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Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy

Leguisamo, NM, Gloria, HC, Kalil, AN, Martins, TV, Azambuja, DB, Meira, Lisiane and Saffi, J (2017) Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy Oncotarget. pp. 1-16.

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Abstract

Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients’ clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

Item Type: Article
Subjects : Biosciences and Medicine
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Leguisamo, NMUNSPECIFIEDUNSPECIFIED
Gloria, HCUNSPECIFIEDUNSPECIFIED
Kalil, ANUNSPECIFIEDUNSPECIFIED
Martins, TVUNSPECIFIEDUNSPECIFIED
Azambuja, DBUNSPECIFIEDUNSPECIFIED
Meira, LisianeL.Meira@surrey.ac.ukUNSPECIFIED
Saffi, JUNSPECIFIEDUNSPECIFIED
Date : 31 January 2017
Identification Number : 10.18632/oncotarget.14909
Copyright Disclaimer : Copyright 2017 The Author(s). Published under a Creative Commons Attribution License (CC BY) which allows anyone to download, reuse, reprint, modify, distribute, and/or copy articles in Oncotarget, so long as the original authors and source are cited.
Uncontrolled Keywords : Colorectal cancer, base excision repair, prognosis, energy metabolism, temozolomide
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 02 May 2017 09:53
Last Modified : 25 Jul 2017 14:13
URI: http://epubs.surrey.ac.uk/id/eprint/814070

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