RESUMO
BACKGROUND: Atrazine (ATZ) is a triazine herbicide that is widely used in agriculture and has been detected in surface and underground water. Recently, laboratory and epidemiological research have found that the bioaccumulation of ATZ in the environment leads to biotoxicity in the human immune and endocrine systems and results in tumor development. OBJECTIVE: To investigate the effects of ATZ exposure on epithelial ovarian cancer (EOC) cells and elucidate the potential mechanisms governing these effects. MATERIALS AND METHODS: The human EOC cell lines Skov3 and A2780 were used in this study to explore the effects and mechanisms of ATZ exposure on EOC. The mouse embryonic osteoblastic precursor MC3T3-E1 cells served as the control cells to determine the effects of ATZ on cancer cell lines. After exposure to ATZ, the MTT assay, flow cytometry, the colony formation assay, immunohistochemical staining, the cell scratch assay, and the Transwell assay were used to evaluate the proliferative activity, invasion, and migration capabilities of EOC cell lines. Moreover, flow cytometry was also applied to detect the level of reactive oxygen species (ROS) in these two EOC cell lines, as well as the MC3T3-E1 cells. To further illustrate the underlying mechanisms governing the effect of ATZ on EOC, real-time PCR and Western blotting were employed to assess the transcription and the expression level of Stat3 signaling pathway-related genes in Skov3 and MC3T3-E1 cells. RESULTS: The results showed that following ATZ treatment, the cell proliferation, migration, and invasion potencies of Skov3 and A2780 cells were increased compared to those of the control group. Meanwhile, the ROS levels of EOC and MC3T3-E1 cells were notably elevated after ATZ treatment. In Skov3 cells, the expression levels of p53 and p21 were downregulated, while those of Cyclin E, vascular endothelial growth factor (VEGF), matrix metallopeptidase 2 (MMP2), MMP9, signal transducers and activators of transcription 3 (Stat3), and p-Stat3 were upregulated by ATZ treatment. In MC3T3-E1 cells, however, ATZ treatment did not affect the level of p53/p21 mRNA compared to the control groups. Moreover, there was no significant change in the expression levels of Stat3 and p-Stat3 in MC3T3-E1 cells exposed to ATZ. This phenomenon was observed while the proliferation rate was enhanced in MC3T3-E1 cells by ATZ. CONCLUSIONS: The results of this study suggest that ATZ effectively promotes the proliferation and metastasis of EOC cells through the Stat3 signaling pathway by inducing low levels of ROS. Additionally, although ATZ might also induce proliferative potential in normal cells, the mechanisms governing its effects in these cells might be different from those in EOC cells.
RESUMO
DNA double-strand breaks (DSBs) are an important mechanism of chemotherapy in epithelial ovarian cancer (EOC). Kin17 DNA and RNA binding protein (KIN17) serves a crucial role in DSB repair. In the present study, the association between KIN17 and EOC, and the effects of KIN17 on EOC cells in vitro were evaluated. A bioinformatics method was used to determine the mRNA expression levels of KIN17 in EOC and its association with EOC prognosis including overall survival (OS) and progression free survival (PFS) time. Western blotting and immunohistochemical staining were used to evaluate the expression levels of KIN17 in EOC samples. Kaplan-Meier and Cox regression analyses were utilized to analyze risk factors for the OS of patients with EOC. A Cell Counting Kit-8 assay was performed to explore the roles of KIN17 in SKOV3 cells. Both the transcription and expression of KIN17 were upregulated in EOC tissues. Furthermore, the OS of patients with EOC with high mRNA expression levels of KIN17 was shorter than that of patients with EOC with low expression levels. High KIN17 expression was an independent risk factor for EOC prognosis. Furthermore, KIN17 knockdown inhibited the proliferation of SKOV3 cells, enhanced the sensitivity of the cells to cisplatin and inhibited the migration ability of the cells. These results suggested that KIN17 may act as an ideal candidate for therapy and as a prognostic biomarker of EOC, although the underlying mechanisms require further exploration.
RESUMO
Ovarian cancer is a deadly gynecologic cancer, and the majority of patients with ovarian cancer experience relapse after traditional treatment. Cisplatin (DDP) is a common chemotherapeutic drug for ovarian cancer, but many patients acquire DDP-resistance after treatment with long-term chemotherapy. The mechanisms of drug-resistance in ovarian cancer are not clear, and we thus aim to investigate novel targets for DDP-resistant ovarian cancer. Differential analysis, KEGG pathway enrichment and protein interaction networks were employed to identify the key genes related to DDP-resistance in ovarian cancer. Subsequently, cell viability, apoptosis and migration were measured to assess the effect of fibroblast growth factor receptor 3 (FGFR3) on DDP-resistance. Further, Pearson correlation analysis and co-expression analysis were used to explore the downstream pathways of FGFR3, and the function of FGFR3 and its downstream targets were further demonstrated by in vitro and nude mice experiments. FGFR3 were expressed at high levels in DDP-resistant ovarian cancer cells. FGFR3 silencing suppressed the activation of PI3K/AKT pathway and impeded the drug-resistance and development of tumor cells. Afterwards, we found that FGFR3 was co-expressed with epidermal growth factor receptor (EGFR). FGFR3 overexpression elevated EGFR phosphorylation and activated PI3K/AKT signaling. Furthermore, in nude mice, silencing FGFR3 and inhibiting EGFR phosphorylation were observed to promote the therapeutic effect of DDP. In conclusion, FGFR3 overexpression enhances DDP-resistance of ovarian cancer by promoting EGFR phosphorylation and further activating PI3K/AKT pathway. This study may offer promising targets for DDP-resistant ovarian cancer.
