RESUMO
The homology-dependent repair (HDR) pathway is involved in deoxyribonucleic acid (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 exonuclease 1 (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. The 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.
Assuntos
Antineoplásicos , Enzimas Reparadoras do DNA , Resistencia a Medicamentos Antineoplásicos , Exodesoxirribonucleases , Neoplasias Gástricas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/metabolismo , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Exodesoxirribonucleases/genética , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para CimaRESUMO
Ulcerative colitis (UC) is a chronic and relapsing inflammatory intestinal disease. Although the morbidity of UC has increased notably in recent years, effective therapeutic treatment remains unsatisfactory. Astragaloside IV (ASI), a monomeric compound isolated from the traditional Chinese medicine herb Ligusticum chuanxiong, exhibits anti-inflammatory effects. The present study aimed to investigate the therapeutic effects of ASI on experimental UC in vitro and in vivo. Cell proliferation was detected via a Cell Counting Kit-8 assay in vitro. In addition, the concentrations of the inflammatory factors myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and nitric oxide (NO) in the colon tissues were determined by ELISA. Western blot analysis was used to examine phosphorylated transcription factor p65 (p-p65), p-inhibitor of NF-κB (IκB), claudin-1 and tight junction protein ZO-1 (ZO-1) protein levels in vitro and in vivo, respectively. The results indicated that lipopolysaccharide (LPS) significantly increased the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 in CCD-18Co cells, which was markedly ameliorated by ASI. In addition to the inhibition of pro-inflammatory cytokines, ASI decreased the levels of p-p65 and p-IκB proteins. In addition, ASI decreased the disease activity index scores, and increased colon lengths in dextran sulfate sodium-induced UC mice. ASI also decreased the levels of the pro-inflammatory factors MPO, TNF-α, IL-1ß, IL-6 and NO, and upregulated the expression of claudin-1 and ZO-1 in colon tissues. Therefore, ASI was effective in ameliorating experimental UC in vitro and in vivo via the inhibition of inflammatory molecules, and the downregulation of NF-κB signaling. In conclusion, ASI may serve as a potential therapeutic agent for the treatment of UC.