The role of apoptosis gene methylation in the pathogenesis of breast and ovarian cancer

Актуальность. Рак молочной железы (РМЖ) и рак яичников (РЯ) наиболее часто диагностируемые типы рака у женщин, характеризующиеся своими клиническими особенностями, включая тяжёлое течение болезни и неблагоприятный прогноз. В России ежегодно умирают от этих видов опухолей более 29000 человек. Важную роль в патогенезе рака играет аберрантное метилирование CpG-островков промоторных областей в генах системы апоптоза. Ранее появились сообщения о гиперметилировании генов DAPK1, APAF1, BCL2, TP53 в некоторых видах опухолей. Однако, данные о роли метилирования этой группы генов в прогрессии РМЖ и РЯ представлены единичными сообщениями, а для генов BIM, BAX до настоящего момента до сих пор не представлены. Целью настоящей работы явилось исследование роли метилирования шести генов системы апоптоза, а именно, про-апоптозных генов APAF1, DAPK1, BIM, BAX, TP53, а также анти-апоптозного гена BCL2 в прогрессии РМЖ и РЯ. Методы. Образцы опухолей РМЖ и РЯ собраны и клинически охарактеризованы в НИИ клинической онкологии ФГБУ РОНЦ имени Н.Н. Блохина. Высокомолекулярную ДНК выделяли из ткани стандартным методом. Анализ уровня метилирования проводили с применением бисульфитной конверсии ДНК и количественной метилспецифичной ПЦР (МС-ПЦР) с детекцией в реальном времени. Для оценки значимости различий между исследуемыми группами применяли непараметрический критерий Манна-Уитни для независимых выборок. Результаты. Показано статистически значимое (р < 0,05) увеличение уровня метилирования генов BCL2, DAPK1 и BAX в образцах опухолей по сравнению с парной гистологически нормальной тканью яичников. При РМЖ наблюдали гиперметилирование четырёх про-апоптозных генов (DAPK1, APAF1, BIM, BAX) и, напротив, гипометилирование BCL2. Кроме того, нами выявлено, что уровень метилирования промоторных CpG-островков генов DAPK1, BIM, BAX, APAF1 статистически значимо коррелирует с клинической стадией (р < 0,001), с размером опухоли (р < 0,02), а для генов BIM, BAX - с метастазированием (р < 0,02) при РМЖ. Также нами было показано, что уровень метилирования гена BAX значимо коррелирует с клинической стадией; размером опухоли и с метастазированием при РЯ (р < 0,05). Заключение. Полученные нами данные показывают, какую роль метилирование исследованных генов апоптоза играет в возникновении и прогрессии РЯ и РМЖ и позволяют оценить их влияние на патофизиологический профиль опухолей яичников и молочной железы. Background. Breast cancer (BC) and ovarian cancer (OC) are the most commonly diagnosed types of cancer in women, which are characterized by severe course and unfavorable prognosis. In Russia, more than 29,000 people die from these types of tumors every year. Aberrant methylation of CpG islands located in the promoter regions of apoptosis genes play an important role in the pathogenesis of this disease. Previously, there were reports of hypermethylation of the DAPK1, APAF1, BCL2, and TP53 genes in some types of tumors. However, reports of the role of the gene methylation in the progression of BC and OC are scarce, and for the BIM and BAX genes, this information is absent. The aim of this study was to elucidate the role of methylation for six genes of the apoptosis system, namely, the pro-apoptotic genes APAF1, DAPK1, BIM, BAX, TP53, as well as the anti-apoptotic gene BCL2, in the progression of BC and OC. Methods. Samples of breast and ovarian tumors were collected and clinically characterized at the N.N. Blokhin Research Institute of Clinical Oncology. High molecular weight DNA was isolated from the tissue using standard methods. The methylation degree was assessed by bisulfite DNA conversion and real-time quantitative methylation-specific PCR (MS-PCR). Significance of differences between the study groups was determined with the nonparametric Mann-Whitney test for independent samples. Results. The degree of BCL2, DAPK1, and BAX gene methylation was significantly increased (p<0.05) in tumor samples compared to matched histologically normal ovarian tissue. Hypermethylation of four pro-apoptotic genes (DAPK1, APAF1, BIM, and BAX) and, in contrast, hypomethylation of BCL2 were observed in BC. In addition, in BC, the promoter CpG island methylation of DAPK1, BIM, BAX, APAF1 genes significantly correlated with the clinical stage (p < 0.001), and with the tumor size (p < 0.02) whereas for BIM and BAX genes, the methylation degree correlated with metastasis (p < 0.02). In OC, the methylation degree of the BAX gene significantly correlated with the clinical stage, with the tumor size, and with metastasis (p < 0.05). Conclusion. The results of this study showed the role of apoptosis gene methylation in the development and progression of BC and OC and also allowed evaluating their influence on the pathophysiological profile of ovarian and breast tumors.

