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1.
J Exp Clin Cancer Res ; 43(1): 156, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822429

RESUMO

BACKGROUND: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. METHODS: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. RESULTS: In response to increased fibronectin secretion and integrin ß1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/ß-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. CONCLUSIONS: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Receptores Frizzled , Células-Tronco Neoplásicas , Neoplasias Ovarianas , Proteínas Serina-Treonina Quinases , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Camundongos , Animais , Receptores Frizzled/metabolismo , Receptores Frizzled/genética , Linhagem Celular Tumoral , Platina/farmacologia , Platina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos
5.
BMJ Case Rep ; 17(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834312

RESUMO

Malignant struma ovarii (MSO) is a rare ovarian teratoma composed primarily of thyroid tissue. Common sites of metastasis include peritoneum, bone, liver, lung, gastrointestinal tract and omentum. We present a woman in her 50s with a history of remote oophorectomy presenting with hypopituitarism and a 2.7 cm sellar mass. Trans-sphenoidal surgery for presumed pituitary macroadenoma achieved near total resection and resultant pathology surprisingly showed ectopic thyroid tissue. The patient acquired her ovarian pathology report from Southeast Asia which showed struma ovarii of the left ovary. The pituitary mass was thus determined to be a metastatic lesion from MSO. She underwent total thyroidectomy and radioactive iodine ablation therapy with good initial response and no regrowth of the tissue or emergence of distant metastases after 5 years of annual follow-up. To our knowledge, this is the first reported case of MSO to the pituitary.


Assuntos
Radioisótopos do Iodo , Neoplasias Ovarianas , Neoplasias Hipofisárias , Estruma Ovariano , Tireoidectomia , Humanos , Feminino , Estruma Ovariano/patologia , Estruma Ovariano/cirurgia , Estruma Ovariano/diagnóstico , Neoplasias Hipofisárias/secundário , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/patologia , Radioisótopos do Iodo/uso terapêutico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/radioterapia , Pessoa de Meia-Idade , Radioterapia Adjuvante
6.
Pediatr Surg Int ; 40(1): 151, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38842682

RESUMO

PURPOSE: Surgical management of ovarian masses in girls still challenging. The aim of the study is to report an 8-year experience in managing children with ovarian masses, and to demonstrate the advantages and the limitations of laparoscopy for such lesions. METHODS: Data of girls aged less than 18 years operated because of an ovarian mass between January 2015 and February 2023 were retrospectively reviewed. Patients were divided into two groups: group A including children operated by laparoscopy, and Group B of patients who underwent open surgery. RESULTS: Eighty-eight children were enrolled. Laparoscopy was performed in 56 patients (63.6%). Group A patients had smaller tumor size (53.6±38.5 vs. 122.2±75.4 mm, P<0.0001), shorter operative time (50.4±20.3 vs. 71.5±36.5 min, P = 0.004), reduced length of hospital stay (1.4±1.1 vs. 3±2.3 days, P<0.0001), and absence of postoperative complications. Only 3 cases (5.7%) of recurrence were seen exclusively within patients followed for benign tumors during a mean follow-up period of 4.6±3 years. CONCLUSION: Laparoscopy should be done in benign ovarian lesions or/and if a torsion is seen. For tumors at high risk of malignancy, laparoscopy can be performed to establish a clear macroscopic diagnosis, for staging of the disease, and resection of small tumors. Conversion to open surgery is indicated in case of doubt.


Assuntos
Laparoscopia , Neoplasias Ovarianas , Humanos , Feminino , Criança , Laparoscopia/métodos , Estudos Retrospectivos , Adolescente , França , Neoplasias Ovarianas/cirurgia , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Duração da Cirurgia , Pré-Escolar , Resultado do Tratamento
7.
J Obstet Gynaecol ; 44(1): 2347430, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38835234

