ABSTRACT
The involvement of alterations in MLH1, an essential mismatch repair component, in BRAFV600E mutated papillary thyroid carcinoma (PTC) has been suggested to be associated with features of tumor aggressiveness. Thirty-two PTC and surrounding normal thyroid tissues were evaluated for 11 representative DNA repair genes expression. BRAFV600E mutational status assessment and clinicopathological correlations were evaluated for their gene and protein expression. BRAFV600E PTC is associated with lower levels of XPD and MLH1 gene expression. Decrease in MLH1 and XPD mRNA levels in BRAFV600E PTC (but not their protein products) are associated with predictors of poor patient outcomes. Considering the complete subset of patients, MGMT and XRCC2 genes were shown down and upregulated, respectively, in PTC tissues. Low expression of MGMT gene and weak XRCC2 protein expression were correlated with characteristics of tumor aggressiveness. These results suggest that an imbalance in DNA repair gene expression in PTC is associated with aggressive clinicopathological features and BRAFV600E mutation.
Subject(s)
DNA Repair/genetics , Mutation/genetics , Proto-Oncogene Proteins B-raf/genetics , Thyroid Cancer, Papillary/genetics , Thyroid Cancer, Papillary/pathology , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Adult , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasm Invasiveness , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
OBJECTIVE: to evaluate the prognostic value of base excision repair proteins in sporadic colorectal cancer. METHODS: Pre-treatment tumor samples from 72 patients with sporadic colorectal adenocarcinoma were assessed for APC, MPG, Polß, XRCC1 and Fen1 expression by immunohistochemistry. The associations of molecular data were analyzed in relation to clinical features and TNM staging as a prognosis predictor and disease-free survival. RESULTS: Higher levels of MPG, Polß and XRCC1, but not Fen1, were associated with unfavorable pathological outcomes, such as poor cellular differentiation, advanced TNM stages, presence of lymphatic and perineural invasions and metastatic lymph nodes. MPG and Polß overexpression were associated with right-sided CRC. However, only MPG high expression is associated with shorter disease-free survival in CRC patients. CONCLUSIONS: Our results suggest that increased expression of MPG, Polß and XRCC1 are more likely to evolve to poor pathological outcomes, but only the elevated expression of MPG protein predicts recurrence. The BER proteins appear to be suitable candidates to refine the TNM current staging of colorectal cancer.
Subject(s)
Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/metabolism , DNA Glycosylases/metabolism , DNA Polymerase beta/metabolism , X-ray Repair Cross Complementing Protein 1/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/pharmacology , Colorectal Neoplasms/drug therapy , Female , Humans , Male , Middle Aged , Prognosis , Promoter Regions, Genetic/geneticsABSTRACT
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.