Publications by authors named "Isabelle Van Seuningen"

102 Publications

MUC1 Mitigates Renal Injury and Inflammation in Endotoxin Induced Acute Kidney Injury by Inhibiting the TLR4-MD2 Axis and Reducing Pro-Inflammatory Macrophages Infiltration.

Shock 2021 Jan 28. Epub 2021 Jan 28.

University Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France CHU Lille, Institute of Pathology, F-59000 Lille, France CHU Lille, Nephrology Department, F-59000 Lille, France CHU Lille, Biochemistry Emergency Department, F-59000 Lille, France.

Abstract: Sepsis is the leading cause of acute kidney injury (AKI) in critical care patients. A cornerstone of sepsis-associated AKI is dysregulated inflammation driven by excessive activation of Toll-like receptor 4 (TLR4) pathway. MUC1, a membrane bound mucin expressed in both epithelial tubular cells and renal macrophages, has been shown to be involved in the regulation of TLRs. Therefore we hypothesized that MUC1 could mitigate the renal inflammatory response to TLR4 activation. To test this hypothesis, we used a murine model of endotoxin-induced AKI by intraperitoneal injection of lipopolysaccharide (LPS). We showed that Muc1-/- mice have a more severe renal dysfunction, an increased activation of the tissular NF-kB pathway and secreted more pro inflammatory cytokines compare to Muc1+/+ mice. By flow cytometry, we observed that the proportion of M1 (pro-inflammatory) macrophages in the kidneys of Muc1-/- mice was significantly increased. In human and murine primary macrophages, we showed that MUC1 is only induced in M1 type macrophages and that macrophages derived from Muc1-/- mice secreted more pro-inflammatory cytokines. Eventually, in HEK293 cells, we showed that (i) MUC1 cytosolic domain (CT) seems necessary for the negative regulation of TLR4 (ii) by proximity ligation assay, MUC1-CT is in close relationship with TLR4 and acts as a competitive inhibitor of the recruitment of MYD88. Overall our results support that in the context of endotoxin-induced AKI, MUC1 plays a significant role in controlling disease severity by regulating negatively the TLR4-MD2 axis.
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http://dx.doi.org/10.1097/SHK.0000000000001742DOI Listing
January 2021

Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells.

Mol Cancer Res 2021 Jan 20. Epub 2021 Jan 20.

Université Lille, CNRS, Inserm, CHU Lille, UMR9020-UMR1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.

The mechanisms whereby the Hippo pathway effector YAP regulates cancer cell stemness, plasticity, and chemoresistance are not fully understood. We previously showed that in 5-fluorouracil (5-FU)-resistant colorectal cancer cells, the transcriptional coactivator YAP is differentially regulated at critical transitions connected with reversible quiescence/dormancy to promote metastasis. Here, we found that experimental YAP activation in 5-FU-sensitive and 5-FU-resistant HT29 colorectal cancer cells enhanced nuclear YAP localization and the transcript levels of the retinoic acid (RA) receptors RARα/γ and RAR target genes , and through RA Response Elements (RARE). In these two cell models, constitutive YAP activation reinforced the expression of the stemness biomarkers and regulators ALDH1A3, LGR5, and OCT4. Conversely, YAP silencing, RAR/RXR inhibition by the pan-RAR antagonist BMS493, and vitamin A depletion downregulated stemness traits and self-renewal. Regarding the mechanisms engaged, proximity-dependent labeling, nuclear YAP pulldown coupled with mass spectrometry, and chromatin immunoprecipitation (ChIP)/re-ChIP experiments revealed: (i) the nuclear colocalization/interaction of YAP with RARγ and RXRs; and (ii) combined genomic co-occupancy of YAP, RARα/γ, and RXRα interactomes at proximal RAREs of and promoters. Moreover, activation of the YAP/RAR-RXR cross-talk in colorectal cancer cells promoted RAR self-activation loops via vitamin A metabolism, RA, and active RAR ligands generated by ALDH1A3. Together, our data identify YAP as a bona fide RAR-RXR transcriptional coactivator that acts through RARE-activated stemness genes. IMPLICATIONS: Targeting the newly identified YAP/RAR-RXR cross-talk implicated in cancer cell stemness maintenance may lead to multitarget combination therapies for patients with colorectal cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0462DOI Listing
January 2021

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

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Nat Med 2020 06 25;26(6):919-931. Epub 2020 May 25.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 T cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.
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http://dx.doi.org/10.1038/s41591-020-0882-8DOI Listing
June 2020

Galectin-3 modulates epithelial cell adaptation to stress at the ER-mitochondria interface.

