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1.
Pol J Pathol ; 70(2): 115-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556562

RESUMO

Ovarian cancer (OC) is the most lethal among gynecologic malignancies worldwide. Unfortunately, in around 70% of cases cancer is diagnosed in late stages (III-IV) which decreases the 5-year survival rate to 25%. The standard of care in ovarian cancer is debulking surgery followed by chemotherapy regimens based on platinum salts. Since 2014 PARP inhibitors became available for OC patients with germline or/and somatic mutations in BRCA1/2, including maintenance therapy. BRCA1/2 Next Generation Sequencing (NGS)-based analysis of formalin-fixed paraffin-embedded (FFPE) ovarian cancer samples becomes the standard of care. The aim of the present study was to evaluate the frequency of mutations in 201 unselected ovarian cancer tissues using the NGS method. In total, pathogenic mutations in both genes were detected in 24% (49/201) of the ovarian cancer cases tested. For 41 patients the results of testing of DNA isolated from blood sample revealed that 17% (35/201) mutations were germline origin, whereas 3% (6/201) mutations were somatic. In 4% (8/201) cases blood sample was inaccessible. The presence of pathogenic mutations was correlated with younger age at diagnosis and serous subtype. Close cooperation between many specialists (gynecologist, pathologist, oncologist, clinical genetics and molecular biologist) is indispensable for efficient and on-time BRCA1/2 ovarian tumor tissue testing.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/genética , Análise Mutacional de DNA , Feminino , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
2.
Ann Agric Environ Med ; 26(3): 415-419, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31559796

RESUMO

INTRODUCTION AND OBJECTIVE: Peroxiredoxin-1 (PRDX-1) belongs to a family of antioxidant enzymes and has proved to be a versatile molecule regulating cell growth, differentiation and apoptosis. PRDX1-regulated signaling pathways play an important role in the progression and metastasis of human tumours, especially in breast, esophageal and lung cancers. The aim of the study was to evaluate the expression of PRDX-1 in ovarian cancer tissues, and to test the clinical value of PRDX-1 as a prognostic factor in this malignancy. MATERIAL AND METHODS: PRDX-1 expression was assessed by automated immunohistochemistry in tumours taken from 55 patients with ovarian cancer during primary surgery. Specimen were formalin-fixed and preserved in paraffin-embedded blocks. The results were correlated with clinicopathological data. RESULTS: A high expression of PRDX-1 was observed in 20% of cases, and was associated with worse compliance to chemotherapy protocol (P<0.002), worse response to chemotherapy (P<0.04), and higher levels of CA 125 after the 1st line treatment (P<0.004). PRDX-1 positive subjects had a significantly lower 5-year disease-free survival (9.1% vs. 42.6%, P<0.01) and a lower 5-year overall survival (9.1% vs. 56.7%; P<0.002). Multivariate analysis showed that a high expression of PRDX-1 is an independent prognostic factor of poor, overall survival (P<0.002) and a disease-free survival (P<0.01). CONCLUSIONS: Results of the study show that PRDX-1 expression in tumour tissues can be another biomarker of prognosis in patients with ovarian cancer.


Assuntos
Neoplasias Ovarianas/diagnóstico , Peroxirredoxinas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Peroxirredoxinas/genética , Prognóstico
3.
Cancer Invest ; 37(9): 440-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31530033

RESUMO

Ovarian cancer is the deadliest gynecologic cancer. The large-scale microRNA (miRNA) expression profiling and individual miRNA validation was performed to find potential novel biomarkers for ovarian cancer. The most consistent overexpression of miRs-200b-3p, 135 b-5p and 182-5p was found in both ascitic fluid and tumors and suggests their potential as oncogenes. miR-451a was consistently underexpressed so may be a tumor suppressor. Results were inconsistent for miR-204-5p, which was overexpressed in ascitic fluid but underexpressed in tumor tissue. miR-203a-3p was generally overexpressed but this failed to be proved in independent sample set in tissue validation.


