Abstract
Wnt/β-catenin (CTNNB1) signaling is crucial for the proliferation and maintenance of intestinal stem cells (ISC), but excessive activation leads to ISC expansion and eventually colorectal cancer. Thus, negative regulators are required to maintain optimal levels of Wnt/β-catenin signaling. Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMP) function in protein synthesis, but have also been implicated in signaling cascades affecting angiogenesis, immunity, and apoptosis. In this study, we investigated the relationship between AIMP2 and Wnt/β-catenin signaling in a murine model of intestinal homeostasis and tumorigenesis. Hemizygous deletion of Aimp2 resulted in enhanced Wnt/β-catenin signaling, increased proliferation of cryptic epithelial cells, and expansion of ISC compartments. In an Apc(Min/+) background, Aimp2 hemizygosity increased adenoma formation. Mechanistically, AIMP2 disrupted the interaction between AXIN and Dishevelled-1 (DVL1) to inhibit Wnt/β-catenin signaling by competing with AXIN. Furthermore, AIMP2 inhibited intestinal organoid formation and growth by suppressing Wnt/β-catenin signaling in an Aimp2 gene dosage-dependent manner. Collectively, our results showed that AIMP2 acts as a haploinsufficient tumor suppressor that fine-tunes Wnt/β-catenin signaling in the intestine, illuminating the regulation of ISC abundance and activity. Cancer Res; 76(15); 4559-68. ©2016 AACR.
Highlights
The intestinal epithelium self-renews every 3 to 5 days through its highly proliferative compartment, the crypt of Lieberku€hn
Aimp2þ/À:ApcMin/þ mice exhibited significantly reduced survival rates when compared with Aimp2þ/þ:ApcMin/þ mice (Fig. 1A)
The size of the polyps increased in Aimp2þ/À:ApcMin/þ mice, invading tumors were not detected, even in moribund Aimp2þ/À:ApcMin/þ mice
Summary
The intestinal epithelium self-renews every 3 to 5 days through its highly proliferative compartment, the crypt of Lieberku€hn. Intestinal stem cells (ISC) expressing leucine-rich repeat-containing G-protein–coupled receptor 5 (LGR5) residing at the bottom of crypts generate all types of cells in the intestinal epithelium [1]. Cryptal mesenchymal cells and Paneth cells (PC) constitute the ISC niche and support the maintenance of ISCs by producing factors such as EGF, Notch, and Wnt [2]. Wnt/b-catenin signaling plays a pivotal role in homeostatic self-renewal of ISCs [3]. Binding of Wnt ligands to its receptors, Frizzled and low-density lipoprotein receptor–related protein 5/6 (LRP5/6) activate a signaling cascade inhibiting the b-catenin destruction complex, which contains axis inhibition protein (AXIN), adenomatous polyposis coli (APC), and glycogen syn-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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