title: Involvement of CDX2 in the cross talk between TNF-α and Wnt signaling pathway in the colon cancer cell line Caco-2.
abstract: Tumor necrosis factor-α (TNF-α) is highly upregulated in inflammation and reduces the expression of the intestinal transcription factor, Caudal-related homeobox transcription factor 2 (CDX2). Wnt/β-catenin signaling is critical for intestinal cell proliferation, but a decreased CDX2 expression has influence on the Wnt signaling-related genes and progression of colorectal cancer. Although several inflammatory signaling pathways, including TNF-α, have been reported to promote Wnt/β-catenin activity and development of cancer, the underlying molecular mechanisms remain unclear. The aim was to investigate the signaling pathways involved in the TNF-α-mediated downregulation of CDX2, and its influence on Wnt/β-catenin signaling components in colon cancer cells. The expression of TNF-α and CDX2 at the invasive front were evaluated by immunohistochemical staining and showed reduced CDX2-positive cells in tumor buddings in areas with TNF-α expression in the surrounding inflammatory cells. In vitro studies revealed that TNF-α treatment showed a dose-dependent decrease of CDX2 messenger RNA (mRNA) and protein expression in Caco-2 cells. Inhibition of nuclear factor-kappaB or p38 pathways showed that these are involved in the TNF-α-dependent downregulation of CDX2. Furthermore, TNF-α-mediated downregulation of CDX2 was found to significantly decrease the mRNA levels of adenomatous polyposis coli (APC), axis inhibition protein 2 (AXIN2) and glycogen synthase kinase-3 beta (GSK3β), whereas the mRNA levels of Wnt targets were significantly elevated in TNF-α-treated Caco-2 cells. These findings were associated with reduced binding of CDX2 to promoter or enhancer regions of APC, AXIN2 and GSK3β. In conclusion, it was found that TNF-α induces the expression of Wnt signaling components through a downregulation of the CDX2 expression that might have a tumor-promoting effect on colon cancer cells.
authors: Department of Gastroenterology, Medical Section, Herlev Hospital, DK-2730 Herlev, Denmark.
authors: Mehmet
authors: M
authors: Coskun
authors: Anders Krüger
authors: AK
authors: Olsen
authors: Michael
authors: M
authors: Bzorek
authors: Susanne
authors: S
authors: Holck
authors: Ulla Højholt
authors: UH
authors: Engel
authors: Ole Haagen
authors: OH
authors: Nielsen
authors: Jesper Thorvald
authors: JT
authors: Troelsen
mesh_terms: D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin