas cluster #2 is characterized by a global overexpression of membrane-bound mucins (). Cluster #2 is associated with shorter overall survival. The patient stratification appears to be independent of usual clinical features (tumor stage, differentiation grade, lymph node invasion) suggesting that the pattern of membrane-bound mucin expression could be a new prognostic marker for PDAC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697168PMC
November 2020

Long non-coding RNAs: the tentacles of chromatin remodeler complexes.

Cell Mol Life Sci 2021 Feb 1;78(4):1139-1161. Epub 2020 Oct 1.

UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, CNRS, Inserm, CHU Lille, 59000, Lille, France.

Chromatin remodeler complexes regulate gene transcription, DNA replication and DNA repair by changing both nucleosome position and post-translational modifications. The chromatin remodeler complexes are categorized into four families: the SWI/SNF, INO80/SWR1, ISWI and CHD family. In this review, we describe the subunits of these chromatin remodeler complexes, in particular, the recently identified members of the ISWI family and novelties of the CHD family. Long non-coding (lnc) RNAs regulate gene expression through different epigenetic mechanisms, including interaction with chromatin remodelers. For example, interaction of lncBRM with BRM inhibits the SWI/SNF complex associated with a differentiated phenotype and favors assembly of a stem cell-related SWI/SNF complex. Today, over 50 lncRNAs have been shown to affect chromatin remodeler complexes and we here discuss the mechanisms involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-020-03646-0DOI Listing
February 2021

Long-term consequences of one anastomosis gastric bypass on esogastric mucosa in a preclinical rat model.

Sci Rep 2020 04 30;10(1):7393. Epub 2020 Apr 30.

Inserm UMRS 1149, UFR de Médecine Paris Diderot, Université de Paris, AP-HP, Paris, France.

Although bariatric surgery is proven to sustain weight loss in morbidly obese patients, long-term adverse effects have yet to be fully characterized. This study compared the long-term consequences of two common forms of bariatric surgery: one-anastomosis gastric bypass (OAGB) and Roux-en-Y Gastric Bypass (RYGB) in a preclinical rat model. We evaluated the influence of biliopancreatic limb (BPL) length, malabsorption, and bile acid (BA) reflux on esogastric mucosa. After 30 weeks of follow-up, Wistar rats operated on RYGB, OAGB with a short BPL (15 cm, OAGB-15), or a long BPL (35 cm, OAGB-35), and unoperated rats exhibit no cases of esogastric cancer, metaplasia, dysplasia, or Barrett's esophagus. Compared to RYGB, OAGB-35 rats presented higher rate of esophagitis, fundic gastritis and perianastomotic foveolar hyperplasia. OAGB-35 rats also revealed the greatest weight loss and malabsorption. On the contrary, BA concentrations were the highest in the residual gastric pouch of OAGB-15 rats. Yet, no association could be established between the esogastric lesions and malabsorption, weight loss, or gastric bile acid concentrations. In conclusion, RYGB results in a better long-term outcome than OAGB, as chronic signs of biliary reflux or reactional gastritis were reported post-OAGB even after reducing the BPL length in a preclinical rat model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-64425-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192900PMC
April 2020

EGF-Containing Membrane-Bound Mucins: A Hidden ErbB2 Targeting Pathway?

J Med Chem 2020 05 13;63(10):5074-5088. Epub 2020 Feb 13.

Univ. Lille, Inserm CHU Lille, UMR-S1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France.

Membrane-bound mucins belong to a heterogeneous family of large O-glycoproteins involved in numerous cancers and inflammatory diseases of the epithelium. Some of them are also involved in protein-protein interactions, with receptor tyrosine kinase ErbB2, and fundamental and clinical data showed that these complexes have a detrimental impact on cancer outcome, thus raising interest in therapeutic targeting. This paper aims to demonstrate that MUC3, MUC4, MUC12, MUC13, and MUC17 have a common evolutionary origin and share a common structural organization with EGF-like and SEA domains. Theoretical structure-function relationship analysis of the conserved domains indicated that the studied membrane-bound mucins share common biological properties along with potential specific functions. Finally, the potential druggability of these complexes is discussed, revealing ErbB2-related pathways of cell signaling to be targeted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b02001DOI Listing
May 2020

Fine-tuning autophagy in pancreatic adenocarcinoma: full blockage is required.

