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Abstract

Colorectal Cancer, serving as a disease involving multiple mutations and different stages, poses a challenge in terms of non-responsiveness to current therapies, necessitating the identification of new druggable targets.

The WNT/β-catenin and RAS pathways are extensively accepted as two essential contributors to CRC tumorigenesis. APC and KRAS mutations occur in CRC commonly and jointly. However, the intricate crosstalk between APC and KRAS remains poorly understood. Recent studies have highlighted the collaborative role of these pathways in advancing tumorigenesis, metastasis , and resistance to therapy in CRC.

This thesis primarily focused on investigating the interaction between myotubularinrelated protein 7 (MTMR7) and the RAS/WNT driver pathways in CRC. Our previous work has shown the inhibitory effect of MTMR7 on RAS/ERK 1/2 signaling and its ability to activate the tumor suppressor PPARγ. Building upon this, now we have discovered that the MTMR7 enzyme and a peptide derived from its CC-domain also act as an inhibitor in the WNT signaling pathway, as evidenced by both in vitro and in vivo studies. Additionally, we found that the stability of β-catenin is contingent upon its interaction with RAS. Disruption of the interaction leads to separate degradation processes for both β-catenin and RAS. Using the MTMR7-full length (FL) plasmid for transfection into three distinct cell lines (HEK293T, SW480, HCT116), Coimmunoprecipitation (Co-IP) was employed to demonstrate that MTMR7 interferes with the interaction of β-catenin and RAS. In summary, MTMR7 functions as a potent WNT signaling inhibitor, showcasing its potential as a therapeutic agent for treatmentresistant CRC.