Cell Death Dis 2020 05 12;11(5):360. Epub 2020 May 12.

University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000, Lille, France.

Cellular stress response contributes to epithelial defense in adaptation to environment changes. Galectins play a pivotal role in the regulation of this response in malignant cells. However, precise underlying mechanisms are largely unknown. Here we demonstrate that Galectin-3, a pro and anti-apoptotic lectin, is required for setting up a correct cellular response to stress by orchestrating several effects. First, Galectin-3 constitutes a key post-transcriptional regulator of stress-related mRNA regulons coordinating the cell metabolism, the mTORC1 complex or the unfolded protein response (UPR). Moreover, we demonstrated the presence of Galectin-3 with mitochondria-associated membranes (MAM), and its interaction with proteins located at the ER or mitochondrial membranes. There Galectin-3 prevents the activation and recruitment at the mitochondria of the regulator of mitochondria fission DRP-1. Accordingly, loss of Galectin-3 impairs mitochondrial morphology, with more fragmented and round mitochondria, and dynamics both in normal and cancer epithelial cells in basal conditions. Importantly, Galectin-3 deficient cells also display changes of the activity of the mitochondrial respiratory chain complexes, of the mTORC1/S6RP/4EBP1 translation pathway and reactive oxygen species levels. Regarding the ER, Galectin-3 did not modify the activities of the 3 branches of the UPR in basal conditions. However, Galectin-3 favours an adaptative UPR following ER stress induction by Thapsigargin treatment. Altogether, at the ER-mitochondria interface, Galectin-3 coordinates the functioning of the ER and mitochondria, preserves the integrity of mitochondrial network and modulates the ER stress response.
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http://dx.doi.org/10.1038/s41419-020-2556-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217954PMC
May 2020

Publisher Correction: MUC4-ErbB2 Oncogenic Complex: Binding studies using Microscale Thermophoresis.

Sci Rep 2020 Apr 14;10(1):6539. Epub 2020 Apr 14.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-63163-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156488PMC
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.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02001DOI Listing
May 2020

Colon cancer stemness as a reversible epigenetic state: Implications for anticancer therapies.

World J Stem Cells 2019 Nov;11(11):920-936

Lille University, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille F-59000, France.

The recent discovery of cancer cell plasticity, . their ability to reprogram into cancer stem cells (CSCs) either naturally or under chemotherapy and/or radiotherapy, has changed, once again, the way we consider cancer treatment. If cancer stemness is a reversible epigenetic state rather than a genetic identity, opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs. However, the systematic use of DNA methyltransferase and histone deacetylase inhibitors, alone or in combination, in advanced solid tumors including colorectal cancers, regardless of their molecular subtypes, does not seem to be the best strategy. In this review, we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells. We raise questions about the relevant use of currently available epigenetic inhibitors (epidrugs) while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms. These markers include the three cluster of differentiation CD133, CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and . Finally, we describe current treatment strategies using epidrugs, and we hypothesize that, using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression, we could identify better candidates for epienzyme targeting.
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http://dx.doi.org/10.4252/wjsc.v11.i11.920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851010PMC
November 2019

MUC4-ErbB2 Oncogenic Complex: Binding studies using Microscale Thermophoresis.

Sci Rep 2019 11 13;9(1):16678. Epub 2019 Nov 13.