RESUMO

BACKGROUND: At present, the discovery of new biomarkers is of great significance for the early diagnosis, treatment and prognosis assessment of ovarian cancer. Previous findings indicated that aberrant G-protein-coupled receptor 176 (GPR176) expression might contribute to tumorigenesis and subsequent progression. However, the expression of GPR176 and the molecular mechanisms in ovarian cancer had not been investigated. METHODS: GPR176 expression was compared with clinicopathological features of ovarian cancer using immunohistochemical and bioinformatics analyses. GPR176-related genes and pathways were analysed using bioinformatics analysis. Additionally, the effects of GPR176 on ovarian cancer cell phenotypes were investigated. RESULTS: GPR176 expression positively correlated with elder age, clinicopathological staging, tumour residual status, and unfavourable survival of ovarian cancer, but negatively with purity loss, infiltration of B cells, and CD8+ T cells. Gene Set Enrichment Analysis showed that differential expression of GPR176 was involved in focal adhesion, ECM-receptor interaction, cell adhesion molecules and so on. STRING and Cytoscape were used to determine the top 10 nodes. Kyoto Encyclopaedia of Genes and Genomes analysis indicated that GPR176-related genes were involved in the ECM structural constituent and organisation and so on. GPR176 overexpression promoted the proliferation, anti-apoptosis, anti-pyroptosis, migration and invasion of ovarian cancer cells with overexpression of N-cadherin, Zeb1, Snail, Twist1, and under-expression of gasdermin D, caspase 1, and E-cadherin. CONCLUSION: GPR176 might be involved in the progression of ovarian cancer. It might be used as a biomarker to indicate the aggressive behaviour and poor prognosis of ovarian cancer and a target of genetic therapy.


Ovarian cancer is a gynecological cancer with high mortality. Due to the limited screening tests and treatments available, most ovarian cancer patients are diagnosed at a late stage and the prognosis is poor. The addition of new cancer diagnostic biomarkers and new intervention targets may improve quality of life and survival for patients with ovarian cancer. Previous studies have revealed the aberrant GPR176 expression might contribute to tumorigenesis and subsequent progression in many other tumours. In our study, GPR176 was found to promote the proliferation, anti-apoptosis, anti-pyroptosis, migration and invasion, EMT, and weakening the cellular adhesion of ovarian cancer cells, and involved in the Bcl-2/Bax or the PI3K/Akt/mTOR pathway. Therefore, abnormal expression of GPR176 might be served as a biomarker for aggressive behaviour and poor prognosis of ovarian cancer and a target for gene therapy.


Assuntos
Neoplasias Ovarianas , Receptores Acoplados a Proteínas G , Humanos , Feminino , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Pessoa de Meia-Idade , Terapia Genética/métodos , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biologia Computacional , Prognóstico , Proliferação de Células/genética , Carcinogênese/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
8.
Sci Rep ; 14(1): 12595, 2024 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824213

RESUMO

Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Japão , Estudos Retrospectivos , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Ftalazinas/efeitos adversos , Ftalazinas/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Indazóis/efeitos adversos , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Adulto , Idoso de 80 Anos ou mais , Trombocitopenia/induzido quimicamente , População do Leste Asiático
9.
J Ovarian Res ; 17(1): 119, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824600

RESUMO

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare pathological histotype in ovarian cancer, while the survival rate of advanced OCCC (Stage III-IV) is substantially lower than that of the advanced serous ovarian cancer (OSC), which is the most common histotype. The goal of this study was to identify high-risk OCCC by comparing OSC and OCCC, with investigating potential risk and prognosis markers. METHODS: Patients diagnosed with ovarian cancer from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) Program. Logistic and Cox regression models were used to identify risk and prognostic factors in high-risk OCCC patients. Cancer-specific survival (CSS) and overall survival (OS) were assessed using Kaplan-Meier curves. Furthermore, Cox analysis was employed to build a nomogram model. The performance evaluation results were displayed using the C-index, calibration plots, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Immunohistochemically approach was used to identify the expression of the novel target (GPC3). RESULTS: In the Cox analysis for advanced OCCC, age (45-65 years), tumor numbers (total number of in situ/malignant tumors for patient), T3-stage, bilateral tumors, and liver metastases could be defined as prognostic variables. Nomogram showed good predictive power and clinical practicality. Compared with OSC, liver metastases had a stronger impact on the prognosis of patients with OCCC. T3-stage, positive distant lymph nodes metastases, and lung metastases were risk factors for developing liver metastases. Chemotherapy was an independent prognostic factor for patient with advanced OCCC, but had no effect on CSS in patients with liver metastases (p = 0.0656), while surgery was significantly related with better CSS in these patients (p < 0.0001) (p = 0.0041). GPC3 expression was detected in all tissue sections, and GPC3 staining was predominantly found in the cytoplasm and membranes. CONCLUSION: Advanced OCCC and OCCC with liver metastases are two types of high-risk OCCC. The constructed nomogram exhibited a satisfactory survival prediction for patients with advanced OCCC. GPC3 immunohistochemistry is expected to accumulate preclinical evidence to support the inclusion of GPC3 in OCCC targeted therapy.


