Inflammation-induced colon cancer in uPA-deficient mice is associated with a deregulated expression of Notch signaling pathway components
| Autor: | George S. Karagiannis, Katerina Angelopoulou, Hara Afaloniati, Emmanouel Karavanis, Theofilos Poutahidis, Theophano A. Psarra, Anastasios Karampatzakis-Kouritas |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
JAG2 JAG1 Clinical Biochemistry Notch signaling pathway Biology 03 medical and health sciences Kruppel-Like Factor 4 Mice 0302 clinical medicine Animals Receptor Notch2 HES1 Receptor Notch1 Receptor Molecular Biology Mice Inbred BALB C Oncogene Cell Biology General Medicine Urokinase-Type Plasminogen Activator Neoplasm Proteins Gene Expression Regulation Neoplastic 030104 developmental biology KLF4 030220 oncology & carcinogenesis Colonic Neoplasms Cancer research Signal transduction Signal Transduction |
| Zdroj: | Molecular and cellular biochemistry. 464(1-2) |
| ISSN: | 1573-4919 |
| Popis: | Notch is an evolutionarily conserved signaling pathway with an important role in development and cell fate determination. Deregulation of Notch signaling has been associated with several pathological conditions, including cancer. Acting as an oncogene in some types of cancers and as a tumor suppressor in other, Notch effects seem to be highly context-dependent in solid tumors. In the present study, we aimed to investigate gene expression levels of Notch pathway constituents, including ligands, receptors, and target genes, during the early stages of inflammation-associated intestinal carcinogenesis. To achieve so, we used our recently developed mouse model, in which colon cancer arises in the absence of urokinase-type plasminogen activator (uPA) due to colitis induced by dextran sodium sulfate (DSS) treatment. Among the cell surface components, ligands Jag1/Jag2 and receptors Notch1/Notch2 were found to be significantly upregulated in the uPA-deficient protumorigenic inflammatory microenvironment. Moreover, several intracellular Notch modulators, i.e. Hes1, Hey1, and Klf4, were also shown to be deregulated with inflammation, yet irrespective of uPA status. Sox9 transcription factor, however, was significantly downregulated in the uPA-deficient/DSS-treated mice that developed colon adenomas as compared to the wild-type/DSS-treated group with no neoplasia identified. The latter finding supports a tumor suppressive role of Sox9 in intestinal carcinogenesis. Our results point towards an early activation of Notch signaling pathway at the receptor-ligand level in inflammation-associated colon neoplasmatogenesis developed in the absence of uPA. Interestingly, such activation may not be accompanied by deregulation of downstream Notch-target genes, possibly due to the effects of other inter-related signaling pathways. |
| Databáze: | OpenAIRE |
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