Ann Transl Med 2019 Mar;7(Suppl 1):S43

Univ. Lille, Inserm, CHU Lille, UMR-S 1172, Jean-Pierre Aubert Research Center (JPARC), Team "Mucins, epithelial differentiation and carcinogenesis", F-59000 Lille, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm.2019.03.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462624PMC
March 2019

Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer.

Cancers (Basel) 2018 Nov 14;10(11). Epub 2018 Nov 14.

Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.

Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers10110440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266399PMC
November 2018

Integrative analysis of the cancer genome atlas and cancer cell lines encyclopedia large-scale genomic databases: MUC4/MUC16/MUC20 signature is associated with poor survival in human carcinomas.

J Transl Med 2018 09 20;16(1):259. Epub 2018 Sep 20.

Inserm, CHU Lille, UMR-S 1172-JPARC-Jean-Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", Univ. Lille, 59000, Lille, France.

Background: MUC4 is a membrane-bound mucin that promotes carcinogenetic progression and is often proposed as a promising biomarker for various carcinomas. In this manuscript, we analyzed large scale genomic datasets in order to evaluate MUC4 expression, identify genes that are correlated with MUC4 and propose new signatures as a prognostic marker of epithelial cancers.

Methods: Using cBioportal or SurvExpress tools, we studied MUC4 expression in large-scale genomic public datasets of human cancer (the cancer genome atlas, TCGA) and cancer cell line encyclopedia (CCLE).

Results: We identified 187 co-expressed genes for which the expression is correlated with MUC4 expression. Gene ontology analysis showed they are notably involved in cell adhesion, cell-cell junctions, glycosylation and cell signaling. In addition, we showed that MUC4 expression is correlated with MUC16 and MUC20, two other membrane-bound mucins. We showed that MUC4 expression is associated with a poorer overall survival in TCGA cancers with different localizations including pancreatic cancer, bladder cancer, colon cancer, lung adenocarcinoma, lung squamous adenocarcinoma, skin cancer and stomach cancer. We showed that the combination of MUC4, MUC16 and MUC20 signature is associated with statistically significant reduced overall survival and increased hazard ratio in pancreatic, colon and stomach cancer.

Conclusions: Altogether, this study provides the link between (i) MUC4 expression and clinical outcome in cancer and (ii) MUC4 expression and correlated genes involved in cell adhesion, cell-cell junctions, glycosylation and cell signaling. We propose the MUC4/MUC16/MUC20 signature as a marker of poor prognostic for pancreatic, colon and stomach cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-018-1632-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149062PMC
September 2018

TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727.

Cancers (Basel) 2018 07 31;10(8). Epub 2018 Jul 31.

INSERM, UMR-S1172, Jean Pierre Aubert Research Center, "Mucins, Epithelial Differentiation and Carcinogenesis" Team, rue Polonovski, 59045 Lille CEDEX, France.

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50⁻80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers10080254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116183PMC
July 2018

Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway.

Biochem J 2017 11 1;474(22):3733-3746. Epub 2017 Nov 1.

Univ. Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences and Cancer, Lille F-59000, France

Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to proliferation, migration and invasion, and on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT-PCR were used to identify proteins and signalling pathways involved. MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of β-catenin expression, localization and activity and decreased expression of several of its target genes. xenografts of MUC5B-deficient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/β-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BCJ20170348DOI Listing
November 2017

The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting.

Crit Rev Oncol Hematol 2017 Mar 10;111:7-19. Epub 2017 Jan 10.

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", F-59000, Lille, France.

RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2017.01.002DOI Listing
March 2017

Flagellin-Mediated Protection against Intestinal Yersinia pseudotuberculosis Infection Does Not Require Interleukin-22.

Infect Immun 2017 02 26;85(2). Epub 2017 Jan 26.

Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204, CIIL-Center for Infection and Immunity of Lille, Lille, France

Signaling through Toll-like receptors (TLRs), the main receptors in innate immunity, is essential for the defense of mucosal surfaces. It was previously shown that systemic TLR5 stimulation by bacterial flagellin induces an immediate, transient interleukin-22 (IL-22)-dependent antimicrobial response to bacterial or viral infections of the mucosa. This process was dependent on the activation of type 3 innate lymphoid cells (ILCs). The objective of the present study was to analyze the effects of flagellin treatment in a murine model of oral infection with Yersinia pseudotuberculosis (an invasive, Gram-negative, enteropathogenic bacterium that targets the small intestine). We found that systemic administration of flagellin significantly increased the survival rate after intestinal infection (but not systemic infection) by Y. pseudotuberculosis This protection was associated with a low bacterial count in the gut and the spleen. In contrast, no protection was afforded by administration of the TLR4 agonist lipopolysaccharide, suggesting the presence of a flagellin-specific effect. Lastly, we found that TLR5- and MyD88-mediated signaling was required for the protective effects of flagellin, whereas neither lymphoid cells nor IL-22 was involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00806-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278166PMC
February 2017

Targeting MUC4 in pancreatic cancer: miRNAs.

