Canonical Wnt suppressor, Axin2, promotes colon carcinoma oncogenic activity

Abstract

Aberrant activation of canonical Wingless-type MMTV integration site family (Wnt) signaling is pathognomonic of colorectal cancers (CRC) harboring functional mutations in either adenomatous polyposis coli or β-catenin. Coincident with Wnt cascade activation, CRCs also up-regulate the expression of Wnt pathway feedback inhibitors, particularly the putative tumor suppressor, Axin2. Because Axin2 serves as a negative regulator of canonical Wnt signaling in normal cells, recent attention has focused on the utility of increasing Axin2 levels in CRCs as a means to slow tumor progression. However, rather than functioning as a tumor suppressor, we demonstrate that Axin2 acts as a potent promoter of carcinoma behavior by up-regulating the activity of the transcriptional repressor, Snail1, inducing a functional epithelialmesenchymal transition (EMT) program and driving metastatic activity. Silencing Axin2 expression decreases Snail1 activity, reverses EMT, and inhibits CRC invasive and metastatic activities in concert with global effects on the Wnt-regulated cancer cell transcriptome. The further identification of Axin2 and nuclear Snail1 proteins at the invasive front of human CRCs supports a revised model wherein Axin2 acts as a potent tumor promoter in vivo.invasion | E-cadherin | basement membrane | GSK3β | tankyrase

Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling

“…In addition, NR4A1, by acting as a strong direct transcriptional inducer for AXIN2 (but not AXIN1), compensates the limiting pool of oncogenic AXIN2 (ref. 32) and (Supplementary Fig. 6f-h), thereby enforcing SMAD7 degradation.…”

Post-translational Glycoprotein Modifications Regulate Colon Cancer Stem Cells and Colon Adenoma Progression in Apcmin/+ Mice through Altered Wnt Receptor Signaling

“…To provide additional evidence that CCSC were regulated by GnT-V levels via the Wnt signaling pathway, colon cancer cells were treated by Wnt-3a, an active ligand for Wnt signaling in colon carcinoma (50), and the Wnt inhibitor CCT036477 (51). As expected, the CCSC population was significantly increased in LS180 cells after treatment with Wnt-3a (Fig.…”

“…less of a change than LS180 (data not shown) likely due to higher activation of Wnt activity by an APC mutation in these cells (50).…”

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

“…49 We also detected AXIN2 promoter hypermethylation with MethylCap-seq both in CRC and adenoma tissues compared to NAT samples, but the prevalence of DMRs was higher in gene body regions (25 hypermethylated DMRs, 13 hypomethylated DMRs). In silico analysis also revealed a remarkable upregulation of AXIN2 mRNA in both disease groups, suggesting the tumor promoting function of AXIN2, 49 especially in MSS CRC cases.…”