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MiR-624-5p enhances cell resistance against cisplatin via PDGFRA/Stat3/PI3K axis in ovarian cancer

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i4.3 ◽

2020 ◽

Vol 19 (4) ◽

pp. 691-698

Author(s):

Lin I-Ju ◽

Tian YongJie

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Cell Line ◽

Cell Lines ◽

Clinical Stage ◽

Luciferase Reporter Assay ◽

Luciferase Reporter ◽

Reporter Assay

Purpose: The purpose of this study was to evaluate the role of miR-624-5p in ovarian cancer.Methods: MiR-624-5p expression in ovarian cancer {OC) cell lines and normal cells (NCs) was evaluated and compared the differential miR-624-5p in OC A2780 cells and cisplatin-resistant OC cell line (A2780/DDP). CCK-8 was used to evaluate changes in cell viability of the A2780 and A2780/DDP cell lines as well as silenced miR-624-5p. Western Blot examined the Stat3 and phosphorylated Pi3k. The binding between PDGFRA and miR-624-5p was predicted on Targetscan and verified through Luciferase Reporter Assay. The role of PDGFRA in A2780/DDP by overexpressing PDGFRA was evaluated by RT-qPCR and CCK-8 assays. RT-qPCR assay also measured miR-624-5p expression responsive to different dosages of cisplatin and CCK8 examined viability levels correspondingly. In addition, the interplay of PDGFRA and miR-624-5p by combined downregulation of both miR-624-5pand PDGFRA were evaluated.Results: OC cells had higher miR-624-5p expression than NCs but lower compared to cisplatinresistant A2780/DDP cells. A2780/DDP cells had higher viability than OC cell line A2780. Stat3 and phosphorylated PI3K were activated in A2780/DDP cells. Silencing miR-624-5p led to lower viability inA2780/DDP cells. miR-624-5p expression dropped as the cisplatin concentration increased, resulting in decreasing viability respectively. Luciferase Reporter assay validated the binding of miR-624-5p and PDGFRA in A2780/DDP cells. Overexpressed PDGFRA induced lower cell viability in A2780/DDP cells. Downregulation of PDGFRA partially restored the lowered viability and inhibited Stat3 as well as phosphorylated Pi3k induced by miR-624-5p inhibitor.Conclusion: MiR-624-5p could add to the cellular resistance to cisplatin in OC in-vitro model, which indicated that it might help unveil the mystery of drug-resistance in clinical stage of ovarian cancer. Keywords: MiR-624-5p, resistance, cisplatin, PDGFRA/Stat3/PI3K, ovarian cancer

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Hypermethylation of the microRNA miR-124, miR-125b, miR-127, and miR-129 in ovarian carcinoma is involved in suppression of their expression and associated with both the development and progression of ovarian cancer

Almanac of Clinical Medicine ◽

10.18786/2072-0505-2019-47-003 ◽

2019 ◽

Vol 47 (1) ◽

pp. 47-53

Author(s):

