Abstract
BackgroundA-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 FindingsAn 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.ConclusionsExpression 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.
Highlights
Lamins A and C are type V intermediate filament proteins that form part of a filamentous network termed the nuclear lamina lining the inner nuclear membrane (INM) [1]
Expression of A-type lamins increases the risk of death from colorectal cancer (CRC) because its presence gives rise to increased invasiveness and potentially a more stem cell-like phenotype
A complex of MAN1 and A-type lamins has been shown to interact with the receptor regulated SMAD and to antagonise TGF-b signalling by inhibiting rSMAD at the INM [18,19]
Summary
Lamins A and C are type V intermediate filament proteins that form part of a filamentous network termed the nuclear lamina lining the inner nuclear membrane (INM) [1]. A-type lamins are alternatively spliced products of the LMNA gene, which has been mapped to chromosome 1q21.3 [2]. Mutations in this gene are the underlying cause of twelve different genetic diseases that are collectively termed laminopathies [3]. A-type lamins interact with important cytoskeletal linker proteins termed nesprins, via SUN domain proteins, connecting the INM to the outer nuclear membrane (ONM) via the lumen [4,5]. A-type lamins interact with a number of binding partners within the nucleus, which in turn interact with and influence the activity of important growth regulators. It has been speculated that expression of Atype lamins may influence tumour progression
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