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Inflammation-induced colon cancer in uPA-deficient mice is associated with a deregulated expression of Notch signaling pathway components

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Abstract

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.

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Acknowledgements

The authors are grateful to the Bodossaki Foundation for the kind donation of the real-time PCR instrumentation, and to Dr. Elisavet Karamanavi for animal breeding, maintaining and experimental handling.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The use of the Pannoramic 250 Flash II whole slide scanner was supported by SIG 1S10OD019961-01 (NCI).

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Authors and Affiliations

  1. Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Hara Afaloniati, Anastasios Karampatzakis-Kouritas & Katerina Angelopoulou

  2. Department of Anatomy & Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    George S. Karagiannis

  3. Histology-Histopathology Laboratory, C’ Army Veterinary Hospital, Camp Makri, Thessaloniki, Greece

    Emmanouel Karavanis

  4. Laboratory of Pharmacology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Theophano A. Psarra

  5. Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Theofilos Poutahidis

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  1. Hara Afaloniati
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Afaloniati, H., Karagiannis, G.S., Karavanis, E. et al. Inflammation-induced colon cancer in uPA-deficient mice is associated with a deregulated expression of Notch signaling pathway components. Mol Cell Biochem 464, 181–191 (2020). https://doi.org/10.1007/s11010-019-03659-9

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