Unit:
Τομέας Βασικών Ιατρικών ΕπιστημώνLibrary of the School of Health Sciences
Dissertation committee:
Βλαχογιανόπουλος Παναναγιώτης, Καθηγητής, Ιατρική, ΕΚΠΑ
Κόλλιας Γεώργιος, Καθηγητής, Ιατρική, ΕΚΠΑ
Κουτσιλίερης Μιχαήλ, Καθηγητής, Ιατρική, ΕΚΠΑ
Γοργούλης Βασίλειος, Καθηγητής, Ιατρική, ΕΚΠΑ
Τζιούφας Αναστάσιος, Καθηγητής, Ιατρική, ΕΚΠΑ
Μανουσάκης Μενέλαος, Καθηγητής, Ιατρική, ΕΚΠΑ
Ηλιόπουλος Αριστείδης, Καθηγητής, Ιατρική, ΕΚΠΑ
Original Title:
Ο ρόλος της κινάσης MK2 στην ανάπτυξη φλεγμονής και καρκίνου του εντέρου
Translated title:
The role of kinase MK2 in intestinal inflammation and cancer
Summary:
MAPKAPK2 (MK2) is a direct downstream substrate of p38 and regulates pro-inflammatory cytokine
production, while it is also involved in the regulation of the cell cycle and apoptosis, suggesting an
important role in carcinogenesis. The role of MK2 in inflammation is the most extensively studied. It is
mediated through the post-transcriptional control of pro-inflammatory cytokines, such as TNF and IL-6,
and has been shown to play an important role in various inflammatory diseases in vivo. MK2 is also the
main kinase that phosphorylates Hsp27, which mediates cytokine expression and has been further
implicated in the regulation of cell proliferation, apoptosis and migration. Hsp27 is often found
upregulated and phosphorylated in cancer and it has been associated with poor prognosis. MK2 has been
proposed as a potential alternative target to p38 inhibition, as it could reproduce the beneficial effects of
p38 inhibitors potentially sparing the accompanying side effects.
The role of MK2 in cancer is not as well studied as in inflammation; in vivo data using MK2 knockout
mice have shown that it plays an important role in the initiation and the early stages of chemically
induced skin tumorigenesis in mice, mainly through the regulation of pro-inflammatory cytokine
expression and the stabilization of the tumor suppressor protein p53. Recently, it was also shown that
mice deficient in MK2 were resistant to the development of AOM/DSS-induced colitis-associated cancer,
although the exact cellular and molecular mechanism underlying this phenotype remained unclear.
In the present study, we have addressed the cell-specific pathophysiological role of MK2 in intestinal
carcinogenesis.
To investigate the cell-specific role of MK2 in intestinal carcinogenesis, we initially generated two new
mouse strains, a complete and a conditional MK2 knockout mouse line, used two mouse models of
intestinal carcinogenesis and performed bone-marrow transfers. We measured tumor number and size and
assessed epithelial proliferation, apoptosis, inflammatory infiltration and angiogenesis in different timepoints
during disease progression. We also performed in vitro experiments to examine the response of
primary intestinal mesenchymal cells lacking MK2 to different stimuli and co-cultures between epithelial
organoids and mesenchymal cells to identify heterotypic interactions between different stroma
populations. Finally, we used two chemical inhibitors of MK2 to assess the effect of pharmacological
inhibition in intestinal tumorigenesis.
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We show that both genetic and chemical inhibition of MK2 was associated with reduced tumor
growth, invasive potential and increased survival in the Apcmin/+ and colitis-associated cancer model.
MK2-deficiency in Apcmin/+ led to deregulation of apoptosis and a significant reduction in epithelial
proliferation and angiogenesis, without affecting inflammation in the intestine. Histopathological
analysis during the course of the disease further revealed an important role of MK2 in tumor
progression rather than initiation, as MK2 knockout mice developed comparable number of
microadenomas during the initiation phase of the disease. Notably, bone-marrow transfers
demonstrated that reduced tumorigenesis was not mediated by its well-described
immunomodulatory roles in immune and inflammatory cells. Deletion of MK2 in intestinal
mesenchymal cells (IMCs) led to both reduced tumor multiplicity and growth. Mechanistically,
MK2 in IMCs was required for Hsp27 phosphorylation and the production of downstream
tumorigenic effector molecules and for the growth and survival of co-cultured intestinal organoids,
dominantly affecting epithelial proliferation, apoptosis and angiogenesis. Genetic ablation of MK2
in intestinal epithelial or endothelial cells was less effective in comparison to its complete deletion,
leading to reduction of tumor size via modulation of epithelial apoptosis and angiogenesisassociated
proliferation, respectively. Similar results were obtained in a model of colitis-associated
carcinogenesis, indicating a mesenchymal-specific role for MK2 also in this model. Our findings
demonstrate the central pathogenic role of mesenchymal-specific MK2/Hsp27 axis in tumorigenesis
and highlight the value of mesenchymal MK2 inhibition in the treatment of cancer.
Main subject category:
Health Sciences
Keywords:
Colorectal cancer, Intestinal inflammation, MK2 kinase
Number of references:
500