Assuntos
Líquido Ascítico/química , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Neoplasias Ovarianas/genética , Ovário/química , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Ovarianas/patologia , Prognóstico
4.
Presse Med ; 48(9): 904-914, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31561847

RESUMO

About 5% of colorectal cancer (CRC) cases occurred in the context of an underlying hereditary predisposition syndrome. Lynch syndrome is the main causes of hereditary CRC but is also associated with a higher risk of other cancers (such as endometrial cancer and ovarian cancer). It is the consequence of constitutional mutation in a MisMatch Repair (MMR) gene, involved in DNA repair: MLH1, MSH2, MSH6 or PMS2; or of the EPCAM gene (MSH2 promotor). If a mutation predisposing to Lynch Syndrome is identified in an individual, special monitoring should be initiated, adapted to estimated cancer risk. Clinical criteria (Amsterdam II and Bethesda) have been validated to identify the patients who should be referred for genetic counseling in order to initiate constitutional DNA testing. Furthermore, the French National Cancer Institute (INCa) systematically recommend tumoral testing looking for MMR system failure in case of CRC diagnosed under 60, endometrial cancer diagnosed under 50 or whatever the age in patients diagnosed with CRC or endometrial cancer harbouring personal or familal history of Lunch Syndrome cancers. In this review, we will discuss how to detect Lynch syndrome (identification of the index case and family screening) and how to monitor it in 2019.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Fatores Etários , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Intestino Grosso , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Linhagem , Vigilância da População/métodos , Guias de Prática Clínica como Assunto , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/genética
6.
JAMA ; 322(7): 666-685, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429902

RESUMO

Importance: Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers. Objective: To update the 2013 US Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Data Sources: Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new key questions and populations); reference lists. Study Selection: Discriminatory accuracy studies, randomized clinical trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction and Synthesis: Data on study methods, setting, population characteristics, eligibility criteria, interventions, numbers enrolled and lost to follow-up, outcome ascertainment, and results were abstracted. Two reviewers independently assessed study quality. Main Outcomes and Measures: Cancer incidence and mortality; discriminatory accuracy of risk assessment tools for BRCA1/2 mutations; benefits and harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions. Results: For this review, 103 studies (110 articles; N = 92 712) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies (n = 43 813) of 8 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve, 0.68-0.96). Twenty-eight studies (n = 8060) indicated that genetic counseling was associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. Twenty studies (n = 4322) showed that breast cancer worry and anxiety were higher after testing for women with positive results and lower for others; understanding of risk was higher after testing. In 8 RCTs (n = 54 651), tamoxifen (relative risk [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Mastectomy was associated with 90% to 100% reduction in breast cancer incidence (6 studies; n = 2546) and 81% to 100% reduction in breast cancer mortality (1 study; n = 639); oophorectomy was associated with 69% to 100% reduction in ovarian cancer (2 studies; n = 2108); complications were common with mastectomy. Conclusions and Relevance: Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Testes Genéticos , Mutação , Neoplasias Ovarianas/genética , Neoplasias da Mama/prevenção & controle , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/prevenção & controle , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/prevenção & controle , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/prevenção & controle , Medição de Risco
7.
JAMA ; 322(7): 652-665, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429903

RESUMO

Importance: Potentially harmful mutations of the breast cancer susceptibility 1 and 2 genes (BRCA1/2) are associated with increased risk for breast, ovarian, fallopian tube, and peritoneal cancer. For women in the United States, breast cancer is the most common cancer after nonmelanoma skin cancer and the second leading cause of cancer death. In the general population, BRCA1/2 mutations occur in an estimated 1 in 300 to 500 women and account for 5% to 10% of breast cancer cases and 15% of ovarian cancer cases. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Evidence Review: The USPSTF reviewed the evidence on risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1/2 mutations in asymptomatic women who have never been diagnosed with BRCA-related cancer, as well as those with a previous diagnosis of breast, ovarian, tubal, or peritoneal cancer who have completed treatment and are considered cancer free. In addition, the USPSTF reviewed interventions to reduce the risk for breast, ovarian, tubal, or peritoneal cancer in women with potentially harmful BRCA1/2 mutations, including intensive cancer screening, medications, and risk-reducing surgery. Findings: For women whose family or personal history is associated with an increased risk for harmful mutations in the BRCA1/2 genes, or who have an ancestry associated with BRCA1/2 gene mutations, there is adequate evidence that the benefits of risk assessment, genetic counseling, genetic testing, and interventions are moderate. For women whose personal or family history or ancestry is not associated with an increased risk for harmful mutations in the BRCA1/2 genes, there is adequate evidence that the benefits of risk assessment, genetic counseling, genetic testing, and interventions are small to none. Regardless of family or personal history, the USPSTF found adequate evidence that the overall harms of risk assessment, genetic counseling, genetic testing, and interventions are small to moderate. Conclusions and Recommendation: The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing. (B recommendation) The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations. (D recommendation).


