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Lamin A/C is a risk biomarker in colorectal cancer.

Willis, N.D. and Cox, T.R. and Rahman-Casans, F. and Smit, K. and Przyborski, S.A. and van den Brandt, P. and van Engeland, M. and Weijenberg, M. and Wilson, R. and de Bruine, A. and Hutchison, C.J. (2008) 'Lamin A/C is a risk biomarker in colorectal cancer.', PLoS ONE., 3 (8). e2988.

Abstract

Background: A-type lamins are type V intermediate filament proteins encoded by the gene LMNA. Mutations in LMNA give rise to diverse degenerative diseases related to premature ageing. A-type lamins also influence the activity of the Retinoblastoma protein (pRb) and oncogenes such a β-catenin. Consequently, it has been speculated that expression of A-type lamins may also influence tumour progression. Methodology/Principal Findings: An archive of colorectal cancer (CRC) and normal colon tissue was screened for expression of A-type lamins. We used the Cox proportional hazard ratio (HR) method to investigate patient survival. Using CRC cell lines we investigated the effects of lamin A expression on other genes by RT-PCR; on cell growth by FACS analysis; and on invasiveness by cell migration assays and siRNA knockdown of targeted genes. We found that lamin A is expressed in colonic stem cells and that patients with A-type lamin-expressing tumours have significantly worse prognosis than patients with A-type lamin negative tumours (HR = 1.85, p = 0.005). To understand this finding, we established a model system based upon expression of GFP-lamin A in CRC cells. We found that expression of GFP-lamin A in these cells did not affect cell proliferation but did promote greatly increased cell motility and invasiveness. The reason for this increased invasiveness was that expression of lamin A promoted up-regulation of the actin bundling protein T-plastin, leading to down regulation of the cell adhesion molecule E-cadherin. Conclusions: Expression of A-type lamins increases the risk of death from CRC because its presence gives rise to increased invasiveness and potentially a more stem cell-like phenotype. This report directly links A-type lamin expression to tumour progression and raises the profile of LMNA from one implicated in multiple but rare genetic conditions to a gene involved in one of the commonest diseases in the Western World.

Item Type:Article
Full text:PDF - Published Version (616Kb)
Status:Peer-reviewed
Publisher Web site:http://dx.doi.org/10.1371/journal.pone.0002988
Publisher statement:Copyright: © 2008 Willis 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.
Record Created:26 Apr 2012 12:05
Last Modified:15 Feb 2013 11:13

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