Promoter Methylation of the MGRN1 Gene Response to Chemotherapy of Epithelial Ovarian Cancer Patients

Abstract Objective: Aberrant DNA methylation is considered to play a critical role in the chemoresistance of epithelial ovarian cancer (EOC). In this study, we explored the relationship between hypermethylation of the Mahogunin Ring Finger 1 (MGRN1) gene promoter and primary chemoresistance in EOC patients.Methods: Hypermethylation of the MGRN1 promoter region in the cancer tissues of platinum-resistant EOC patients was observed by genome-wide methylation level analysis. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was used to analyze the methylation level of the MGRN1 promoter region. MGRN1 mRNA and protein expression were examined using RT-qPCR and IHC assays, respectively. The effect of MGRN1 methylation on the cellular response to cisplatin was detected by knockdown assays in SKOV3 cells. Additionally, we performed transcriptome analysis using RNA-seq and explored the possible mechanism by which MGRN1 expression affects the resistance of ovarian cancer cells to platinum. Results: The RRBS assay showed that the upstream region of MGRN1 from -1148 to -1064 was significantly hypermethylated in chemoresistant EOC patients (P=1.78×10−7). The MALDI-TOF mass spectrometry assays revealed a strong association between hypermethylation of the MGRN1 upstream region and platinum resistance in patients with EOC. Spearman’s correlation analysis revealed a significantly negative connection between the methylation level of MGRN1 and its expression in EOC. In vitro analysis demonstrated that knockdown of MGRN1 reduced the sensitivity of cells to cisplatin and that expression of EGR1 was significantly decreased in SKOV3 cells with low levels of MGRN1 expression. Similarly, EGR1 mRNA expression was lower in platinum-resistant EOC patients and was positively correlated with MGRN1 mRNA expression. Conclusion: The hypermethylation of the MGRN1 promoter region and low expression of MGRN1 were associated with platinum resistance in EOC patients.

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Hypermethylation of mismatch repair gene hMSH2 associates with platinum-resistant disease in epithelial ovarian cancer

Clinical Epigenetics ◽

10.1186/s13148-019-0748-4 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Hua Tian ◽

Li Yan ◽

Li Xiao-fei ◽

Sun Hai-yan ◽

Chen Juan ◽

...

Keyword(s):

Mass Spectrometry ◽

Ovarian Cancer ◽

Dna Methylation ◽

Epithelial Ovarian Cancer ◽

Upstream Region ◽

Platinum Resistance ◽

Maldi Tof Mass Spectrometry ◽

Platinum Resistant ◽

Aberrant Dna Methylation ◽

Low Expression

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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Promoter Methylation of the MGRN1 Gene Predicts Prognosis and Response to Chemotherapy of High-Grade Serous Ovarian Cancer Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.659254 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiao-fei Li ◽

Hai-yan Sun ◽

Tian Hua ◽

Hai-bo Zhang ◽

Yun-jie Tian ◽

...

Keyword(s):

Ovarian Cancer ◽

Mrna Expression ◽

Promoter Region ◽

Upstream Region ◽

Platinum Resistance ◽

High Grade ◽

Serous Ovarian Cancer ◽

Kaplan Meier ◽

Response To Chemotherapy ◽

Low Expression

Aberrant DNA methylation is considered to play a critical role in the chemoresistance of epithelial ovarian cancer (EOC). In this study, we explored the relationship between hypermethylation of the Mahogunin Ring Finger 1 (MGRN1) gene promoter and primary chemoresistance and clinical outcomes in high-grade serous ovarian cancer (HGSOC) patients. The MALDI-TOF mass spectrometry assays revealed a strong association between hypermethylation of the MGRN1 upstream region and platinum resistance in HGSOC patients. Spearman’s correlation analysis revealed a significantly negative connection between the methylation level of MGRN1 and its expression in HGSOC. In vitro analysis demonstrated that knockdown of MGRN1 reduced the sensitivity of cells to cisplatin and that expression of EGR1 was significantly decreased in SKOV3 cells with low levels of MGRN1 expression. Similarly, EGR1 mRNA expression was lower in platinum-resistant HGSOC patients and was positively correlated with MGRN1 mRNA expression. Kaplan-Meier analyses showed that high methylation of the MGRN1 promoter region and low expression of MGRN1 were associated with worse survival of HGSOC patients. In multivariable models, low MGRN1 expression was an independent factor predicting poor outcome. Furthermore, low expression of EGR1 was also been confirmed to be significantly related to the poor prognosis of HGSOC patients by Kaplan-Meier. The hypermethylation of the MGRN1 promoter region and low expression of MGRN1 were associated with platinum resistance and poor outcomes in HGSOC patients, probably by altering EGR1 expression.

