Lamin A/C Is a Risk Biomarker in Colorectal Cancer

PLoS One. 2008 Aug 20;3(8):e2988. doi: 10.1371/journal.pone.0002988.

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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alternative Splicing
  • Biomarkers / analysis
  • Biomarkers, Tumor / metabolism
  • Cell Death
  • Colon / physiology
  • Colonic Neoplasms / pathology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lamin Type A / genetics
  • Lamin Type A / metabolism*
  • Prognosis
  • Risk Assessment

Substances

  • Biomarkers
  • Biomarkers, Tumor
  • LMNA protein, human
  • Lamin Type A
  • lamin C