TNF-alpha Activates MUC2 Transcription via NF-kappaB but Inhibits via JNK Activation

Ahn, Dae-Ho; Crawley, Suzanne C.; Hokari, Ryota; Kato, Shingo; Yang, Stacey C.; Li, Jian Dong; Kim, Young S.

doi:10.1159/000083636

Cited by 74 publications

(64 citation statements)

References 40 publications

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“…MUC2 is a secreted mucin than can be regulated through different pathways such as MAPK, NF-kB and Ras/MEK in colon cancer cells (Lee et al, 2002;Kim et al, 2004;Ahn et al, 2005). Muc2 À/À mice present increased proliferation and migration and decreased apoptosis of intestinal epithelial cells and develop spontaneous tumors that progress to invasive carcinomas, suggesting a role for Muc2 in tumor suppression (Velcich et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors

et al. 2010

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Infection of gastric mucosa by Helicobacter pylori induces an inflammatory response with increased levels of proinflammatory cytokines. Among them, tumor necrosis factor (TNF)-a, interleukin (IL)-1b and IL-6 induce the activation of signaling pathways that regulate genes expression, such as MUC2 and MUC4 intestinal mucins ectopically detected in gastric tumors. This study evaluated if the predominant inflammatory cell type correlates with MUC2 and MUC4 expression in human intestinal gastric tumors (n ¼ 78). In addition, we analyzed the regulatory effects of the associated inflammatory signaling pathways on their expression in gastric cancer cell lines, and in a mouse model with hyperactivated STAT3 signaling pathway. Tumors with predominant lymphoplasmocytic infiltrate (chronic inflammation), presented higher levels of MUC2 and were more differentiated than tumors with predominant polymorphonuclear infiltrate (acute inflammation). These differences can be attributed to specific cytokines, because TNF-a and IL-1b induced MUC2 but no MUC4 expression in gastric cancer cell lines. The two groups of tumors expressed similar levels of MUC4 that correlated with the expression of STAT3 transcription factor, implicated in the activation of genes through the IL-6 pathway. In gastric tissues frommice, Muc2 was not detected, whereas Muc4 was found in the gastric tumors developed in the gp130 Y757F/Y757F mice, with hyperactivated STAT3. These data indicate that the signaling pathways associated with the inflammatory response can modulate the expression of MUC2 and MUC4 intestinal mucin genes, in human and mouse gastric tumors.

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Section: Discussionmentioning

confidence: 99%

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors

et al. 2010

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“…6,8 We showed that LPSinduced CDX2 and MUC2 mRNA expression in cultured BECs disappeared on transfection of CDX2 siRNA, and that forced expression of CDX2 by using the CDX2 expression vector upregulated MUC2 expression in cultured BECs, supporting reports that CDX2 exists upstream of MUC2 and activates transcription of MUC2. 6,8 However, it is also known that MUC2 has NF-kB-binding sites in the promoter region, 32,36 and the activation of NF-kB could directly trigger Intestinal metaplasia of bile ducts H Ikeda et al MUC2 expression. In fact, MG132, an inhibitor of NF-kB, inhibited CDX2 mRNA expression and also MUC2 mRNA expression in this study (Figure 7a).…”