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

The MUC4 membrane-bound mucin is a large O-glycoprotein involved in epithelial homeostasis. At the cancer cell surface MUC4 interacts with ErbB2 receptor via EGF domains to promote cell proliferation and migration. MUC4 is highly regarded as a therapeutic target in pancreatic cancer as it is not expressed in healthy pancreas, while it is neoexpressed in early preneoplastic stages (PanINs). However, the association/dissociation constant of MUC4-ErbB2 complex is unknown. Protein-protein interactions (PPIs) have become a major area of research in the past years and the characterization of their interactions, especially by biophysical methods, is intensively used in drug discovery. To characterize the MUC4-ErbB2 interaction, we used MicroScale Thermophoresis (MST), a powerful method for quantitative protein interaction analysis under challenging conditions. We worked with CHO cell lysates containing either the transmembrane β subunit of MUC4 (MUC4β) or a truncated mutant encompassing only the EGF domains (MUC4). MST studies have led to the characterization of equilibrium dissociation constants (K) for MUC4β-ErbB2 (7-25 nM) and MUC4/ErbB2 (65-79 nM) complexes. This work provides new information regarding the MUC4-ErbB2 interaction at the biophysical level and also confirms that the presence of the three EGF domains of MUC4 is sufficient to provide efficient interaction. This technological approach will be very useful in the future to validate small molecule binding affinities targeting MUC4-ErbB2 complex for drug discovery development in cancer. It will also be of high interest for the other known membrane mucins forming oncogenic complexes with ErbBs at the cancer cell surface.
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http://dx.doi.org/10.1038/s41598-019-53099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853952PMC
November 2019

Gemcitabine-induced epithelial-mesenchymal transition-like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal-like phenotype.

Mol Carcinog 2019 11 2;58(11):1985-1997. Epub 2019 Aug 2.

Department of Digestive Surgery and Transplantation, Université de Lille, Inserm, CHU Lille, UMR-S 1172, Lille, France.

Growing body of evidence suggests that epithelial-mesenchymal transition (EMT) is a critical process in tumor progression and chemoresistance in pancreatic cancer (PC). The aim of this study was to analyze the role of EMT-like changes in acquisition of resistance to gemcitabine in pancreatic cells of the mesenchymal or epithelial phenotype. Therefore, chemoresistant BxPC-3, Capan-2, Panc-1, and MiaPaca-2 cells were selected by chronic exposure to increasing concentrations of gemcitabine. We show that gemcitabine-resistant Panc-1 and MiaPaca-2 cells of mesenchymal-like phenotype undergo further EMT-like molecular changes mediated by ERK-ZEB-1 pathway, and that inhibition of ERK1/2 phosphorylation or ZEB-1 expression resulted in a decrease in chemoresistance. Conversely, gemcitabine-resistant BxPC-3 and Capan-2 cells of epithelial-like phenotype did not show such typical EMT-like molecular changes although the expression of the tight junction marker occludin could be found decreased. In pancreatic cancer patients, high ZEB-1 expression was associated with tumor invasion and tumor budding. In addition, tumor budding was essentially observed in patients treated with neoadjuvant chemotherapy. These findings support the notion that gemcitabine treatment induces EMT-like changes that sustain invasion and chemoresistance in PC cells.
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http://dx.doi.org/10.1002/mc.23090DOI Listing
November 2019

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia.

Cancers (Basel) 2019 Jun 17;11(6). Epub 2019 Jun 17.

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

HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior-posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an "undruggable" target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces.
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http://dx.doi.org/10.3390/cancers11060837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627208PMC
June 2019

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.

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

Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.

Tumour Biol 2017 Jul;39(7):1010428317707372

1 Université de Lille, Inserm, CHU Lille, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis," Jean-Pierre Aubert Research Center (JPARC), Lille, France.

Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.
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http://dx.doi.org/10.1177/1010428317707372DOI Listing
July 2017

Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers.

Lung Cancer 2017 07 10;109:92-100. Epub 2017 May 10.

Sorbonne Universités, UPMC Univ. Paris 06, GRC no 04, Theranoscan, 4 rue de la Chine, F-75252 Paris, France; AP-HP, GH HUEP, Hôpital Tenon, Service de Pneumologie, 4 rue de la Chine, F-75970 Paris, France. Electronic address:

Objectives: To evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers.

Materials And Methods: MUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4α immunohistochemistry was performed on surgical samples from 52 patients with IMA (n=25) or LPA (n=27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements.

