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MLH1 function is context dependent in colorectal cancers
  1. Thomas Jackson1,
  2. Mohamed A H Ahmed1,
  3. Rashmi Seth1,
  4. Darryl Jackson1,
  5. Mohammad Ilyas1,2
  1. 1Division of Pathology, School of Molecular Medical Sciences, Queen's Medical Centre Campus, University of Nottingham, Nottingham, UK
  2. 2Biomedical Research Unit, Queen's Medical Centre Campus, Nottingham University Hospitals Trust, Nottingham, Nottingham, UK
  1. Correspondence to Professor Mohammad Ilyas, Division of Pathology, School of Molecular Medical Sciences, Queen's Medical Centre, Nottingham University, Nottingham NG7 2UH, UK; mohammad.ilyas{at}nottingham.ac.uk

Abstract

Background and aims Loss of mismatch repair (MMR) function in sporadic colorectal cancer occurs most commonly because of inactivation of MLH1, and it causes an increase in mutation rate. However, it is uncertain whether loss of MMR alters any other cellular function. The aim of this study was to investigate the role of MMR in regulating cell numbers and apoptosis.

Methods MLH1 protein levels were manipulated by (a) cloning and forcibly expressing MLH1 in HCT116 (a cell line with MLH1 mutation) and RKO (a cell line with MLH1 silencing), and (b) knockdown of MLH1 in SW480 (a cell line with normal MMR function). Cell number and apoptotic bodies were measured in standard and ‘high stress’ (ie, after staurosporine exposure) conditions.

Results Restoration of MLH1 function in HCT116 and RKO resulted in increased cell number (p<0.001 for both cell lines) and decreased numbers of floating apoptotic bodies (p<0.01 in HCT116) in standard culture conditions. However, on induction of apoptotic stress, restoration of MLH1 resulted in reduced cell numbers (p<0.005). Knockdown of MLH1 in SW480 had no effect on cell numbers or apoptosis.

Conclusions MLH1 function may be context dependent: in ‘low stress’ conditions it may act to inhibit apoptosis, while in ‘high stress’ conditions it may induce apoptosis. However, within the context of chromosomal instability, the effect of MLH1 on cell numbers is limited.

  • Cancer genetics
  • colorectal cancer
  • context-dependence
  • mismatch repair
  • MLH1
  • molecular pathology

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Footnotes

  • Funding This work was funded by the University of Nottingham.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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