Lamin A/C is a risk biomarker in colorectal cancer

Willis, ND.; Cox, TR.; Rahman-Casans, F.; Smit, K.; Przyborski, SA.; van den Brandt, P.; van Engeland, M.; Weijenberg, M.; Wilson, R.; de Bruine, A.; Hutchison, CJ.

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.

Citation

Willis, N., Cox, T., Rahman-Casans, F., Smit, K., Przyborski, S., van den Brandt, P., …Hutchison, C. (2008). Lamin A/C is a risk biomarker in colorectal cancer. PLoS ONE, 3(8), Article e2988. https://doi.org/10.1371/journal.pone.0002988

• Journal Article Type: Article
• Publication Date: Jan 1, 2008
• Deposit Date: Mar 30, 2012
• Publicly Available Date: May 17, 2012
• Journal: PLoS ONE
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 8
• Article Number: e2988
• DOI: https://doi.org/10.1371/journal.pone.0002988
• Public URL: https://durham-repository.worktribe.com/output/1501331