title: 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 epithelial-mesenchymal 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.
authors: Division of Molecular Medicine and Genetics, Department of Internal Medicine, and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Zhao-Qiu
authors: ZQ
authors: Wu
authors: Thomas
authors: T
authors: Brabletz
authors: Eric
authors: E
authors: Fearon
authors: Amanda L
authors: AL
authors: Willis
authors: Casey Yuexian
authors: CY
authors: Hu
authors: Xiao-Yan
authors: XY
authors: Li
authors: Stephen J
authors: SJ
authors: Weiss
mesh_terms: D060466:Axin Protein / Q000378:metabolism*; D001485:Basement Membrane / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D038501:Tankyrases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D060466:Axin Protein; D015820:Cadherins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D000071250:Snail Family Transcription Factors; D038501:Tankyrases; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C491761:AXIN2 protein, human; C000604407:SNAI1 protein, human; C418109:TNKS protein, human