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Testes Genéticos , Mutação , Neoplasias Ovarianas/genética , Neoplasias da Mama/prevenção & controle , Neoplasias das Tubas Uterinas/genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/prevenção & controle , Neoplasias Peritoneais/genética , Medição de Risco
8.
Zhonghua Fu Chan Ke Za Zhi ; 54(8): 541-547, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31461811

RESUMO

Objective: To detect phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) protein expression in epithelial ovarian cancer and cell lines, and to examine the effects of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor AZD6244 on cell proliferation, apoptosis as well as cell cycle of ovarian cancer cells. To explore the function and significance of MAPK/extracellular signal-regulated kinase (ERK) signaling pathway in the development of ovarian cancer. Methods: (1) A total of 104 cases of patients with ovarian cancer who accepted the treatment of gynecological surgery and being confirmed by pathological examination in First Affiliated Hospital, Dalian Medical University from January 2004 to December 2013 were selected. The expressions of p-ERK1/2 protein were detected by immunohistochemistry in ovarian cancer specimens, and the relationship between the expressions of p-ERK1/2 and the clinical features of patients was analyzed. (2) p-ERK1/2 and other related proteins were determined by western blot in various ovarian cancer cells, including SKOV3, OV2008, C13, A2780S, A2780CP, OVCAR4, OVCAR5, OVCAR8 and CAOV3 treated with or without MEK inhibitor. The cellular proliferation, apoptosis and cell cycle of ovarian cancer cells after treatment with MEK inhibitor were analyzed by methyl thiazolyl tetrazolium (MTT) assay and flow cytometry, respectively. Results: (1) The immunohistochemical method showed that p-ERK1/2 between low grade serous carcinoma and clear cell carcinoma were not significantly higher expressed (P>0.05) . However, a lower level of the p-ERK1/2 expression were observed among high grade serous carcinoma, mucinous carcinoma and endometrioid carcinoma (all P<0.05) . There was no significant correlation between the protein expression of p-ERK1/2 and patients' age, pathological stage of surgery, and preoperative serum CA(125) level (P>0.05). (2) Western blot showed that the protein p-ERK1/2 was widely expressed in various ovarian cancer cell lines such as SKOV3, OV2008, C13, A2780S, A2780CP, OVCAR4, OVCAR5, OVCAR8 and CAOV3. After treatment with AZD6244 (5, 10 µmol/L), the level of p-ERK1/2 in OVCAR5 and OVCAR8 decreased significantly in dose-dependent manner. Additionally, we found a reduction of the expression level of cyclin D1, caspase-3 and appeared cleaved poly adenosine diphosphate ribose polymerase (PARP) in OVCAR5 and OVCAR8, compared with control groups. MTT assays showed that OVCAR5, OVCAR8 and A2780S were differently inhibited in the dose-dependent manner after being treated with different concentrations of AZD6244 (0, 2.5, 5, 10, 25, 50 and 100 µmol/L, all P<0.05). Further tested by flow cytometry, the results showed that AZD6244 (5, 10 µmol/L) was able to induce the apoptosis of OVCAR5, OVCAR8 and A2780S, as well as G(0)/G(1) phase arrest, both in a dose-dependent manner (P<0.05). Conclusions: As the main active and functional unit of MAPK/ERK signaling pathway, p-ERK1/2 protein is expressed in both the tissues and various ovarian cancer cell lines. AZD6244 could down-regulated the expression of p-ERK1/2 in ovarian cancer cells, accompanied by the decreased proliferation and increased cell apoptosis of ovarian cancer cells. In conclusion, MAPK/ERK signaling pathway might play a role in the development and progression of ovarian cancer, and may be provide a novel option for molecular targeted therapies of the disease.


