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MACC1 induces tumor progression in transgenic mice and colorectal cancer patients via increased pluripotency markers Nanog and Oct4

Item Type:Article
Title:MACC1 induces tumor progression in transgenic mice and colorectal cancer patients via increased pluripotency markers Nanog and Oct4
Creators Name:Lemos, C. and Hardt, M.S. and Juneja, M. and Voss, C. and Foerster, S. and Jerchow, B. and Haider, W. and Blaker, H. and Stein, U.
Abstract:PURPOSE: We have previously identified the gene MACC1 as a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Here, we report for the first time the generation of transgenic mouse models for MACC1. EXPERIMENTAL DESIGN: We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with ApcMin mice (vil-MACC1/ApcMin). RESULTS: vil-MACC1/ApcMin mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large sized tumors (>/= 3 mm diameter; P = 0.0024). A detailed histopathological analysis of these lesions demonstrated that the tumors from the vil-MACC1/ApcMin mice had a more invasive phenotype and consequently, showed a significantly reduced survival time as compared to ApcMin mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/ApcMin mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors as compared to ApcMin controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro, and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r = 0.7005 and r = 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively). CONCLUSIONS: We provide proof of principle that MACC1-induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct-4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression.
Keywords:Colorectal Cancer, Tumor Progression, MACC1, Wnt Signaling, Pluripotency , Animals, Mice
Source:Clinical Cancer Research
Publisher:American Association for Cancer Research (U.S.A.)
Page Range:2812-2824
Date:1 June 2016
Official Publication:https://doi.org/10.1158/1078-0432.CCR-15-1425
PubMed:View item in PubMed

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