A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-β in pancreatic carcinogenesis

Jonckheere, Nicolas; Perrais, Michaël; Mariette, C.; Batra, Surinder K.; Aubert, Jean; Pigny, Pascal; Seuningen, Isabelle Van

doi:10.1038/sj.onc.1207769

Cited by 61 publications

(60 citation statements)

References 40 publications

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“…The molecular mechanisms for this involvement in tumorigenesis may be caused by the EGF-like domain in MUC4 that is known to interact with ErbB2 and alter epithelial cell growth. MUC4 has been shown to be upregulated by interleukin 6 (IL-6) and transforming growth factor b (TGFb) in gastric and pancreatic cell lines (Jonckheere et al 2004;Mejias-Luque et al 2008); therefore, the role of these cytokines in gastric tumorigenesis should be further studied. MUC5B is predominantly found in both the saliva and the respiratory tract and has been shown to bind SabA adhesion expression strains of H. pylori at neutral pH (Linden et al 2008b).…”

Section: Discussionmentioning

confidence: 99%

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Gastric Mucus Alterations Associated With MurineHelicobacterInfection

Schmitz

Durham

et al. 2009

J Histochem Cytochem.

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The C57BL/6 mouse has been shown to develop gastric adenocarcinoma after Helicobacter felis infection. This model was used to determine whether mucin and trefoil factor (TFF) expression after infection was altered in a similar fashion to the changes seen in the protective gastric mucus layer of the human stomach after H. pylori infection. Our results indicate that this mouse model mimics many of the changes seen after human H. pylori infection, including increased expression of muc4 and muc5b and loss of muc5ac. These alterations in mucin expression occurred as early as 4 weeks postinfection, before the development of significant mucous metaplasia or gastric dysplasia. The decrease in muc5ac expression occurred only in the body of the stomach and was not secondary to the adaptive immune response to infection, because a similar decrease in expression was seen after infection of B6.Rag-1−/− mice, which lack B and T cells. Intriguingly, the increased expression of Muc4 and Muc5b in infected C57BL/6 mice was not seen in the infected B6.Rag-1−/− mice. Because B6.Rag-1−/− mice do not develop gastric pathology after H. felis infection, these findings point to the potential role of Muc4 and Muc5b in disease progression. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials. (J Histochem Cytochem 57:457–467, 2009)

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Section: Discussionmentioning

confidence: 99%

“…MUC4 is known to encode a membrane-bound mucin that is overexpressed in pancreatic adenocarcinomas (Jonckheere et al 2004). In addition, overexpression of MUC4 in A375 human melanoma cells promotes spontaneous metastasis Komatsu et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Gastric Mucus Alterations Associated With MurineHelicobacterInfection

Schmitz

Durham

et al. 2009

J Histochem Cytochem.

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“…Reverse transcription (RT)-PCR for Smad7 was performed using a 5Ј-TCCTGCTGTGCAAAGTGTTC-3Ј forward primer and 5Ј-TTGTTGTCCG AATTGAGCTG-3Ј reverse primer targeting Smad7 at 1,906 bp and 2,353 bp, respectively, as previously reported (18). RT-PCR for GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was performed as previously described (39).…”

Section: Methodsmentioning

confidence: 99%

Smad7 Promotes and Enhances Skeletal Muscle Differentiation

Kollias

Perry

Miyake

et al. 2006

Molecular and Cellular Biology

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Transforming growth factor ␤1 (TGF-␤1) and myostatin signaling, mediated by the same Smad downstream effectors, potently repress skeletal muscle cell differentiation. Smad7 inhibits these cytokine signaling pathways. The role of Smad7 during skeletal muscle cell differentiation was assessed. In these studies, we document that increased expression of Smad7 abrogates myostatin-but not TGF-␤1-mediated repression of myogenesis. Further, constitutive expression of exogenous Smad7 potently enhanced skeletal muscle differentiation and cellular hypertrophy. Conversely, targeting of endogenous Smad7 by small interfering RNA inhibited C2C12 muscle cell differentiation, indicating an essential role for Smad7 during myogenesis. Congruent with a role for Smad7 in myogenesis, we observed that the muscle regulatory factor (MyoD) binds to and transactivates the Smad7 proximal promoter region. Finally, we document that Smad7 directly interacts with MyoD and enhances MyoD transcriptional activity. Thus, Smad7 cooperates with MyoD, creating a positive loop to induce Smad7 expression and to promote MyoD driven myogenesis. Taken together, these data implicate Smad7 as a fundamental regulator of differentiation in skeletal muscle cells.

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“…Total RNA (1.5 g) was used to synthesize cDNA (Advantage TM RT-for-PCR kit, Clontech) as described (43). PCR was performed on 5 l of cDNA using specific pairs of primers (MWG-Biotech, Ebersberg, Germany) for MUC4 (44) and 28S rRNA as the internal control. PCR were carried out in 50-l final solutions (5 l of 10ϫ PCR buffer containing 15 mM MgCl 2 , 4 l of 2.5 mM dNTPs, 10 pmol of each primer, and 1 unit of Taq polymerase (Roche Diagnostics).…”

Section: Methodsmentioning

confidence: 99%

The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells

Jonckheere

Vincent

Perrais

et al. 2007

Journal of Biological Chemistry

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The human gene MUC4 encodes a large transmembrane mucin that is developmentally regulated and expressed along the undifferentiated pseudostratified epithelium, as early as 6.5 weeks during fetal development. Immunohistochemical analysis of Muc4 expression in developing mouse lung and gastrointestinal tract showed a different spatio-temporal pattern of expression before and after cytodifferentiation. The molecular mechanisms governing MUC4 expression during development are, however, unknown. Hepatocyte nuclear factors (HNF), forkhead box A (FOXA), GATA, and caudal-related homeobox transcription factors (TFs) are known to control cell differentiation of gut endoderm derived-tissues during embryonic development. They also control the expression of cell-and tissuespecific genes and may thus control MUC4 expression. To test this hypothesis, we studied and deciphered the molecular mechanisms responsible for MUC4 transcriptional regulation by these TFs. Experiments using small interfering RNA, cell cotransfection, and site-directed mutagenesis indicated that MUC4 is regulated at the transcriptional level by CDX-1 and -2, HNF-1␣ and -1␤, FOXA1/A2, HNF-4␣ and -4␥, and GATA-4, -5, and -6 factors in a cell-specific manner. Binding of TFs was assessed by chromatin immunoprecipitation, and gel-shift assays.Altogether, these results demonstrate that MUC4 is a target gene of endodermal TFs and thus point out an important role for these TFs in regulating MUC4 expression during epithelial differentiation during development, cancer, and repair.

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A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-β in pancreatic carcinogenesis

Cited by 61 publications

References 40 publications

Gastric Mucus Alterations Associated With MurineHelicobacterInfection

Gastric Mucus Alterations Associated With MurineHelicobacterInfection

Smad7 Promotes and Enhances Skeletal Muscle Differentiation

The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells

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