Assuntos
Carcinoma Epitelial do Ovário , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Neoplasias Ovarianas/genética
9.
Cancer Sci ; 110(10): 3204-3214, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385416

RESUMO

Peritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV-3. Microarray and gene profiling analyses indicated that autophagy-related genes were enriched in selected malignant sublines. Detection of LC3-II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high-density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy-related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti-autophagy cancer drugs.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Perfilação da Expressão Gênica/métodos , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Proteínas de Ligação a RNA/genética , Animais , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Camundongos , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Medicina de Precisão , Prognóstico , Microambiente Tumoral
10.
Cancer Sci ; 110(10): 3068-3078, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432577

RESUMO

The programmed cell death 1/programmed cell death 1 ligand 1 pathway was successfully targeted in cancer immunotherapy. Elevated interleukin-17 (IL-17), which is known in autoimmune diseases, has recently been recognized in cancer patients. We investigated the role of IL-17 in the regulation of expression of programmed cell death 1 ligand 1 in ovarian cancer by evaluating changes in the number of IL-17-producing cluster of differentiation 4 helper T cells (Th17) and γδT cells (γδT17) in PBMC of 52 gynecological cancer patients (including 30 ovarian cancer patients) and 18 healthy controls. The occupancy ratio of Th17 and γδT17 was higher in ovarian cancer and endometrial cancer patients than in controls, determined by multi-color flow cytometry (Th17: P < 0.0001 and P = 0.0002, respectively; γδT17: P = 0.0020 and P = 0.0084, respectively). IL-17 mRNA level was elevated in PBMC of ovarian cancer patients (P = 0.0029), as measured by RT-PCR. The neutrophil-to-lymphocyte ratio, which is a prognostic biomarker of ovarian cancer, correlated with Th17 occupancy ratio in patients (P = 0.0068). We found that programmed cell death 1 ligand 1 expression and its associated factors (IL-6 and phospho-signal transducer and activator of transcription 3) were induced by IL-17 in an ovarian cancer cell line. These results suggest that increased Th17 counts and IL-17 level, which correlated with high neutrophil-to-lymphocyte ratio and programmed cell death 1 ligand 1 expression, are potential biomarkers for poor prognosis in ovarian cancer and likely indications for application of programmed cell death 1 ligand 1 pathway inhibitors.


Assuntos
Antígeno B7-H1/genética , Neoplasias do Endométrio/genética , Interleucina-16/metabolismo , Interleucina-17/genética , Neoplasias Ovarianas/genética , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias do Endométrio/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-17/metabolismo , Linfócitos Intraepiteliais/metabolismo , Neoplasias Ovarianas/imunologia , Fosforilação , Prognóstico , Células Th17/metabolismo , Regulação para Cima
11.
Expert Opin Investig Drugs ; 28(9): 771-785, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449760

RESUMO

Introduction: Molecular analyzes including molecular descriptor/phenotype interactions have led to better characterization of epithelial ovarian cancer patients, including a definition of a BRCA wild-type (BRCAwt) phenotype. Understanding how and when to use agents targeted against dependent BRCAwt pathways or other molecular events at disease progression is an important translational and therapeutic direction in ovarian cancer research. Areas covered: In this overview, we provide definitions and descriptions of a BRCAwt genotype and phenotype. We discuss novel investigational drugs that hold promise for the treatment of BRCAwt ovarian cancer, including inhibitors of poly(ADP-ribose) polymerase, ribonucleotide reductase, DNA protein kinase-catalytic subunit, ataxia-telangiectasia-mutated kinase (ATM), ataxia-telangiectasia mutated and Rad3-related kinase (ATR), CHK 1/2, cyclin kinases, glutaminase-1, WEE1 kinase, as well as tumor microenvironment and angiogenesis inhibitors. This article explores the known and the emerging areas of clinical research on patients with BRCAwt ovarian cancer. Expert opinion: Discovery of molecular changes tied to annotated disease information, along with an expanding array of pathway targets and targeted therapeutic agents, creates optimism and opportunity for women with ovarian cancer. Using precision oncology approaches, clinical researchers are, and will be, poised to select more effective treatments for ovarian cancer patients.


Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Drogas em Investigação/farmacologia , Feminino , Humanos , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
12.
Life Sci ; 233: 116715, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31376371

RESUMO

AIMS: PDZ and LIM domain protein 4 (PDLIM4) is frequently repressed in cancer tissues. However, the expression and role of PDLIM4 in ovarian cancer has not been addressed. MAIN METHODS: In this study, we examined the expression and prognostic significance of PDLIM4 in ovarian cancer. The function of PDLIM4 in ovarian cancer cell growth, invasion, and tumorigenesis was further explored. KEY FINDINGS: PDLIM4 is downregulated in ovarian cancer compared to adjacent normal ovarian tissues. Downregulation of PDLIM4 is correlated with advanced tumor stage and lymph node metastasis. Low PDLIM4 expression is significantly associated with shorter overall survival in patients with ovarian cancer (P = 0.0136). Biologically, PDLIM4 overexpression suppresses the proliferation, colony formation, migration, and invasion of both CAOV3 and SKOV3 ovarian cancer cells, compared to empty vector-transfected cells. Consistently, in vivo data show that PDLIM4 overexpression inhibits the growth of SKOV3 xenograft tumors. Mechanistic investigation reveals that overexpression of PDLIM4 blocks the phosphorylation of STAT3 and represses STAT3-dependent transcriptional activation. Moreover, ectopic expression of PDLIM4 downregulates the expression of CCND1 and MMP9 in ovarian cancer cells. Rescue experiments demonstrate that overexpression of constitutively active STAT3 reverses PDLIM4-induced anticancer effects on ovarian cancer cells. SIGNIFICANCE: Overall, PDLIM4 downregulation is associated with aggressive tumor features and poor prognosis in ovarian cancer patients. PDLIM4 suppresses ovarian cancer cell growth and invasion by inhibiting STAT3 signaling. This study provides a potential therapeutic target for ovarian cancer.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio LIM/metabolismo , Neoplasias Ovarianas/patologia , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Proteínas com Domínio LIM/genética , Metástase Linfática , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fosforilação , Prognóstico , Fator de Transcrição STAT3/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Med Oncol ; 36(8): 71, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270633

RESUMO

BRCA1 is involved in double-strand DNA damage repair pathways, and mutations in the gene are associated with hereditary breast and ovarian cancers. With great help of the development of high-throughput DNA sequencing techniques numerous single-nucleotide polymorphisms (SNPs) and insertion deletion (Indel) mutations are detected on both coding and non-coding/regulatory regions of the BRCA1. Mutations may cause pathogenic or benign changes on the protein function or affect its expression. In the last decade, use of genetic screening tests to detect mutations on such genes has become greatly popular. However, it is very important to know the effect of the detected mutations, which is mostly possible by the use of predictive softwares, and also the related family history to be able to correctly analyse the screening results and to inform the patient. Therefore, use of in silico and in vitro techniques to score the pathogenicity of detected variants on genes like BRCA1 is now of great importance. Otherwise, results obtained from screening tests and family history cannot be analysed precisely.


Assuntos
Proteína BRCA1/genética , Genes BRCA1 , Testes Genéticos/métodos , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Neoplasias da Mama/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único
14.
Clin Cancer Res ; 25(19): 5729-5731, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31337645

RESUMO

Epithelial ovarian cancers (EOC) can be defined across different histologic subtypes by specific DNA methylation profiles which correlate with outcome. Identification of distinct EOC methylation subgroups emphasizes the role of epigenetic remodeling to establish unique EOC etiology during transformation, and harbors the potential to direct personalized medicine and patient care.See related article by Bodelon et al., p. 5937.


Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Epiteliais e Glandulares , Neoplasias Ovarianas/genética , Metilação de DNA , Feminino , Humanos
15.
Life Sci ; 232: 116648, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301414

RESUMO

AIMS: Laminin γ2 (LAMC2) is over-expressed in ovarian cancer, and its high expression facilitates cell invasion. Nevertheless, the effects of LAMC2 on other ovarian cancer cell functions and its underlying mechanism remain largely unclear. Bioinformatics analysis shows that LAMC2 is a predicted target of miR-125a-5p and miR-193a-3p. Therefore, the present study aimed to investigate the effects of LAMC2 in ovarian cancer progression and determine whether LAMC2 expression is under the regulation of miR-125a-5p or miR-193a-3p in ovarian cancer. MATERIALS AND METHODS: Immunohistochemistry staining, western blot and qPCR were used to detect LAMC2 expression profiles. CCK-8, flow cytometry and tumour formation assays were used to assess cell proliferation, apoptosis and tumorigenesis. The interaction between miR-125a-5p/miR-193a-3p and LAMC2 were determined by the luciferase gene reporter assay. KEY FINDINGS: The results showed that LAMC2 was over-expressed in ovarian cancer tissues and cell lines. Over-expression of LAMC2 significantly promoted cell proliferation and repressed cell apoptosis, as well as increased the expression levels of p38, p-p38, c-myc and CREB, and translocated p38 protein to the nucleus. In addition, the promotion of cell proliferation and repression of cell apoptosis mediated by LAMC2 over-expression were all weakened when p38 was downregulated. Moreover, LAMC2 expression was negatively regulated by miR-125a-5p, which inhibited the nuclear accumulation of p38 protein. Upregulation of LAMC2 significantly abolished the effects of miR-125a-5p on cell proliferation inhibition and cell apoptosis promotion, as well as tumourigenesis repression. SIGNIFICANCE: The present study clarified that LAMC2 functioned as an oncogene in ovarian cancer through upregulating p38 under the regulation of miR-125a-5p.


Assuntos
Laminina/fisiologia , MicroRNAs/fisiologia , Neoplasias Ovarianas/patologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética
17.
Ceska Gynekol ; 84(3): 212-215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31324112

RESUMO

OBJECTIVE: Case description of advanced biphasic synovial sarcoma in the tubo-ovarian area. DESIGN: Case report. SETTING: Department of Pathology, Znojmo Hospital. METHODS: Own observation, review of the literature. CONCLUSION: The diagnosis of synovial sarcoma must be considered in all spindle cell and undifferentiated tumours in various anatomical sites including female reproductive organs.


Assuntos
Neoplasias das Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Sarcoma Sinovial/patologia , Animais , Neoplasias das Tubas Uterinas/genética , Tubas Uterinas , Feminino , Humanos , Proteínas de Fusão Oncogênica/genética , Neoplasias Ovarianas/genética , Ovário , Sarcoma Sinovial/genética , Sarcoma Sinovial/cirurgia
18.
Gene ; 713: 143969, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299360

RESUMO

BACKGROUND: Ovarian cancer (OvCa) is one of the most lethal gynecologic malignancies worldwide. Pelvic and abdominal metastasis is a leading cause for the poor prognosis of OvCa patients. The relationship between long non-coding RNAs (lncRNAs) and OvCa remains unclear. Identifying key lncRNAs related with OvCa metastasis is crucial for research on the mechanism of OvCa metastasis. This study was designed to investigate the role of a novel lncRNA, which we named SOCAR, in serous OvCa. METHODS: LncRNA microarray and Real-time PCR were used to examine SOCAR expression in high grade serous ovarian cancer (HGSOC) and normal ovary tissues. The proliferation, migration and invasion of OvCa cell lines SKOV-3 and OVCAR-3 were analyzed by CCK-8, Transwell and Scratch wound healing assays. Western blotting was used to detect the expression of Wnt/ß-catenin pathway-related proteins. RESULTS: A novel serous OvCa-related lncRNA, SOCAR, was identified via microarray. SOCAR was overexpressed in primary HGSOC tumors compared with normal ovary tissues, and the expression of SOCAR correlated with progression in HGSOC patients. SOCAR also had higher expression in metastatic HGSOC tissues compared with primary cancer tissues. Moreover, upregulation of SOCAR promoted proliferation, migration and invasion in OvCa cells. Expression of Wnt1, ß-catenin and MMP-9 were all increased by SOCAR overexpression. CONCLUSION: SOCAR is related with HGSOC oncogenesis and progression. It may promote proliferation, migration and invasion in OvCa cells partially by upregulating MMP-9 through the Wnt/ß-catenin pathway.