Oncoscience 2015 12;2(10):799-800. Epub 2015 Sep 12.

Inserm, UMR-S1172, Jean-Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", Lille cedex, France; Université Lille 2 Droit et Santé, Lille cedex, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671926PMC
http://dx.doi.org/10.18632/oncoscience.249DOI Listing
December 2015

The mucin MUC4 is a transcriptional and post-transcriptional target of K-ras oncogene in pancreatic cancer. Implication of MAPK/AP-1, NF-κB and RalB signaling pathways.

Biochim Biophys Acta 2015 Dec 22;1849(12):1375-84. Epub 2015 Oct 22.

Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.

The membrane-bound mucinMUC4 is a high molecularweight glycoprotein frequently deregulated in cancer. In pancreatic cancer, one of the most deadly cancers in occidental countries, MUC4 is neo-expressed in the preneoplastic stages and thereafter is involved in cancer cell properties leading to cancer progression and chemoresistance. K-ras oncogene is a small GTPase of the RAS superfamily, highly implicated in cancer. K-ras mutations are considered as an initiating event of pancreatic carcinogenesis and K-ras oncogenic activities are necessary components of cancer progression. However, K-ras remains clinically undruggable. Targeting early downstream K-ras signaling in cancer may thus appear as an interesting strategy and MUC4 regulation by K-ras in pancreatic carcinogenesis remains unknown. Using the Pdx1-Cre; LStopL-K-rasG12D mouse model of pancreatic carcinogenesis, we show that the in vivo early neo-expression of the mucin Muc4 in pancreatic intraepithelial neoplastic lesions (PanINs) induced by mutated K-ras is correlated with the activation of ERK, JNK and NF-κB signaling pathways. In vitro, transfection of constitutively activated K-rasG12V in pancreatic cancer cells led to the transcriptional upregulation of MUC4. This activation was found to be mediated at the transcriptional level by AP-1 and NF-κB transcription factors via MAPK, JNK and NF-κB pathways and at the posttranscriptional level by a mechanism involving the RalB GTPase. Altogether, these results identify MUC4 as a transcriptional and post-transcriptional target of K-ras in pancreatic cancer. This opens avenues in developing new approaches to target the early steps of this deadly cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagrm.2015.10.014DOI Listing
December 2015

Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells.

Biochim Biophys Acta 2015 Oct 31;1853(10 Pt A):2392-403. Epub 2015 May 31.

Inserm, UMR-S1172, Jean-Pierre Aubert Research Center, Team "Mucins, Epithelial Differentiation and Carcinogenesis", Rue Polonovski, 59045 Lille cedex, France; Université de Lille 2, 42 rue Paul Duez, 59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, 59037 Lille cedex, France. Electronic address:

MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To control cancer progression, miRNAs became very recently, major targets and tools to inhibit oncogene expression. Inhibiting MUC1 using miRNAs appears thus as an attractive strategy to reduce cancer progression. However, potent miRNAs and associated mechanisms regulating MUC1 expression remain to be identified. To this aim, we undertook to study MUC1 regulation by miRNAs in pancreatic cancer cells and identify those with tumor suppressive activity. MiRNAs potentially targeting the 3'-UTR, the coding region, or the 5'-UTR of MUC1 were selected using an in silico approach. Our in vitro and in vivo experiments indicate that miR-29a and miR-330-5p are strong inhibitors of MUC1 expression in pancreatic cancer cells through direct binding to MUC1 3'-UTR. MUC1 regulation by the other selected miRNAs (miR-183, miR-200a, miR-876-3p and miR-939) was found to be indirect. MiR-29a and miR-330-5p are also deregulated in human pancreatic cancer cell lines and tissues and in pancreatic tissues of Kras(G12D) mice. In vitro, miR-29a and miR-330-5p inhibit cell proliferation, cell migration, cell invasion and sensitize pancreatic cancer cells to gemcitabine. In vivo intra-tumoral injection of these two miRNAs in xenografted pancreatic tumors led to reduced tumor growth. Altogether, we have identified miR-29a and miR-330-5p as two new tumor suppressive miRNAs that inhibit the expression of MUC1 oncogenic mucin in pancreatic cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamcr.2015.05.033DOI Listing
October 2015

The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2.