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MiR-200c-3p Contrasts PD-L1 Induction by Combinatorial Therapies and Slows Proliferation of Epithelial Ovarian Cancer through Downregulation of β-Catenin and c-Myc

Cells ◽

10.3390/cells10030519 ◽

2021 ◽

Vol 10 (3) ◽

pp. 519

Author(s):

Eleni Anastasiadou ◽

Elena Messina ◽

Tiziana Sanavia ◽

Lucia Mundo ◽

Federica Farinella ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Therapeutic Strategy ◽

Target Genes ◽

Ovarian Cancer Cells ◽

Oncogenic Signaling ◽

Experimental Conditions ◽

Skov3 Cells ◽

In Silico Analyses ◽

Post Therapy

Conventional/targeted chemotherapies and ionizing radiation (IR) are being used both as monotherapies and in combination for the treatment of epithelial ovarian cancer (EOC). Several studies show that these therapies might favor oncogenic signaling and impede anti-tumor responses. MiR-200c is considered a master regulator of EOC-related oncogenes. In this study, we sought to investigate if chemotherapy and IR could influence the expression of miR-200c-3p and its target genes, like the immune checkpoint PD-L1 and other oncogenes in a cohort of EOC patients’ biopsies. Indeed, PD-L1 expression was induced, while miR-200c-3p was significantly reduced in these biopsies post-therapy. The effect of miR-200c-3p target genes was assessed in miR-200c transfected SKOV3 cells untreated and treated with olaparib and IR alone. Under all experimental conditions, miR-200c-3p concomitantly reduced PD-L1, c-Myc and β-catenin expression and sensitized ovarian cancer cells to olaparib and irradiation. In silico analyses further confirmed the anti-correlation between miR-200c-3p with c-Myc and β-catenin in 46 OC cell lines and showed that a higher miR-200c-3p expression associates with a less tumorigenic microenvironment. These findings provide new insights into how miR-200c-3p could be used to hold in check the adverse effects of conventional chemotherapy, targeted therapy and radiation therapy, and offer a novel therapeutic strategy for EOC.

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Rs3802278 in 3’-UTR of SULF1 associated with platinum resistance and survival in Chinese epithelial ovarian cancer patients

Journal of Chemotherapy ◽

10.1080/1120009x.2021.1913702 ◽

2021 ◽

pp. 1-6

Author(s):

Feiyue Zeng ◽

Yujie Liu ◽

Qianying Ouyang ◽

Zeen Sun ◽

Keqiang Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Patients ◽

Platinum Resistance

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Clinical Importance of Myc Family Oncogene Aberrations in Epithelial Ovarian Cancer

JNCI Cancer Spectrum ◽

10.1093/jncics/pky047 ◽

2018 ◽

Vol 2 (3) ◽

Cited By ~ 1

Author(s):

MoonSun Jung ◽

Amanda J Russell ◽

Catherine Kennedy ◽

Andrew J Gifford ◽

Kylie-Ann Mallitt ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Mrna Expression ◽

Clinical Significance ◽

Copy Number ◽

Family Members ◽

Activity Score ◽

Gene Copy ◽

Myc Oncogene ◽

Statistical Algorithm

Abstract Background The Myc oncogene family has been implicated in many human malignancies and is often associated with particularly aggressive disease, suggesting Myc as an attractive prognostic marker and therapeutic target. However, for epithelial ovarian cancer (EOC), there is little consensus on the incidence and clinical relevance of Myc aberrations. Here we comprehensively investigated alterations in gene copy number, expression, and activity for Myc and evaluated their clinical significance in EOC. Methods To address inconsistencies in the literature regarding the definition of copy number variations, we developed a novel approach using quantitative polymerase chain reaction (qPCR) coupled with a statistical algorithm to estimate objective thresholds for detecting Myc gain/amplification in large cohorts of serous (n = 150) and endometrioid (n = 80) EOC. MYC, MYCN, and MYCL1 mRNA expression and Myc activity score for each case were examined by qPCR. Kaplan–Meier and Cox-regression analyses were conducted to assess clinical significance of Myc aberrations. Results Using a large panel of cancer cell lines (n = 34), we validated the statistical algorithm for determining clear thresholds for Myc gain/amplification. MYC was the most predominantly amplified of the Myc oncogene family members, and high MYC mRNA expression levels were associated with amplification in EOC. However, there was no association between prognosis and increased copy number or gene expression of MYC/MYCN/MYCL1 or with a pan-Myc transcriptional activity score, in EOC, although MYC amplification was associated with late stage and high grade in endometrioid EOC. Conclusion A systematic and comprehensive analysis of Myc genes, transcripts, and activity levels using qPCR revealed that although such aberrations commonly occur in EOC, overall they have limited impact on outcome, suggesting that the biological relevance of Myc oncogene family members is limited to certain subsets of this disease.

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