Assuntos
Biomarcadores Tumorais/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/genética , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Cistadenocarcinoma Seroso/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Ovarianas/genética , Prognóstico , Células Tumorais Cultivadas
19.
Gynecol Oncol ; 154(3): 516-523, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31340883

RESUMO

OBJECTIVE: Endometrioid ovarian carcinomas (EOCs) comprise 5-10% of all ovarian cancers and commonly co-occur with synchronous endometrioid endometrial cancer (EEC). We sought to examine the molecular characteristics of pure EOCs in patients without concomitant EEC. METHODS: EOCs and matched normal samples were subjected to massively parallel sequencing targeting 341-468 cancer-related genes (n = 8) or whole-genome sequencing (n = 28). Mutational frequencies of EOCs were compared to those of high-grade serous ovarian cancers (HGSOCs; n = 224) and EECs (n = 186) from The Cancer Genome Atlas, and synchronous EOCs (n = 23). RESULTS: EOCs were heterogeneous, frequently harboring KRAS, PIK3CA, PTEN, CTNNB1, ARID1A and TP53 mutations. EOCs were distinct from HGSOCs at the mutational level, less frequently harboring TP53 but more frequently displaying KRAS, PIK3CA, PIK3R1, PTEN and CTNNB1 mutations. Compared to synchronous EOCs and pure EECs, pure EOCs less frequently harbored PTEN, PIK3R1 and ARID1A mutations. Akin to EECs, EOCs could be stratified into the four molecular subtypes: 3% POLE (ultramutated), 19% MSI (hypermutated), 17% copy-number high (serous-like) and 61% copy-number low (endometrioid). In addition to microsatellite instability, a subset of EOCs harbored potentially targetable mutations, including AKT1 and ERBB2 hotspot mutations. EOCs of MSI (hypermutated) subtype uniformly displayed a good outcome. CONCLUSIONS: EOCs are heterogeneous at the genomic level and harbor targetable genetic alterations. Despite the similarities in the repertoire of somatic mutations between pure EOCs, synchronous EOCs and EECs, the frequencies of mutations affecting known driver genes differ. Further studies are required to define the impact of the molecular subtypes on the outcome and treatment of EOC patients.


Assuntos
Carcinoma Endometrioide/classificação , Carcinoma Epitelial do Ovário/classificação , Neoplasias Ovarianas/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/classificação , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Análise Mutacional de DNA , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos
20.
Gynecol Oncol ; 154(3): 524-530, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31353053

RESUMO

OBJECTIVE: To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. METHODS: Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. RESULTS: Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn't meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53-81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P < 0.05) and leukocyte expression of pro-inflammatory genes declined (P = 0.03) after completion of therapy. Decrease from baseline of serum IL-6 and IL-8 preceded response to chemotherapy (P < 0.0014). Change from baseline IL-10 preceded complete response. CONCLUSION: Use of propranolol during primary treatment of EOC is feasible and treatment resulted in decrease in markers of adrenergic stress response. In combination with chemotherapy, propranolol potentially results in improved QOL over baseline.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Propranolol/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Idoso , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/cirurgia , Quimioterapia Adjuvante , Citocinas/sangue , Citocinas/genética , Citocinas/imunologia , Estudos de Viabilidade , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Estudos Longitudinais , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Projetos Piloto , Estudos Prospectivos , Qualidade de Vida
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