Oncotarget 2015 May;6(13):10853-67

Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Lille cedex 59045, France.

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers because of a lack of early diagnostic markers and efficient therapeutics. The fluorinated analog of deoxycytidine, gemcitabine and emerging FOLFIRINOX protocol (5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin) are the main chemotherapies to treat PDAC. The ErbB2/HER2 oncogenic receptor is commonly overexpressed in PDAC. In this context, we aimed to decipher the ErbB2-mediated mechanisms of chemoresistance to the two main chemotherapy protocols used to treat PDAC.ErbB2 knocking down (KD) in CAPAN-1 and CAPAN-2 cells led to an increased sensitivity to gemcitabine and an increased resistance to irinotecan/SN-38 both in vitro and in vivo (subcutaneous xenografts) This was correlated to an increase of hCNT1 and hCNT3 transporters and ABCG2, MRP1 and MRP2 ATP-binding cassette transporters expression and resistance to cell death. We also show that MRP2 is repressed following activation of JNK, Erk1/2 and NF-κB pathways by ErbB2. Finally, in datasets of human PDAC samples, ErbB2 and MRP2 expression was conversely correlated. Altogether, we propose that ErbB2 mediates several intracellular mechanisms linked to PDAC cell chemoresistance that may represent potential targets in order to ameliorate chemotherapy response and allow stratification of patients eligible for either gemcitabine or FOLFIRINOX treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484424PMC
http://dx.doi.org/10.18632/oncotarget.3414DOI Listing
May 2015

Cryosectioning the intestinal crypt-villus axis: an ex vivo method to study the dynamics of epigenetic modifications from stem cells to differentiated cells.

Stem Cell Res 2015 Jan 27;14(1):105-13. Epub 2014 Dec 27.

Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis," rue Polonovski, Lille, France; Université Lille 2 Droit et Santé, Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Lille, France.

The intestinal epithelium is a particularly attractive biological adult model to study epigenetic mechanisms driving adult stem cell renewal and cell differentiation. Since epigenetic modifications are dynamic, we have developed an original ex vivo approach to study the expression and epigenetic profiles of key genes associated with either intestinal cell pluripotency or differentiation by isolating cryosections of the intestinal crypt-villus axis. Gene expression, DNA methylation and histone modifications were studied by qRT-PCR, methylation-specific PCR and micro-chromatin immunoprecipitation, respectively. Using this approach, it was possible to identify segment-specific methylation and chromatin profiles. We show that (i) expression of intestinal stem cell markers (Lgr5, Ascl2) exclusively in the crypt is associated with active histone marks, (ii) promoters of all pluripotency genes studied and transcription factors involved in intestinal cell fate (Cdx2) harbour a bivalent chromatin pattern in the crypts and (iii) expression of differentiation markers (Muc2, Sox9) along the crypt-villus axis is associated with DNA methylation. Hence, using an original model of cryosectioning along the crypt-villus axis that allows in situ detection of dynamic epigenetic modifications, we demonstrate that regulation of pluripotency and differentiation markers in healthy intestinal mucosa involves different and specific epigenetic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scr.2014.12.002DOI Listing
January 2015

Overexpression of chemokine receptor CXCR2 and ligand CXCL7 in liver metastases from colon cancer is correlated to shorter disease-free and overall survival.

Cancer Sci 2015 Mar 5;106(3):262-9. Epub 2015 Mar 5.

Inserm, U837, Team-5 (Mucins, Epithelial Differentiation, and Carcinogenesis), Jean-Pierre Aubert Research Centre, Université Lille, France; Department of Digestive and Visceral Surgery, GHICL, Saint-Vincent de Paul Hospital, Lille, France.

