Lamin A/C Is a Risk Biomarker in Colorectal Cancer

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.

Side population cells have the characteristics of cancer stem-like cells/cancer-initiating cells in bone sarcomas

“…(Perez-Pinera et al, 2008). LMNA is reported to encode lamin A, which is a putative colonic epithelial stem cell marker and is also a prognostic factor in colorectal cancer (Willis et al, 2008). On the other hand, four genes (ANKRD11, PHLDA3, APOL1 and MSX1) are known as tumour-suppressor factors.…”

Loss of A-type lamins and genomic instability

“…9,10 Interestingly, changes in the expression of A-type lamins are observed in leukemias, lymphomas, small cell lung and ovarian cancer, as well as colon carcinoma, often associated with poor prognosis. [11][12][13] The cellular mechanisms affected by these malignancy-associated alterations of A-type lamins are only beginning to be unraveled. 14 Alterations of telomere biology and defects in repair of DNA damage are among the leading causes for genomic instability, and clear contributors to aging and cancer phenotypes.…”

Accelerated ageing: from mechanism to therapy through animal models

“…Finally, animal models will predictably play a key role as tools for investigating not only the implications of the Zmpste24/lamin A system in accelerated and physiological ageing, but also in other important processes such as cancer. In this regard, recent work illustrates the relevance of this system in cancer and supports its interest as target of anti-cancer therapies (Willis et al 2008), an aspect that will be the subject of future studies based on the use of currently available and newly developed animal models. In summary, the use of genetically modified mice has allowed investigating the molecular mechanisms underlying progeroid laminopathies and has lead, in a very short period of time, to clinical trials for testing rationally designed treatments against these dramatic diseases.…”