E. A. Braga ◽

I. V. Pronina ◽

D. O. Utkin ◽

E. A. Filippova ◽

A. M. Burdennyy ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Ovarian Tissue ◽

Clinical Stage ◽

Methylation Status ◽

Metastatic Spread ◽

Aberrant Methylation ◽

Ovarian Carcinomas ◽

Microrna Gene ◽

Microrna Genes

Rationale: We have previously identified a group of microRNA genes (MIR-107, MIR-1258, MIR-130b, MIR-34b/c, MIR-9-1, MIR-9-3 et al.), whose methylation was involved into the development and progression of ovarian cancer. Aim: To expand the range of microRNA genes hypermethylated in ovarian cancer and to study the role of this modification in the pathogenesis and progression of ovarian cancer. Materials and methods: The study was performed on a series of 76 ovarian cancer and 13 peritoneal metastases samples. The method of bisulfite DNA conversion followed by methylation-specific polymerase chain reaction (PCR) was used to assess the methylation status of the microRNA genes; the expression of these genes was measured by quantitative real-time PCR. Results: Compared to histologically unchanged ovarian tissue, there was a significant increase in methylation frequencies in the tumor samples for 6 microRNA genes studied: MIR-124-1, MIR-124-2, MIR-124-3, MIR-125B-1, MIR-127, and MIR-129-2 (p ≤ 10-3). The expression level of 4 microRNAs (miR-124-3p, miR-125b-5p, miR-127-5p, miR-129-5p) encoded by these genes was suppressed, with a significant correlation between changes in their expression levels and the gene methylation (rs = 0.63–0.94, p ≤ 10-4). In addition, there were statistically significant associations between methylation of 5 genes (MIR-124-2, MIR-124-3, MIR-125B-1, MIR-127, and MIR-129-2) and the parameters of cancer progression, such as its clinical stage, metastatic spread, tumor size and invasion, and to a lesser extent with a decrease in the differentiation grade. The association of 5 microRNA genes with metastatic spread was confirmed by the analysis of peritoneal macro-metastases from 13 patients. Conclusion: We have demonstrated the functional significance of aberrant methylation in a group of microRNA genes for suppression of their expression in ovarian carcinomas. There is an association of microRNA gene hypermethylation with the progression of ovarian cancer, including metastatic spread to the peritoneum.

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Role of solid tumor size compared with whole tumor size to predict pathologic malignant grade or prognosis in clinical stage IA lung adenocarcinoma: A multicenter study.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.7058 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 7058-7058

Author(s):

Y. Tsutani ◽

Y. Ibuki ◽

T. Ikeda ◽

Y. Miyata ◽

H. Nakayama ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Multicenter Study ◽

Solid Tumor ◽

Tumor Size ◽

Clinical Stage ◽

Clinical Stage Ia ◽

Stage Ia ◽

Malignant Grade

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A Retrospective Cross-Sectional Cohort Trial Assessing the Prevalence of MTHFR Polymorphisms and the Influence of Diet on Platinum Resistance in Ovarian Cancer Patients

Cancers ◽

10.3390/cancers13205215 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5215

Author(s):

Caitlin Phillips-Chavez ◽

Jermaine Coward ◽

Michael Watson ◽

Janet Schloss

Keyword(s):