Our aim was to analyze the potential role of chemokine receptors CXCR2 and CXCR4 signalling pathways in liver metastatic colorectal cancer (CRC) relapse. CXCR2, CXCR4, and their chemokine ligands were evaluated in liver metastases of colorectal cancer in order to study their correlation with overall and disease-free survival of patients having received, or not received, a neoadjuvant chemotherapy regimen. Quantitative RT-PCR and CXCR2 immunohistochemical staining were carried out using CRC liver metastasis samples. Expression levels of CXCR2, CXCR4, and their ligands were statistically analyzed according to treatment with neoadjuvant chemotherapy and patients' outcome. CXCR2 and CXCL7 overexpression are correlated to shorter overall and disease-free survival. By multivariate analysis, CXCR2 and CXCL7 expressions are independent factors of overall and disease-free survival. Neoadjuvant chemotherapy increases significantly the expression of CXCR2: treated group 1.89 (0.02-50.92) vs 0.55 (0.07-3.22), P = 0.016. CXCL7 was overexpressed close to significance, 0.40 (0.00-7.85) vs 0.15 (0.01-7.88), P = 0.12. We show the involvement of CXCL7/CXCR2 signalling pathways as a predictive factor of poor outcome in metastatic CRC. 5-Fluorouracil-based chemotherapy regimens increase the expression of these genes in liver metastasis, providing one explanation for aggressiveness of relapsed drug-resistant tumors. Selective blockage of CXCR2/CXCL7 signalling pathways could provide new potential therapeutic opportunities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.12603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376434PMC
March 2015

The MUC1 oncomucin regulates pancreatic cancer cell biological properties and chemoresistance. Implication of p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways.

Biochem Biophys Res Commun 2015 Jan 13;456(3):757-62. Epub 2014 Dec 13.

Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Rue Polonovski, 59045 Lille Cedex, France; Université de Lille 2, 42 rue Paul Duez, 59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, 59037 Lille Cedex, France. Electronic address:

MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To this aim, we undertook to study MUC1 biological effects on pancreatic cancer cells and identify pathways mediating these effects. Our in vitro experiments indicate that inhibiting MUC1 expression decreases cell proliferation, cell migration and invasion, cell survival and increases cell apoptosis. Moreover, lack of MUC1 in these cells profoundly altered their sensitivity to gemcitabine and 5-Fluorouracil chemotherapeutic drugs. In vivo MUC1-KD cell xenografts in SCID mice grew slower. Altogether, we show that MUC1 oncogenic mucin alters proliferation, migration, and invasion properties of pancreatic cancer cells and that these effects are mediated by p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2014.12.025DOI Listing
January 2015

The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells.

Biochim Biophys Acta 2014 Nov 6;1843(11):2432-7. Epub 2014 Jul 6.

Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France. Electronic address:

MUC1 is a membrane-bound mucin known to participate in tumor proliferation. It has been shown that MUC1 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplasia to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is gastro-esophageal reflux and MUC1 was previously shown to be up-regulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC1 plays a role in biological properties of human esophageal cancer cells. For that, a stable MUC1-deficient esophageal cancer cell line was established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of MUC1-deficient cells were analyzed. Our results show that esophageal cancer cells lacking MUC1 were less proliferative and had decreased migration and invasion properties. These alterations were accompanied by a decreased activity of NFKB p65, Akt and MAPK (p44/42, JNK and p38) pathways. MCM6 and TSG101 tumor-associated markers were also decreased. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC1. Altogether, the data indicate that MUC1 plays a key role in proliferative, migrating and invasive properties of esophageal cancer cells as well as in tumor growth promotion. MUC1 mucin appears thus as a good therapeutic target to slow down esophageal tumor progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamcr.2014.06.021DOI Listing
November 2014

Of autophagy and in vivo pancreatic carcinogenesis: the p53 status matters!

Clin Res Hepatol Gastroenterol 2014 Sep 14;38(4):423-5. Epub 2014 Jun 14.

Inserm, UMR837, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Jean-Pierre-Aubert Research Center, rue Polonovski, 59045 Lille cedex, France; Université Lille-Nord de France, 1, place de Verdun, 59045 Lille cedex, France; Centre hospitalier régional et universitaire de Lille, place de Verdun, 59037 Lille cedex, France.

