Importance of MYC IRES in intestinal homeostasis and carcinogenesis
Final Report Abstract
With around 80,000 new cases in Germany, colorectal cancer (CRC) is the most common tumour disease of the gastrointestinal tract and the second most common tumour disease in general. The lifetime risk of developing CRC for inhabitants of Central Europe is around 6%. 50% of all patients with the disease suffer syn- or metachronous metastasis. The survival rates of patients with metastasised CRC have improved significantly over the last two decades thanks to multimodal therapy concepts and surgical resection of metastases, but the median survival rate is less than two years after diagnosis. Most CRCs arise from adenomas, which in turn arise from normal mucosa through monoclonal expansion, whereby a sequential accumulation of mutations occurs. In over 95% of cases, there is a mutation in the WNT signalling pathway, which affects the tumour suppressor gene APC in over 80% of cases, irrespective of whether microsatellite-stable or -unstable variants of CRC are involved. The different mutations of the WNT signalling pathway lead to an accumulation of β-catenin, its translocation into the cell nucleus and activation of β-catenin/Lef/TCF-dependent target genes. The oncogene MYC is an essential target gene of this signalling pathway for tumour development. A comparison of the expression of genes in CRC with the expression in the surrounding mucosa reveals a significant activation of MYC-induced genes and a significant repression of MYC-inhibited genes. In a genetic mouse model of CRC oncogenesis (APCfl/fl), it was shown that homozygous deletion of the MYC gene in the intestine can completely abolish the hyperproliferation triggered by the loss of APC. MYC thus represents the central gene of CRC. In preliminary work, we were able to show that in CRC, in addition to the transcriptional regulation of MYC by the WNT signalling pathway, regulation also occurs at the translational level. Of particular importance here is the so-called Internal Ribosome Entry Site (IRES), which enables 5'-cap-independent translation initiation. The IRES is an approximately 350 bp sequence in the MYC 5' untranslated region (UTR), which is particularly important during embryonic development and in highly proliferating or stressed tissue, such as tumours. A number of our preliminary studies suggest that MYC-IRES translation is of fundamental importance in CRC and that MYC protein expression is regulated via the IRES element. Inhibition of the structure thus represents a promising approach for reducing oncogenic MYC levels in CRC. As part of this funded project, the translation initiation factor eIF3D was identified as a regulator of MYC expression, whereby the depletion of eIF3D impairs the proliferation and viability of CRC cells and thus represents a potential therapeutic target in CRC. In addition, the effect of the cardiac glycoside cymarin was investigated both mechanistically and in terms of therapeutic applicability. Our hypothesis is that cymarin acts on its primary target, the cellular Na+/K+-ATPase, and thereby indirectly regulates MYC expression via its 3' UTR. We also hypothesise that the anti-tumour effect of cymarin is based on the (re-)activation of the immune system, and particularly the T cell population after reduction of MYC levels.
