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


RESULTS
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.
Willis
Naomi D
ND
School of Biological and Biomedical Sciences, Durham University, Durham, United Kingdom.
Cox
Thomas R
TR
Rahman-Casañs
Syed F
SF
Smits
Kim
K
Przyborski
Stefan A
SA
van den Brandt
Piet
P
van Engeland
Manon
M
Weijenberg
Matty
M
Wilson
Robert G
RG
de Bruïne
Adriaan
A
Hutchison
Christopher J
CJ
D000328:Adult; D017398:Alternative Splicing; D015415:Biomarkers / Q000032:analysis; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death; D003106:Colon / Q000502:physiology; D003110:Colonic Neoplasms / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D018570:Risk Assessment
D015415:Biomarkers; D014408:Biomarkers, Tumor; C494847:LMNA protein, human; D034904:Lamin Type A; C440308:lamin C