Autophagy is a lysosomal recycling process essential for tissue or cell homeostasis. The role of autophagy in cancer is complex with either tumor suppressive or pro-carcinogenetic activities. This question has been addressed by Kevin Ryan's laboratory by using Kras-driven genetic engineering mouse models in order to decipher the involvement of essential Atg5/7 autophagy genes and p53 status in pancreatic homeostasis and carcinogenetic progression. The authors show that combined loss of autophagy and p53 dramatically promotes progression from early Pancreatic Intraepithelial Neoplasia (PanIN) lesions towards adenocarcinoma and alters the cellular metabolism with an enrichment of anabolic pathway that can fuel the tumor growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinre.2014.04.009DOI Listing
September 2014

Mucins and tumor resistance to chemotherapeutic drugs.

Biochim Biophys Acta 2014 Aug 29;1846(1):142-51. Epub 2014 Apr 29.

Inserm, UMR837, Jean Pierre Aubert Research Center, Team #5 "Mucins, Epithelial Differentiation and Carcinogenesis", rue Polonovski, 59045 Lille Cedex, France; Université Lille Nord de France, Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille Cedex, France.

Epithelial cancer patients not considered eligible for surgical resection frequently benefit from chemotherapy. Chemotherapy is the treatment of cancer with one or combination of cytotoxic or cytostatic drugs. Recent advances in chemotherapy allowed a great number of cancer patients to receive treatment with significant results. Unfortunately, resistance to chemotherapeutic drug treatment is a major challenge for clinicians in the majority of epithelial cancers because it is responsible for the inefficiency of therapies. Mucins belong to a heterogeneous group of large O-glycoproteins that can be either secreted or membrane-bound. Implications of mucins have been described in relation to cancer cell behavior and cell signaling pathways associated with epithelial tumorigenesis. Because of the frequent alteration of the pattern of mucin expression in cancers as well as their structural and functional characteristics, mucins are thought to also be involved in response to therapies. In this report, we review the roles of mucins in chemoresistance and the associated underlying molecular mechanisms (physical barrier, resistance to apoptosis, drug metabolism, cell stemness, epithelial-mesenchymal transition) and discuss the therapeutic tools/strategies and/or prognosis biomarkers for personalized chemotherapy that could be proposed from these studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbcan.2014.04.008DOI Listing
August 2014

Comment on: Functional MUC4 suppress epithelial-mesenchymal transition in lung adenocarcinoma metastasis. Gao L, Liu J, Zhang B, Zhang H, Wang D, Zhang T, Liu Y, Wang C. Tumour Biol. 2013, in press.

Tumour Biol 2014 Apr 17;35(4):3941-2. Epub 2013 Nov 17.

UMR837, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Inserm, rue Polonovski, 59045, Lille Cedex, France,

Gao and collaborators (Tumour Biol, 2013) have investigated the role of mucin 4 (MUC4) in lung cancer and have concluded that a loss of MUC4 results in epithelial mesenchymal transition via beta-catenin nuclear translocation and that MUC4 expression is correlated with a risk of lymph node metastasis in a cohort of 20 lung adenocarcinoma patients. This surprising analysis is contradictory to most of the scientific knowledge and literature regarding MUC4 contribution in epithelial cancers that is very hardly discussed in their manuscript.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13277-013-1390-yDOI Listing
April 2014

Helicobacter pylori urease and flagellin alter mucin gene expression in human gastric cancer cells.

Gastric Cancer 2014 Apr 24;17(2):235-46. Epub 2013 May 24.

Inserm, UMR837, JPARC, Team "Mucins, Epithelial Differentiation and Carcinogenesis", Bâtiment G. Biserte, Rue Polonovski, 59045, Lille Cedex, France.

Background: Helicobacter pylori (Hp), which is one of the causative agents in human gastric adenocarcinoma, is known to interact with mucous gel and alter mucin gene expression. The aim of this work was to study, using an in vitro model of cell infection, the effects of urease, flagellin, and CagA virulence factors on the regulation of the four 11p15 mucin genes (MUC2, MUC5AC, MUC5B, and MUC6).

Methods: KATO-III and AGS gastric cancer cells were infected for 1, 3 or 6 h with Hp wild-type strains (ATCC 43504, N6, and SS1) or corresponding isogenic mutants deficient for urease subunit B, flagellin subunit A, and CagA. mRNA levels of MUC2, MUC5B, MUC5AC and MUC6 were assessed by RT-PCR, and functional activity of their promoters was measured by transient transfection assays.