Results: MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4α-positive IMA (n=11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4α-negative IMA (n=14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression.

Conclusions: LPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4α expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes.
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http://dx.doi.org/10.1016/j.lungcan.2017.05.007DOI Listing
July 2017

Dual role of MUC1 mucin in kidney ischemia-reperfusion injury: Nephroprotector in early phase, but pro-fibrotic in late phase.

Biochim Biophys Acta Mol Basis Dis 2017 06 31;1863(6):1336-1349. Epub 2017 Mar 31.

Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France; CHU Lille, Pathology Institute, Centre de Biologie Pathologie, Rue Oscar Lambret, F-59037 Lille, France. Electronic address:

Acute kidney injury (AKI) is characterized by acute tubular necrosis (ATN) which involves mainly proximal tubules. Past AKI is associated with higher risk of chronic kidney disease (CKD). The MUC1 mucin is a large glycoprotein responsible for epithelial protection and locates to convoluted distal tubules and collecting ducts. Since MUC1 activates the epithelial-mesenchymal transition (EMT) in carcinoma cells, we hypothesized that MUC1 could be involved in epithelial tubular cell plasticity, a process that not only accompanies epithelial repair, but also participates into kidney fibrosis, histological substratum of CKD. In cultured human proximal cells and in human kidney allograft biopsies, we observed MUC1 induction in proximal tubules displaying ATN. Transient MUC1 induction localized with mesenchymal and stem-cell markers and was associated in vitro with reduced anoikis. In a mouse ischemia-reperfusion (IR) model, Muc1 expression mitigates severe tubular injury, as WT displayed less ATN than Muc1 KO mice. But, WT mice displayed more severe kidney fibrosis than Muc1 KO 28days after ischemia. Besides, sustained Muc1 expression in WT was associated with less kidney M2 macrophages. Human kidney biopsies performed within the first week (W1) of transplantation in the context of IR showed MUC1 W1 induction associated with EMT markers. Protocol biopsies performed 3months after demonstrated sustained abnormal MUC1 induction in atrophic tubules within kidney fibrosis. Altogether these data showed that sustained abnormal MUC1 induction accompanies failing epithelial repair, chronic inflammation and kidney fibrosis. In conclusion, MUC1 exerts opposite effects during kidney response to IR: first protective and then harmful.
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http://dx.doi.org/10.1016/j.bbadis.2017.03.023DOI Listing
June 2017

Galectin-3 is a non-classic RNA binding protein that stabilizes the mucin MUC4 mRNA in the cytoplasm of cancer cells.

Sci Rep 2017 03 6;7:43927. Epub 2017 Mar 6.

Univ. Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, F-59000 Lille, France.

Pancreatic cancer cells express high levels of MUC1, MUC4 and MUC16 mRNAs that encode membrane-bound mucins. These mRNAs share unusual features such as a long half-life. However, it remains unknown how mucin mRNA stability is regulated. Galectin-3 (Gal-3) is an endogenous lectin playing important biological functions in epithelial cells. Gal-3 is encoded by LGALS3 which is up-regulated in pancreatic cancer. Despite the absence of a RNA-recognition motif, Gal-3 interacts indirectly with pre-mRNAs in the nucleus and promotes constitutive splicing. However a broader role of Gal-3 in mRNA fate is unexplored. We report herein that Gal-3 increases MUC4 mRNA stability through an intermediate, hnRNP-L which binds to a conserved CA repeat element in the 3'UTR in a Gal-3 dependent manner and also controls Muc4 mRNA levels in epithelial tissues of Gal3 mice. Gal-3 interacts with hnRNP-L in the cytoplasm, especially during cell mitosis, but only partly associates with protein markers of P-Bodies or Stress Granules. By RNA-IP plus RNA-seq analysis and imaging, we demonstrate that Gal-3 binds to mature spliced MUC4 mRNA in the perinuclear region, probably in hnRNP-L-containing RNA granules. Our findings highlight a new role for Gal-3 as a non-classic RNA-binding protein that regulates MUC4 mRNA post-transcriptionally.
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http://dx.doi.org/10.1038/srep43927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338267PMC
March 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.
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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.
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http://dx.doi.org/10.1128/IAI.00806-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278166PMC
February 2017

Regulation of cellular quiescence by YAP/TAZ and Cyclin E1 in colon cancer cells: Implication in chemoresistance and cancer relapse.

