Abstract
Objective: Chemoresistance is a major challenge in epithelial ovarian cancer (EOC) treatment. Chromatin target of protein arginine methyltransferase (CHTOP) was identified as a potential biomarker in chemoresistant EOC cell lines using label-free LC-MS/MS quantitative proteomics. Thus, the aim of this study is to investigate the role of CHTOP in chemoresistant EOC and the underlying mechanism.Methods: The expression of CHTOP in human ovarian cancer cells and tissues was detected using immunofluorescence (IF), western blot (WB), and immunohistochemistry (IHC), respectively. Flow cytometry and TUNEL assay were employed to detect the effect of CHTOP knockdown (KD) in chemoresistant EOC cell apoptosis, while colony and sphere formation assays were used to evaluate its effect on cell stemness. The association of CHTOP with cell metastasis was determined using Matrigel invasion and wound-healing assays.Results: The higher level expression of CHTOP protein was found in chemoresistant EOC cells as compared to their sensitive parental cells or normal epithelial ovarian cells. Results from IHC and bioinformatic analysis showed CHTOP was highly expressed in human ovarian cancer tissues and associated with a poor progression-free survival in patients. In addition, CHTOP KD significantly enhanced cisplatin-induced apoptosis, reduced the stemness of chemoresistant EOC cells, and decreased their metastatic potential.Conclusion: Our findings suggest that CHTOP is associated with apoptosis, stemness, and metastasis in chemoresistant EOC cells and might be a promising target to overcome chemoresistance in EOC treatment.
Highlights
Ovarian cancer is the most lethal gynecological malignancies worldwide
Results from Western Blot (WB) and IF showed that chromatin target of protein arginine methyltransferase (CHTOP) was highly expressed in Epithelial ovarian cancer (EOC)-cis and metastatic cells (SKOV3 and OV90) as compared to sensitive cells and normal epithelial ovarian cells (HOSE) (Figure 1C)
Our results showed that CHTOP was highly expressed in cisplatin-resistant and metastatic EOC cell lines, and no positive expression was found in normal epithelial ovarian cells, indicating that CHTOP may play an essential role in EOC chemoresistance and metastasis
Summary
Ovarian cancer is the most lethal gynecological malignancies worldwide. In 2017, over 22,000 women were diagnosed with ovarian cancer and ∼ 14,080 died of the disease [1]. Epithelial ovarian cancer (EOC) accounts for ∼ 85–95% of all ovarian cancer cases, and more than 70% of EOC patients were diagnosed in the advanced stages due to poor early screening techniques [2]. Chemotherapy is the mainstay for the treatment of ovarian cancer. Despite an initial high response rate to chemotherapy, over 85% of advanced EOC patients experienced cancer relapse within 18 to 24 months because of the clonal expansion of either acquired or innate drug-resistant tumor cells. The 5-year overall survival rate for advanced ovarian cancer is only ∼ 30% [3]. Chemoresistance is a major obstacle to long-term remission and effective strategies to overcome chemoresistance would have a positive clinical impact
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