Results: Infection of KATO-III cells with Hp wild-type strains resulted in an early (at 1 h) transient expression of MUC2, MUC5AC, and MUC6 mRNA concomitant with those of interleukin (IL)-1β, IL-8, and TNF-α cytokines. In these cells, the UreB(-) isogenic mutant induced strong activation of MUC5AC expression, and UreB-responsive elements were located in the -486/-1 region of the promoter. FlaA(-) and CagA(-) mutants had no effect on mucin gene mRNA levels in KATO-III cells. In AGS cells, Hp-responsive elements were identified in all promoters, and overexpression of NF-κB induced upregulation of MUC5AC promoter activity when infected with the UreB(-) isogenic mutant.

Conclusion: These results indicate that Hp infection of gastric cancer cells alters 11p15 mucin gene transcription and that MUC5AC downregulation is mediated by urease virulence factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10120-013-0267-5DOI Listing
April 2014

Membrane-bound mucin modular domains: from structure to function.

Biochimie 2013 Jun 20;95(6):1077-86. Epub 2012 Nov 20.

Inserm, UMR837, Jean Pierre Aubert Research Center, Team #5 Mucins, Epithelial Differentiation and Carcinogenesis, 1 Rue Polonovski, 59045 Lille Cedex, France.

Mucins belong to a heterogeneous family of large O-glycoproteins composed of a long peptidic chain called apomucin on which are linked hundreds of oligosaccharidic chains. Among mucins, membrane-bound mucins are modular proteins and have a structural organization usually containing Pro/Thr/Ser-rich O-glycosylated domains (PTS), EGF-like and SEA domains. Via these modular domains, the membrane-bound mucins participate in cell signalling and cell interaction with their environment in normal and pathological conditions. Moreover, the recent knowledge of these domains and their biological activities led to the development of new therapeutic approaches involving mucins. In this review, we show 3D structures of EGF and SEA domains. We also describe the functional features of the evolutionary conserved domains of membrane-bound mucins and discuss consequences of splice events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2012.11.005DOI Listing
June 2013

GATA-4/-6 and HNF-1/-4 families of transcription factors control the transcriptional regulation of the murine Muc5ac mucin during stomach development and in epithelial cancer cells.

Biochim Biophys Acta 2012 Aug 25;1819(8):869-76. Epub 2012 Apr 25.

Jean Pierre Aubert Research Center, Lille cedex, France.

During human embryonic and fetal development of the gastrointestinal tract, the gene encoding the MUC5AC mucin has a spatio-temporal pattern of expression restricted to the stomach. In order to better understand the molecular mechanisms responsible for this restricted pattern of expression, we have studied Muc5ac expression in the developing stomach of the mouse and correlated it to that of transcription factors known to be involved in cell differentiation programs during development. Our results indicate that GATA-6 and HNF-4α expression increased concomitantly with the induction of Muc5ac expression in embryonic stomach. We then studied Muc5ac transcriptional regulation by these transcription factors and showed that they all transactivate Muc5ac promoter. We also identified several active GATA-4/-5/-6 and HNF-1/-4 cis-elements using gel shift assays, chromatin immunoprecipitation and site-directed mutagenesis. Among all Muc5ac regulators, only GATA-6 and HNF-4a expression was concomitant to that of Muc5ac in the developing stomach. This is thus in favor of an important role for these two transcription factors as regulators of expression of the Muc5ac mucin during stomach development and in epithelial cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagrm.2012.04.003DOI Listing
August 2012

Tif1γ suppresses murine pancreatic tumoral transformation by a Smad4-independent pathway.

Am J Pathol 2012 Jun 31;180(6):2214-21. Epub 2012 Mar 31.

INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France.

Transcriptional intermediary factor 1γ (TIF1γ; alias, TRIM33/RFG7/PTC7/ectodermin) belongs to an evolutionarily conserved family of nuclear factors that have been implicated in stem cell pluripotency, embryonic development, and tumor suppression. TIF1γ expression is markedly down-regulated in human pancreatic tumors, and Pdx1-driven Tif1γ inactivation cooperates with the Kras(G12D) oncogene in the mouse pancreas to induce intraductal papillary mucinous neoplasms. In this study, we report that aged Pdx1-Cre; LSL-Kras(G12D); Tif1γ(lox/lox) mice develop pancreatic ductal adenocarcinomas (PDACs), an aggressive and always fatal neoplasm, demonstrating a Tif1γ tumor-suppressive function in the development of pancreatic carcinogenesis. Deletion of SMAD4/DPC4 (deleted in pancreatic carcinoma locus 4) occurs in approximately 50% of human cases of PDAC. We, therefore, assessed the genetic relationship between Tif1γ and Smad4 signaling in pancreatic tumors and found that Pdx1-Cre; LSL-Kras(G12D); Smad4(lox/lox); Tif1γ(lox/lox) (alias, KSSTT) mutant mice exhibit accelerated tumor progression. Consequently, Tif1γ tumor-suppressor effects during progression from a premalignant to a malignant state in our mouse model of pancreatic cancer are independent of Smad4. These findings establish, for the first time to our knowledge, that Tif1γ and Smad4 both regulate an intraductal papillary mucinous neoplasm-to-PDAC sequence through distinct tumor-suppressor programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2012.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378851PMC
June 2012

