Upregulation of exonuclease 1 caused by homology-dependent repair confers cisplatin resistance to gastric cancer cells

Abstract

The homology-dependent repair (HDR) pathway is involved in DNA damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents, including cisplatin (CDDP). Here, we explored the interactions between EXO1, a core gene in the HDR pathway, and CDDP resistance in gastric cancer (GC). Using bioinformatics analysis, we identified the HDR pathway as the most amplified pathway in DDR in GC. In addition, EXO1 was the core gene in the HDR pathway and showed the most significant amplification in GC. The amplification of EXO1 resulted in higher EXO1 expression in cancerous tissues, with malignant prognostic effects. Moreover, we upregulated or downregulated EXO1 in GC cells to examine its effects on the cell malignant phenotype and CDDP resistance in vitro and in vivo. Depletion of EXO1 inhibited cell proliferatory, migratory and invasive activities, and provided apoptosis resistance to GC cells. EXO1 expression was elevated in CDDP-resistant cells. Ectopic expression of EXO1 increased the resistance of GC cells to CDDP, while downregulation of EXO1 increased the sensitivity of GC cells. Taken together, our study indicates that the HDR pathway is an important player in CDDP resistance in GC through the regulation of EXO1.

A high-throughput exonuclease assay based on the fluorescent base analog 2-aminopurine

“…More than ten exo- and endonucleases are active in different forms of mammalian DNA repair (reviewed in 38 ). Furthermore, upregulation of EXO1 is associated with increased malignancies and correlated with a poor prognosis 39,40 , whereas the inhibition of APE2 has shown to reduce growth and malignancies 41,42 . Finally, also ExoN, the replicative exonuclease of the SARS-CoV-2 virus is the target of novel promising antiviral drugs 43 .…”

Key candidate genes and pathways in T lymphoblastic leukemia/lymphoma identified by bioinformatics and serological analyses

“…The product of EXO1 gene has exonuclease activity, and its function is mainly involved in mismatch repair and recombination. It is upregulated in tumor tissues, including gastric cancer, lung adenocarcinoma, and ovarian cancer (36)(37)(38). Tumor occurrence and development can be mediated through involvement in hypoxia related pathways, which are usually caused by an imbalance in the supply and demand of nutrients in the tumor microenvironment.…”

“…Under hypoxic conditions, cancer cells secrete angiogenic factors to promote abnormal angiogenesis. In addition, hypoxia increases the malignancy of tumors and allows cancer cells to invade and metastasize, leading to the insensitivity of cancer cells to chemotherapy or radiotherapy (37,42). In contrast, the depletion of EXO1 inhibits cell proliferation, migration, and invasive activity of tumors (37).…”

“…In addition, hypoxia increases the malignancy of tumors and allows cancer cells to invade and metastasize, leading to the insensitivity of cancer cells to chemotherapy or radiotherapy (37,42). In contrast, the depletion of EXO1 inhibits cell proliferation, migration, and invasive activity of tumors (37). This study determined that the concentrations of HGB and EPO in the peripheral blood of patients with T-ALL/T-LBL are clinically significant in assessing these conditions.…”

High-Throughput Exonuclease Assay Based on the Fluorescent Base Analogue 2-Aminopurine

“…More than 10 exo- and endonucleases are active in different forms of mammalian DNA repair (reviewed in ref ). Furthermore, upregulation of EXO1 is associated with increased malignancies and correlated with a poor prognosis, , whereas the inhibition of APE2 has shown to reduce growth and malignancies. , Finally, ExoN, the replicative exonuclease of the SARS-CoV-2 virus, is also the target of novel promising antiviral drugs …”