A Role for AXIN2 in Oncogenesis.

Abstract

The axis inhibition proteins 1 and 2 (AXIN1, AXIN2) are negative regulators of Wnt/beta-catenin signaling. The Wnt pathway has a key role in cell fate and development and is dysregulated in 90% of colorectal cancers (CRCs). In 2011, we reported a family with a CRC/oligodontia (lack of several teeth) phenotype. Affected individuals carry a heterozygous, germline mutation in AXIN2. This mutation introduces a premature stop codon and segregates with the oligodontia/CRC phenotype. This family is the second case of an AXIN2 mutation associated with oligodontia/CRC.

A premature stop codon suggests that mutant transcripts might undergo nonsense-mediated degradation, but transcripts from both wild-type and mutant allele were detected in the proband’s lymphocytes, predicting that the mutant allele can encode a truncated protein, trAXIN2. The trAXIN2 protein is more stable than wid-type, displayed a reduced function in Wnt/beta-catenin target gene inhibition, retained interactions with beta-catenin, AXIN1 and AXIN2, and inhibited colony formation in a Wnt-dependent CRC cell line similar to AXIN2. This protein appears to be hypomorphic, which could produce reduced function in vivo, but with massive over-expression in vitro, increased protein stability may mask a reduced functionality. A knock-in mouse model has been generated to further explore the significance of this allele in cancer and development.

Sequence alterations in AXIN1 and AXIN2 have been reported in a subset of many cancers. Whether these mutations have an active role in cancer is unclear. In a mouse model of CRC, loss of one or both alleles of Axin2 did not alter survival time, but may alter the distribution of tumors in the colon. These studies are ongoing. The AXIN proteins were classically thought of as tumor suppressors, but some studies suggest that high levels of AXIN2 might actually promote tumor phenotypes such as invasion and metastasis. Moreover, stabilization of AXIN proteins has been proposed as a therapeutic strategy for cancer; therefore, it is important to better understand the role of AXIN proteins in normal cells and cancer cells. This work has begun to clarify how AXIN2 functions at a biochemical level, and how AXIN2 mutations or changes in gene dosage impact tumor development.