Oncotarget 2016 Aug;7(35):56699-56712

University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.

Our aim was to decipher the role and clinical relevance of the YAP/TAZ transcriptional coactivators in the regulation of the proliferation/quiescence balance in human colon cancer cells (CCC) and survival after 5FU-based chemotherapy. The prognostic value of YAP/TAZ on tumor relapse and overall survival was assessed in a five-year follow-up study using specimens of liver metastases (n = 70) from colon cancer patients. In 5FU-chemoresistant HT29-5F31 and -chemosensitive HCT116 and RKO CCC, a reversible G0 quiescent state mediated by Cyclin E1 down-regulation was induced by 5FU in 5F31 cells and recapitulated in CCC by either YAP/TAZ or Cyclin E1 siRNAs or the YAP inhibitor Verteporfin. Conversely, the constitutive active YAPdc-S127A mutant restricted cellular quiescence in 5FU-treated 5F31 cells and sustained high Cyclin E1 levels through CREB Ser-133 phosphorylation and activation. In colon cancer patients, high YAP/TAZ level in residual liver metastases correlated with the proliferation marker Ki-67 (p < 0.0001), high level of the YAP target CTGF (p = 0.01), shorter disease-free and overall survival (p = 0.008 and 0.04, respectively). By multivariate analysis and Cox regression model, the YAP/TAZ level was an independent factor of overall (Hazard ratio [CI 95%] 2.06 (1.02-4.16) p = 0.045) and disease-free survival (Hazard ratio [CI 95%] 1.98 (1.01-3.86) p = 0.045). Thus, YAP/ TAZ pathways contribute to the proliferation/quiescence switch during 5FU treatment according to the concerted regulation of Cyclin E1 and CREB. These findings provide a rationale for therapeutic interventions targeting these transcriptional regulators in patients with residual chemoresistant liver metastases expressing high YAP/TAZ levels.
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http://dx.doi.org/10.18632/oncotarget.11057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302946PMC
August 2016

Hemidesmosome integrity protects the colon against colitis and colorectal cancer.

Gut 2017 10 1;66(10):1748-1760. Epub 2016 Jul 1.

Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.

Objective: Epidemiological and clinical data indicate that patients suffering from IBD with long-standing colitis display a higher risk to develop colorectal high-grade dysplasia. Whereas carcinoma invasion and metastasis rely on basement membrane (BM) disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/BM anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions. Herein, we analyse the role of the α6β4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells (IECs) to the laminin-containing BM.

Design: We developed new mouse models inducing IEC-specific ablation of α6 integrin either during development (α6) or in adults (α6).

Results: Strikingly, all α6 mutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma. The sequence of events leading to disease onset entails hemidesmosome disruption, BM detachment, IL-18 overproduction by IECs, hyperplasia and enhanced intestinal permeability. Likewise, IEC-specific ablation of α6 integrin induced in adult mice (α6) resulted in fully penetrant colitis and tumour progression. Whereas broad-spectrum antibiotic treatment lowered tissue pathology and IL-1β secretion from infiltrating myeloid cells, it failed to reduce Th1 and Th17 response. Interestingly, while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation.

Conclusions: We provide for the first time evidence that loss of IECs/BM interactions triggered by hemidesmosome disruption initiates the development of inflammatory lesions that progress into high-grade dysplasia and carcinoma. Colorectal neoplasia in our mouse models resemble that seen in patients with IBD, making them highly attractive for discovering more efficient therapies.
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http://dx.doi.org/10.1136/gutjnl-2015-310847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595104PMC
October 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.

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

The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential.

Int J Cancer 2016 Mar 30;138(6):1472-81. Epub 2015 Oct 30.

Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.

The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.
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http://dx.doi.org/10.1002/ijc.29891DOI Listing
March 2016

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