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ISSN: 1948-5956
Journal of Cancer Science & Therapy
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AXIN2: Tumor Suppressor, Oncogene or Both in Colorectal Cancer?

Gregory S. Yochum*

Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, USA

*Corresponding Author:
Gregory S. Yochum, Ph.D
Assistant Professor
Department of Biochemistry & Molecular Biology
The Pennsylvania State University College of Medicine, USA
E-mail: [email protected]

Received Date: July 20, 2012; Accepted Date: July 23, 2012; Published Date: July 25, 2012

Citation: Yochum GS (2012) AXIN2: Tumor Suppressor, Oncogene or Both in Colorectal Cancer? J Cancer Sci Ther 4: xii-xiii. doi: 10.4172/1948-5956.1000e109

Copyright: © 2012 Yochum GS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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The Wnt/β-catenin signaling pathway controls intestinal homeostasis and is frequently deregulated in colorectal cancer (CRC) (for a comprehensive review, see [1]). By tightly regulating the levels and subcellular location of the β-catenin transcriptional co-activator, the Wnt pathway governs cellular proliferation in the intestinal crypt. Mutations in components of this pathway, most often in the adenomatous polyposis coli (APC) tumor suppressor, are found in approximately 90% of spontaneously arising CRCs. Moreover, germline mutations in APC cause familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by early onset of colon adenomas. In the absence of a Wnt signal, cytoplasmic β-catenin associates with a destruction complex of proteins containing APC, glycogen synthase kinase 3 beta (GSK3β), casein kinase 1 (CK1) and axis inhibitor proteins 1 and 2 (AXIN1 and AXIN2). Here, β-catenin is phosphorylated and subsequently targeted for degradation by the proteasome. An intact destruction complex ensures that Wnt/β- catenin target genes are repressed in differentiated cells. In the presence of Wnt, the destruction complex is inactivated, β-catenin protein levels increase and β-catenin is translocated to the nucleus to drive expression of growth-promoting genes including c-MYC and CCND1. The APC mutations that commonly occur in CRC are believed, in part, to render the destruction complex inactive resulting in deregulated Wnt/β-catenin signaling and increased cellular proliferation. AXIN2 is a direct Wnt/β-catenin target gene and as such, it is thought to serve in a negative feedback loop to ensure homeostatic levels of β-catenin.

The early and predominant model in the CRC field suggests AXIN2 is a tumor suppressor gene. In a survey of 105 tumor samples, Liu et al. [2] found that 11 contained mutations in the AXIN2 gene that resulted in premature stop codons. These mutations would be predicted to promote oncogenesis by interfering with the ability of truncated AXIN2 to form a fully functional β-catenin destruction complex. However, these samples contained wild-type APC and thus represented a small fraction of CRC cases. It is therefore possible that AXIN2 may serve an oncogenic role in the more common CRCs that harbor nonsense mutations in APC.

Several studies over the years have either indirectly or directly supported the hypothesis that AXIN2 is oncogenic. First, AXIN2 expression in FAP polyps and colon carcinomas is increased in comparison to levels seen in uninvolved colonic mucosa [3,4]. Second, a recent analysis of 287 established cells lines from various tissues confirmed that AXIN2 mRNA levels are highest in lines derived from colorectal cancers [5]. Third, AXIN2 promotes chromosome instability-a process positively associated with oncogenesis [6]. Fourth, AXIN2 association with centrosomes impairs the mitotic checkpoint pathway [6,7]. Finally, AXIN2 knockdown diminished Wnt/β-catenin signaling in an siRNA-based library screen [8]. These properties are not in line with the notion that AXIN2 predominantly serves as a tumor suppressor in CRCs.

A recent report in PNAS by Stephen Weiss’s group provides additional evidence supporting an oncogenic role of AXIN2 in CRC [9]. In this compelling study, Wu et al. [9] found that AXIN2 stabilizes levels of the Snail 1 transcriptional repressor in the nucleus. Snail 1 directly down-regulates E-cadherin expression thereby promoting epithelial to mesenchymal transition (EMT). Tumor cells have long been known to acquire an EMT phenotype as they metastasize distant organs. A microarray analysis found that silencing AXIN2 expression in CRC cell lines decreased expression of mesenchymal markers, such as vimentin and fibronectin, and increased expression of epithelial markers including E-cadherin. Furthermore, as compared to control cells, AXIN2-depleted CRC cells displayed greater migratory properties in a cell invasion assay. Finally, silencing AXIN2 expression reduced the number and size of lung metastases when these CRC cells were injected into athymic nude mice. These new findings clearly demonstrate that AXIN2 plays a pro-tumorigenic role in colon cancer by promoting cellular metatasis.

AXIN2 functions as a tumor suppressor in some CRCs (i.e., when APC is wild type), but functions as an oncogene in most CRCs (i.e., when APC is mutated). What implications do these reports have for therapeutic management of this deadly disease? Several elegant studies have identified the ADP-ribosylating enzymes, tankyrase 1/2, as druggable targets (for a review, see [5]). Tankyrase transfers an ADP ribose moiety to substrates including AXIN1 and AXIN2. ADPribosylated AXIN1 and AXIN2 are subsequently ubiquitinated and targeted for degradation by the proteosome. Small molecule inhibitors, such as XAV939, IWRs and JW compounds, bind tankyrase with high affinity and stabilize AXIN1 and AXIN2 proteins in CRC cells. These compounds decrease β-catenin levels and reduce CRC growth in vitro and in vivo. In light of recent work, stabilizing AXIN2 may be detrimental as a therapeutic strategy. Therefore, efforts are required to develop more specific tankyrase inhibitors that target AXIN1 and not AXIN2. Alternatively, siRNA-based approaches designed to reduce AXIN2 could be used in combination with tankyrase inhibitors to improve the therapeutic outcome.

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