Section: Intestinal Metaplasia Of Bile Ducts H Ikeda Et Almentioning

confidence: 99%

Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

Ikeda

Sasaki

Ishikawa

et al. 2007

Laboratory Investigation

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The mechanism of transformation of biliary epithelium leading to intestinal metaplasia, which is significantly involved in biliary diseases, remains unclear. CDX2, an intestine-specific transcription factor, is thought to regulate intestinal mucin MUC2 (mucus core protein) expression. We took advantage of polycystic kidney (PCK) rats as a model of chronic suppurative cholangitis with intestinal metaplasia and of cultured biliary epithelial cells (BECs) from PCK rats to clarify the causal relation between bacterial components such as pathogen-associated molecular patterns (PAMPs) and the development of intestinal metaplasia of bile ducts. Histological, immunohistochemical, and in situ hybridization studies were conducted in PCK rat livers. In cultured BECs, CDX2 and MUC2 were expressed following treatment with PAMPs and inhibitors (anti-Toll-like receptor (TLR)2/TLR4 antibody, nuclear factor-kB (NF-kB) inhibitor MG132). Chronic suppurative cholangitis with intestinal metaplasia developed as the PCK rats aged, and intestinal metaplasia and aberrant CDX2 and MUC2 expression developed in parallel. Intraluminal bacteria and the expression of TLR2 and TLR4 in BECs were demonstrated in the bile ducts, showing chronic suppurative cholangitis. In cultured BECs, treatment with PAMPs induced upregulation of CDX2 and MUC2 expression, and this effect was abolished by pretreatment with anti-TLR2 and anti-TLR4 antibody and MG132. A knockdown of CDX2 by CDX2 small interfering RNA inhibited MUC2 expression in cultured BECs induced by PAMPs, and transfection of CDX2 expression vector induced MUC2 expression. In conclusion, bacterial components may induce upregulation of the CDX2 expression followed by MUC2 expression via TLR and the NF-kB system in cultured BECs, and could be related to the development of intestinal metaplasia of the bile ducts. Intestinal metaplasia associated with the aberrant expression of MUC2 1-4 is reportedly involved in tumorigenesis in several organs. Recent studies revealed that CDX2, a caudalrelated homeobox gene encoding an intestine-specific transcription factor, is a regulatory factor of intestinal development and expression of intestinal genes including MUC2 and is involved in intestinal metaplasia. 2,4,5-8 CDX2-dependent intestinal metaplasia is noted in Barrett's esophagus with MUC2 expression, and bile acid and chronic acid exposure have been reported to induce CDX2 expression. 2,[4][5][6]8,9 Intestinal metaplasia is also involved in the pathogenesis of biliary diseases. For example, in chronic cholangitis such as hepatolithiasis, intestinal metaplasia with goblet cells occurs, and MUC2 is aberrantly expressed in goblet cells colocalized with CDX2.

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“…For example, the balance between NF-nB and JNK activity controls dendritic cell survival (17). JNK inhibition results in NF-nB activation in multiple myeloma cell lines (18), and NF-nB activation induces MUC2 transcription whereas JNK activation inhibits this induction in human colon epithelial cells (19). Previously, we found that induction of intestinal cell differentiation is associated with increased JNK activity and c-Jun phosphorylation (20).…”

Section: Introductionmentioning

confidence: 98%

Regulation of PTEN Expression in Intestinal Epithelial Cells by c-Jun NH2-Terminal Kinase Activation and Nuclear Factor-κB Inhibition

et al. 2007

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The tumor suppressor protein phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in intestinal cell proliferation and differentiation and tumor suppression by antagonizing phosphatidylinositol 3-kinase. Despite its importance, the molecular mechanisms regulating PTEN expression are largely undefined. Here, we show that treatment of the colon cancer cell line HT29 with the differentiating agent sodium butyrate (NaBT) increased PTEN protein and mRNA expression and induced c-Jun NH 2 -terminal kinase (JNK) activation. Inhibition of JNK by chemical or genetic methods attenuated NaBTinduced PTEN expression. In addition, our findings showed a cross-talk between nuclear factor KB (NF-KB) and JNK with respect to PTEN regulation. Overexpression of the NF-KB superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-KB subunit reduced both basal and NaBT-mediated JNK activation and PTEN expression. Moreover, we showed that overexpression of PTEN or treatment with NaBT increased expression of the cyclindependent kinase inhibitor p27 kip1 in HT29 cells; this induction was attenuated by inhibition of PTEN or JNK expression or overexpression of p65. Finally, we show a role for PTEN in NaBT-mediated cell death and differentiation. Our findings suggest that the JNK/PTEN and NF-KB/PTEN pathways play a critical role in normal intestinal homeostasis and colon carcinogenesis. [Cancer Res 2007;67(16):7773-81]

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TNF-alpha Activates MUC2 Transcription via NF-kappaB but Inhibits via JNK Activation

Cited by 74 publications

References 40 publications

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors

Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

Regulation of PTEN Expression in Intestinal Epithelial Cells by c-Jun NH2-Terminal Kinase Activation and Nuclear Factor-κB Inhibition

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