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

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

doi:10.18632/oncotarget.14909

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.

Highlights

Colorectal carcinoma (CRC) is the third most common malignancy worldwide, and over 1 million new cases of colorectal carcinoma are diagnosed each year [1]
A diagram showing the relative expression of four base excision repair (BER) genes in paired samples of colorectal tumours and adjacent non-tumour samples from 25 patients with high expression for both methylpurine-DNA glycosylase (MPG) and XRCC1 genes is shown in Supplementary Figure 1
We investigated if alterations in BER, mismatch repair (MMR) and direct repair pathways are associated with a particular clinical outcome in Colorectal cancer (CRC) and have prognostic value

Summary

Introduction

Colorectal carcinoma (CRC) is the third most common malignancy worldwide, and over 1 million new cases of colorectal carcinoma are diagnosed each year [1]. Disease prognosis and therapy selection for CRC largely depends on pathology-related staging following the tumour-node-metastasis (TNM) classification and staging system. TNM staging seldom predicts the clinical outcome of CRC patients accurately. Highlighting the limitations of the TNM classification system is the observation that 20-40% of patients with relatively low-grade, stage II colorectal cancer rapidly worsen and die [2, 3]. Despite significant advances in diagnosis and treatment, CRCrelated mortality remains unchanged for the past 20 years www.impactjournals.com/oncotarget and patients with advanced disease derive limited if any benefit from the recent advances in adjuvant therapy [4]. Cancer recurrence is common within the first few years following treatment completion, indicating stem cells repopulation [6] and drug resistance [7]

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Results

Conclusion