Cox, Thomas Robert (2007) Lamin A/C as a prognostic biomarker in colorectal cancer. Doctoral thesis, Durham University.
Lamins A and C (A-type lamins) are type V nuclear intermediate filament proteins which form a complex meshwork underlining the inner nuclear membrane termed the nuclear lamina. A-type lamins have been implicated in NA replication, regulation of gene transcription, apoptosis and regulating the activity of several growth promoters. As such mutations in A-type lamins give rise to diverse range of genetic diseases related to premature ageing and it has been speculated but not proven that expression of A-type lamins may influence tumour progression. To test this hypothesis, a large (n=656) retrospective archive of colorectal cancer specimens from the Netherlands Cohort Study on Diet and Cancer was screened for the expression of A-type lamins. Data clearly show that patients lacking A- type lamin expression in their tumours have a significantly better prognosis compared to clinicopathologically similar patients expressing A-type lamins [HR = 0.59, (95% CI: 0.409 - 0.858). p=0.006].Data also show that expression of lamin A in an in vitro colorectal cancer model leads to genome-wide changes and in particular promotes a significant down- regulation in Bone Morphogenic Protein 4 (BMP4) a member of the TGF-β superfamily which has already been linked to the pathogenesis of some solid tumours and also show that A-type lamin expression acts as a negative regulator of BMP4 mediated growth suppression. A-type lamin expression also results in a concomitant up-regulation in expression of the actin bundling protein T-plastin and down-regulation in expression of the cell adhesion molecule E-cadherin leading to a more motile, less adherent cellular phenotype in lamin A expressing cells. Thus expression of A-type lamins may increase the risk of death in colorectal cancer because its presence gives rise to increased invasiveness due to the negative regulation of BMP mediated growth suppression. This is the first evidence directly linking the expression of A-type lamins to mechanisms promoting tumour progression.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||26 Jun 2012 15:21|