Oncotarget

Research Papers:

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

Natalia M. Leguisamo _, Helena C. Gloria, Antonio N. Kalil, Talita V. Martins, Daniel B. Azambuja, Lisiane B. Meira and Jenifer Saffi

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Oncotarget. 2017; 8:54199-54214. https://doi.org/10.18632/oncotarget.14909

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Abstract

Natalia M. Leguisamo1, Helena C. Gloria1, Antonio N. Kalil1,2, Talita V. Martins2, Daniel B. Azambuja1,2, Lisiane B. Meira3,* and Jenifer Saffi1,*

1Genetic Toxicology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil

2Oncology and Colorectal Surgery, Santa Casa de Misericórdia de Porto Alegre (ISCMPA), Porto Alegre, Rio Grande do Sul, Brazil

3Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom

*These authors share senior authorship

Correspondence to:

Natalia M. Leguisamo, email: [email protected]

Keywords: colorectal cancer, base excision repair, prognosis, energy metabolism, temozolomide

Received: February 29, 2016    Accepted: November 30, 2016    Published: January 31, 2017

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.


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