WNT5A inhibits metastasis and alters splicing of Cd44 in breast cancer cells

Jiang, Wen, Crossman, David K, Mitchell, Elizabeth H, Sohn, Philip, Crowley, Michael R and Serra, Rosa (2013) WNT5A inhibits metastasis and alters splicing of Cd44 in breast cancer cells. PLoS One, 8 (3). ISSN 1932-6203

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Abstract

Wnt5a is a non-canonical signaling Wnt. Low expression of WNT5A is correlated with poor prognosis in breast cancer patients. The highly invasive breast cancer cell lines, MDA-MB-231 and 4T1, express very low levels of WNT5A. To determine if enhanced expression of WNT5A would affect metastatic behavior, we generated WNT5A expressing cells from the 4T1 and MDA-MB-231 parental cell lines. WNT5A expressing cells demonstrated cobblestone morphology and reduced in vitro migration relative to controls. Cell growth was not altered. Metastasis to the lung via tail vein injection was reduced in the 4T1-WNT5A expressing cells relative to 4T1-vector controls. To determine the mechanism of WNT5A action on metastasis, we performed microarray and whole-transcriptome sequence analysis (RNA-seq) to compare gene expression in 4T1-WNT5A and 4T1-vector cells. Analysis indicated highly significant alterations in expression of genes associated with cellular movement. Down-regulation of a subset of these genes, Mmp13, Nos2, Il1a, Cxcl2, and Lamb3, in WNT5A expressing cells was verified by semi-quantitative RT-PCR. Significant differences in transcript splicing were also detected in cell movement associated genes including Cd44. Cd44 is an adhesion molecule with a complex genome structure. Variable exon usage is associated with metastatic phenotype. Alternative spicing of Cd44 in WNT5A expressing cells was confirmed using RT-PCR. We conclude that WNT5A inhibits metastasis through down-regulation of multiple cell movement pathways by regulating transcript levels and splicing of key genes like Cd44.

Item Type: Article
Additional Information: © 2013 Jiang et al. 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.
Uncontrolled Keywords: alternative splicing,animals,antigens, cd44,blotting, western,breast neoplasms,cell line, tumor,cell movement,computational biology,dna primers,female,fluorescent antibody technique,gene expression profiling,humans,mice,microarray analysis,microscopy, phase-contrast,neoplasm metastasis,proto-oncogene proteins,reverse transcriptase polymerase chain reaction,wnt proteins
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 27 Jan 2014 13:58
Last Modified: 21 Apr 2020 22:32
URI: https://ueaeprints.uea.ac.uk/id/eprint/46176
DOI: 10.1371/journal.pone.0058329

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