Ovarian Cancer ◽

Survival Rate ◽

Serum Folate ◽

Platinum Resistance ◽

Aberrant Methylation ◽

Dietary Zinc ◽

Mthfr Polymorphism ◽

Mthfr Polymorphisms ◽

Platinum Sensitivity

Ovarian cancer has the lowest survival rate in gynaecologic malignancies with a 5-year survival rate of 43%. Platinum resistance is one of the main drivers of ovarian cancer mortality, of which aberrant methylation has been cited as a significant contributor. Understanding the essential role of the methylenetetrahydrofolate reductase enzyme (MTHFR) on DNA synthesis and repair, and how nutrient status can vastly affect its performance, led to the investigation of MTHFR status and dietary influence on platinum response in epithelial ovarian cancer (EOC) patients. Twenty-five adult female patients who completed first-line platinum-based chemotherapy for primary ovarian cancer were selected from Icon Cancer Centres in Australia. Participants were grouped based on platinum response. A full medical and family history, food frequency questionnaire and single blood test were completed, testing for MTHFR polymorphisms, serum folate, serum and active B12 and homocysteine levels. Nineteen of twenty-five participants had an MTHFR polymorphism. Of those, 20% were compound heterozygous, 12% were heterozygous C677T (CT), 4% homozygous C677T, 12% homozygous A1298C and 28% were heterozygous A1298C (AC). Statistically significant associations were found between dietary zinc (p = 0.0086; 0.0030; 0.0189) and B12 intakes in CT genotypes (p = 0.0157; 0.0030; 0.0068) indicating that zinc or vitamin B12 intakes below RDI were associated with this genotype. There were strong associations of vitamin B6 intakes in AC genotypes (p = 0.0597; 0.0547; 0.0610), and dietary folate in compound heterozygotes with sensitive and partially sensitive disease (p = 0.0627; 0.0510). There were also significant associations between serum folate (p = 0.0478) and dietary B12 (p = 0.0350) intakes above RDI and platinum sensitivity in wild-types as well as strong associations with homocysteine levels (p = 0.0886) and zinc intake (p = 0.0514). Associations with dietary B12 (p = 0.0514) and zinc intakes (p = 0.0731) were also strong in resistant wild types. Results indicate that dietary zinc, B12 and B6 intakes may be associated with platinum sensitivity dependent on MTHFR genotype. These results require further research to clarify the dosages necessary to elicit a response; however, they provide a novel foundation for acknowledging the role of diet on treatment response in EOC.

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The current role of gemcitabine in ovarian cancer

Seminars in Oncology ◽

10.1053/sonc.2001.24368 ◽

2001 ◽

Vol 28 (2D) ◽

pp. 18-24

Author(s):

Robert F. Ozols

Keyword(s):

Ovarian Cancer ◽

Current Role

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ROLE OF LIPID PROFILE IN OVARIAN CARCINOMA PATIENTS

International Journal of Medical and Biomedical Studies ◽

10.32553/ijmbs.v3i8.501 ◽

2019 ◽

Vol 3 (8) ◽

Author(s):

Dr. Manisha ◽

Dr. Ruchi Jindal

Keyword(s):

Ovarian Cancer ◽

Lipid Profile ◽

Cancer Patients ◽

Ovarian Tumor ◽

Ovarian Cancer Risk ◽

Low Level ◽

Medical College ◽

Group I ◽

History Of

Background: The term "ovarian cancer" includes several different types of cancer that arise from cells of the ovary, most commonly, tumors arise from the epithelium or lining cells of the ovary. Ovarian cancer risk is positively associated with higher consumption of dietary cholesterol and eggs, and inversely associated with a higher intake of vegetables. High consumption of fats may increase circulating estrogen levels, thus increasing the possibility of cell damage and proliferation that is responsible for cancerous growth. Material & Methods: The present study was conducted at Geetanjali Medical College and Hospital, Udaipur (Rajasthan). Total 100 cases (females) attending the obstetrics and gynecology department for some gynecological and other problem were selected for this study between the age of 40-60 years, who were attending cancer centre at GEETANJALI MEDICAL COLLEGE AND HOSPITAL, Udaipur (Rajasthan). GROUP I: - It consisted of healthy females control subjects (n=50) .By routine examination and tests, we ensured that all the subjects were healthy and there were no signs and symptoms or history of ovarian tumor and diseases GROUP II: - It consisted of ovarian cancer females subjects (n=50) with a history of ovarian tumor. Results: Higher level of cholesterol, LDL, VLDL and low level of HDL are found in ovarian cancer patients. Conclusion: The present study we highlights the importance and role of serum lipid profile in diagnosis, prognosis and recurrence of the disease. The study shows that serum level of cholesterol, LDL, VLDL was elevated in patients of ovarian cancer while low level of HDL are found in ovarian cancer patients. Key words: lipid profile, ovarian cancer.

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