Abstract
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. We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with Apc(Min) mice (vil-MACC1/Apc(Min)). vil-MACC1/Apc(Min) mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large tumors (≥3-mm diameter; P = 0.0024). A detailed histopathologic analysis of these lesions demonstrated that the tumors from the vil-MACC1/Apc(Min) mice had a more invasive phenotype and, consequently, showed a significantly reduced survival time than Apc(Min) mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/Apc(Min) mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors compared with Apc(Min) 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). We provide proof of principle that MACC1-induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression. Clin Cancer Res; 22(11); 2812-24. ©2016 AACR.
Highlights
Worldwide, colorectal cancer is one of the most common malignancies with more than 1 million cases diagnosed every year [1]
Transgenic MACC1 mRNA and protein were targeted to the intestinal epithelial cells (IEC) of vil-MACC1 mice (Supplementary Fig. S1C and S1D)
This expression pattern is consistent with the endogenous expression of the villin gene [30], confirming that the MACC1 transgene is expressed in the entire vertical axis, including the cells of the crypts
Summary
Colorectal cancer is one of the most common malignancies with more than 1 million cases diagnosed every year [1]. Colorectal carcinogenesis is a multistep process associated with the accumulation of genetic alterations and mutations in oncogenes and tumor-suppressor genes [2]. Prominent among these is the tumor-suppressor polyposis adenomatous coli (APC) gene, which is somatically mutated in more than 80% of sporadic colorectal tumors [3]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). C. Lemos and M.S. Hardt contributed to this article
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