Coskun, Mehmet5; Olsen, Anders Krüger3; Bzorek, Michael3; Holck, Susanne6; Engel, Ulla Højholt3; Nielsen, Ole Haagen7; Troelsen, Jesper Thorvald3
1 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet2 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section of Diagnostic Sciences, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet5 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet6 Section of Diagnostic Sciences, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet7 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Carcinogenesis, 2014, Vol 35, Issue 5, p. 1185-1192