Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer

Abstract Purpose One major reason of the high mortality of epithelial ovarian cancer (EOC) is due to platinum-based chemotherapy resistance. Aberrant DNA methylation may be a potential mechanism underlying the development of platinum resistance in EOC. The purpose of this study is to discover potential aberrant DNA methylation that contributes to drug resistance. Methods By initially screening of 16 platinum-sensitive/resistant samples from EOC patients with reduced representation bisulfite sequencing (RRBS), the upstream region of the hMSH2 gene was discovered hypermethylated in the platinum-resistant group. The effect of hMSH2 methylation on the cellular response to cisplatin was explored by demethylation and knockdown assays in ovarian cancer cell line A2780. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was employed to examine the methylation levels of hMSH2 upstream region in additional 40 EOC patient samples. RT-qPCR and IHC assay was used to detect the hMSH2 mRNA and protein expression in extended 150 patients. Results RRBS assay discovered an upstream region from − 1193 to − 1125 of hMSH2 was significant hypermethylated in resistant EOC patients (P = 1.06 × 10−14). In vitro analysis demonstrated that global demethylation increased cisplatin sensitivity along with a higher expression of the hMSH2 mRNA and protein. Knockdown hMSH2 reduced the cell sensitivity to cisplatin. MALDI-TOF mass spectrometry assay validated the strong association of hypermethylation of hMSH2 upstream region with platinum resistance. Spearman’s correlation analysis revealed a significantly negative connection between methylation level of hMSH2 upstream region and its expression. The Kaplan-Meier analyses showed the high methylation of hMSH2 promoter region, and its low expressions are associated with worse survival. In multivariable models, hMSH2 low expression was an independent factor predicting poor outcome (P = 0.03, HR = 1.91, 95%CI = 1.85–2.31). Conclusion The hypermethylation of hMSH2 upstream region is associated with platinum resistant in EOC, and low expression of hMSH2 may be an index for the poor prognosis.

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GRP137 promotes cell proliferation and metastasis through regulation of the PI3K/AKT pathway in human ovarian cancer

Tumori Journal ◽

10.5301/tj.5000703 ◽

2018 ◽

Vol 104 (5) ◽

pp. 330-337 ◽

Cited By ~ 4

Author(s):

Li-qian Zhang ◽

Su-qing Yang ◽

Xiang-dong Qu ◽

Xian-jun Chen ◽

Hong-sheng Lu ◽

...

Keyword(s):

Ovarian Cancer ◽

G Protein ◽

Biological Activities ◽

Xenograft Model ◽

Akt Pathway ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

G Protein Coupled Receptor ◽

Skov3 Cells ◽

G Protein Coupled

Purpose: Ovarian cancer is one of the leading causes of death for women worldwide. The present study aims to investigate the role of G protein-coupled receptor 137 (GPR137) in the biological activities of ovarian cancer cells. Methods: (QUERY: Please supply Methods for Abstract) Results: G protein-coupled receptor 137 was highly expressed in clinical ovarian cancer tissues and exhibited the highest protein levels in SKOV3 cells and OVCAR3 cells. Knockdown of GPR137 caused significant decreases in cell proliferative rates and colony formation abilities in SKOV3 cells and OVCAR3 cells and also inhibited the in vivo tumorigenesis in a xenograft model. It was observed that knockdown of GPR137 inhibited cell motility by up to 40% in SKOV3 cells and approximately 65% in OVCAR3 cells in wound-healing assay. Cell migration abilities were consistently inhibited by 68.2% in SKOV3 cells and 59.3% in OVCAR3 cells, whereas cell invasion abilities were inhibited by 64.0% and 74.2% in SKOV3 and OVCAR3 cells, respectively, after knockdown of GPR137. When GPR137 was depleted, epithelial markers were increased, while mesenchymal markers decreased. Conclusions: Our data suggest that GPR137 plays pro-oncogenic roles in ovarian cancer via regulation of the PI3K/AKT pathway. These observations might pave new insights into therapeutic strategies against human ovarian cancer.

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Fucosterol Suppresses the Progression of Human Ovarian Cancer by Inducing Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

Marine Drugs ◽

10.3390/md18050261 ◽

2020 ◽

Vol 18 (5) ◽

pp. 261 ◽

Cited By ~ 1

Author(s):

Hyocheol Bae ◽

Jin-Young Lee ◽

Gwonhwa Song ◽

Whasun Lim

Keyword(s):

Ovarian Cancer ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Cancer Cells ◽

Cell Cycle Progression ◽

Xenograft Model ◽

Tumor Formation ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Anticancer Properties

Ovarian cancer is difficult to diagnose early and has high rates of relapse and mortality. Therefore, the treatment of ovarian cancer needs to be improved. Recently, several studies have been conducted in an attempt to develop anticancer drugs from naturally derived ingredients. Compared to traditional chemotherapy, natural compounds can overcome drug resistance with lower side effects. Fucosterol, a phytosterol present in brown algae, reportedly possesses many bioactive effects, including anticancer properties. However, the anticancer effects of fucosterol in ovarian cancer remain unexplored. Therefore, we investigated the effects of fucosterol on progression in human ovarian cancer cells. Fucosterol inhibited cell proliferation and cell-cycle progression in ovarian cancer cells. Additionally, fucosterol regulated the proliferation-related signaling pathways, the production of reactive oxygen species, mitochondrial function, endoplasmic reticulum stress, angiogenesis, and calcium homeostasis. Moreover, it decreased tumor formation in a zebrafish xenograft model. These results indicate that fucosterol could be used as a potential therapeutic agent in ovarian cancer.

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