DNA base excision repair proteins APE‐1 and XRCC‐1 are overexpressed in oral tongue squamous cell carcinoma

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Excerpt

Oral squamous cell carcinoma (OSCC) accounts for more than 90% of the malignant tumors of the oral cavity and for 38% of the head and neck malignant neoplasms 1. Oral tongue is the most affected site (OTSCC), and most patients are diagnosed with locoregional advanced disease, with a 5‐year survival rate around 40% 1. Surgery remains the primary treatment modality of choice for patients with OTSCC, with postoperative radiotherapy or concurrent chemoradiotherapy being the standard treatment over the past few decades. However, the treatment response and outcomes vary among patients 2. Despite all scientific and technological advances regarding OTSCC, its unpredictable clinical course brings to light the important role of the host's genetic characteristics in the etiopathogenesis and biological behavior of this tumor 1. From this perspective, the development of predictive and prognostic biomarkers for OTSCC would represent a significant advance, collaborating in the future development of therapeutic targets.
Among the several potential biomarkers, DNA repair genes and their corresponding proteins stand out. DNA repair systems play a critical role in protecting the human genome from damage caused by environmental carcinogens, such as alcohol, tobacco, and ultraviolet radiation. Mutations in DNA repair genes may be responsible for tumor development and resistance of malignant cells to chemotherapeutic agents 6. The major pathway for oxidative DNA damage repair is the base excision repair (BER) pathway 6. Key genes such as apurinic/apyrimidinic endonuclease 1 (APE‐1) and X‐ray repair cross‐complementing 1 (XRCC‐1) are required for viability and efficient repair of DNA damage in the BER pathway 6. APE‐1 is the main apurinic/apyrimidinic (AP) endonuclease in eukaryotic cells 8. The two best characterized functions of APE‐1 are production of a DNA primer for repair synthesis and coordination of the repair activities of other BER proteins 8. Following hydrolysis by a DNA glycosylase, APE‐1 processes the AP site by making an incision in the phosphodiester backbone immediately 5′ to the abasic site 8. Subsequently, BER‐associated proteins polymerize the replacement nucleotide(s) and ligate the recent polymerized nucleotides to the final sequence 8. Additionally, APE‐1 is a multifunctional protein that participates in other critical cellular processes, including oxidative stress response; regulation of transcription factors, such as Fos, Jun, NF‐κB, and p53; cell cycle control; and apoptosis 7. Substantial evidence indicates an important role for XRCC‐1 in the single‐strand break repair (SSBR) and BER 7. Apparently devoid of any enzymatic activity, this protein is thought to act as a scaffolding protein for other repair factors. XRCC‐1 has been shown to physically interact with several enzymes known to be involved in SSBRs, including DNA ligase IIIa, DNA polymerase β, APE‐1, polynucleotide kinase/phosphatase, poly(ADP‐ribose) polymerases 1 and 2 (PARP‐1 and PARP‐2), and 8‐oxoguanine DNA glycosylase (OGG1) 4.
The expression of proteins associated with DNA repair, including APE‐1 and XRCC‐1, has been demonstrated in several types of cancer, including carcinomas of cervix, ovary, prostate, gastro‐esophageal tract, pancreas, lung, bladder, and head and neck, as well as in osteosarcoma and pediatric ependymoma 3. The goal of this study was to investigate the immunoexpression of APE‐1 and XRCC‐1 and its association with clinical, histologic, and survival parameters in a cohort of OTSCC in order to investigate a possible prognostic value of these proteins.
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