The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways.

PLoS One 2012 29;7(2):e32232. Epub 2012 Feb 29.

Inserm, UMR837, Jean Pierre Aubert Research Center, Team #5 Mucins, epithelial differentiation and carcinogenesis, Lille, France.

The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential interacting partners in human pancreatic tumour development. However, the way they function is still largely unknown. In this work, we aimed to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4 in a human pancreatic adenocarcinomatous cell line. Using co-immunoprecipitation and GST pull-down, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2 via the EGF domains of MUC4. Stable cell clones were generated in which either MUC4 or ErbB2 were knocked down (KD) by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. Our results show that ErbB2 and MUC4, which interact physically, activate different intracellular signalling pathways to regulate biological properties of CAPAN-2 pancreatic cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032232PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290552PMC
July 2012

The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein.

Biochem Biophys Res Commun 2011 Sep 26;413(2):325-9. Epub 2011 Aug 26.

Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 Mucins, Epithelial Differentiation and Carcinogenesis, rue Polonovski, 59045 Lille Cedex, France.

MUC4 is a membrane-bound mucin known to participate in tumor progression. It has been shown that MUC4 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplastic lesions to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is the gastro-esophageal reflux, and MUC4 was previously shown to be upregulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC4 plays a role in biological properties of human esophageal cancer cells. For that stable MUC4-deficient cancer cell lines (shMUC4 cells) were established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of shMUC4 cells were analyzed. Our results show that shMUC4 cells were less proliferative, had decreased migration properties and did not express S100A4 protein when compared with MUC4 expressing cells. Absence of MUC4 did not impair shMUC4 invasiveness. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC4. Altogether, these data indicate that MUC4 plays a key role in proliferative and migrating properties of esophageal cancer cells as well as is a tumor growth promoter. MUC4 mucin appears thus as a good therapeutic target to slow-down esophageal tumor progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2011.08.095DOI Listing
September 2011

The mouse Muc5b mucin gene is transcriptionally regulated by thyroid transcription factor-1 (TTF-1) and GATA-6 transcription factors.

FEBS J 2011 Jan 3;278(2):282-94. Epub 2010 Dec 3.

Inserm, U837, Jean Pierre Aubert Research Center, Lille, France.

MUC5B is one of the major mucin genes expressed in the respiratory tract. Previous studies in our laboratory have demonstrated that MUC5B is expressed in human lung adenocarcinomas and during lung morphogenesis. Moreover, in human lung adenocarcinoma tissues, a converse correlation between MUC5B and thyroid transcription factor-1 (TTF-1) expression, a lung-specific transcription factor, has been established. However, the molecular mechanisms that govern the regulation of MUC5B expression in the lung are largely unknown. In order to better understand the biological role of MUC5B in lung pathophysiology, we report the characterization of the promoter region of the mouse Muc5b mucin gene. The promoter is flanked by a TATA box (TACATAA) identical to that in the human gene. Human and murine promoters share 67.5% similarity over the first 170 nucleotides. By RT-PCR, co-transfection studies and gel-shift assays, we show that Muc5b promoter activity is completely inhibited by TTF-1, whereas factors of the GATA family (GATA-4/GATA-5/GATA-6) are activators. Together, these results demonstrate, for the first time, that Muc5b is a target gene of transcription factors (TTF-1, GATA-6) involved in lung differentiation programs during development and carcinogenesis, and identify TTF-1 as a strong repressor of Muc5b. The characterization of the structural and functional features of the Muc5b mucin gene will provide us with a strong base to develop studies in murine models aimed at the identification of its biological role in lung pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1742-4658.2010.07945.xDOI Listing
January 2011