Assuntos
Adenocarcinoma de Células Claras , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/metabolismo , Pessoa de Meia-Idade , Prognóstico , Idoso , Adenocarcinoma de Células Claras/patologia , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/mortalidade , Programa de SEER , Adulto , Nomogramas , Fatores de Risco
10.
Can Vet J ; 65(6): 594-597, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38827594

RESUMO

A Swiss mountain dog, ~3 y old, was brought to a veterinary clinic because of a progressive enlargement of the abdomen. Upon clinical examination, a large mass was detected. After surgical extraction, the mass was confirmed to be a large ovarian teratoma. The weight of the tumor was > 16% of the dog's overall body weight. The dog recovered fully after surgery. The observations from this case suggest that, although teratomas are rare, prompt and accurate diagnosis is necessary to prevent further growth of these masses and to ensure positive outcomes.


Tératome ovarien chez un chien de montage suisse. Un chien de montagne suisse âgé d'environ 3 ans a été présenté dans une clinique vétérinaire en raison d'une augmentation de volume progressive de l'abdomen. Lors de l'examen clinique, une grosse masse a été détectée. À la suite du retrait chirurgical, la masse a été confirmée comme étant un large tératome ovarien. Le poids de la masse tumorale était > 16 % du poids total du chien. Le chien a récupéré complètement après la chirurgie. Les observations à partir de ce cas suggèrent, bien que les tératomes soient rares, un diagnostic rapide et exact est nécessaire pour prévenir une croissance ultérieure de ces masses et assurer une issue positive.(Traduit par Dr Serge Messier).


Assuntos
Doenças do Cão , Neoplasias Ovarianas , Teratoma , Animais , Cães , Teratoma/veterinária , Teratoma/cirurgia , Teratoma/diagnóstico , Teratoma/patologia , Feminino , Neoplasias Ovarianas/veterinária , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Doenças do Cão/cirurgia , Doenças do Cão/diagnóstico , Doenças do Cão/patologia
11.
Cancer Immunol Immunother ; 73(8): 145, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38832992

RESUMO

Ovarian cancer is one of the most lethal malignant tumors, characterized by high incidence and poor prognosis. Patients relapse occurred in 65-80% after initial treatment. To date, no effective treatment has been established for these patients. Recently, CD47 has been considered as a promising immunotherapy target. In this paper, we reviewed the biological roles of CD47 in ovarian cancer and summarized the related mechanisms. For most types of cancers, the CD47/Sirpα immune checkpoint has attracted the most attention in immunotherapy. Notably, CD47 monoclonal antibodies and related molecules are promising in the immunotherapy of ovarian cancer, and further research is needed. In the future, new immunotherapy regimens targeting CD47 can be applied to the clinical treatment of ovarian cancer patients.


Assuntos
Antígeno CD47 , Progressão da Doença , Neoplasias Ovarianas , Humanos , Antígeno CD47/metabolismo , Antígeno CD47/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Feminino , Imunoterapia/métodos , Animais
12.
PLoS One ; 19(6): e0304704, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38833451

RESUMO

OBJECTIVE: To evaluate the diagnostic performance of circulating tumor cells (CTCs) using tapered-slit membrane filter (TSF)-based chipsets for the differential diagnosis of adnexal tumors. METHODS: A total of 230 women with indeterminate adnexal tumors were prospectively enrolled. The sensitivity, specificity, and accuracy of the CTC-detecting chipsets were analyzed according to postoperative pathological results and compared with those of cancer antigen (CA)-125 and imaging tests. RESULTS: Eighty-one (40.3%) benign tumors, 31 (15.4%) borderline tumors, and 89 (44.3%) ovarian cancers were pathologically confirmed. The sensitivity, specificity, and accuracy of CTC-detecting chipsets (75.3%, 58.0%, and 67.1%) for differentiating ovarian cancer from benign tumors were similar to CA-125 (78.7%, 53.1%, and 66.5%), but lower than CT/MRI (94.2%, 77.9%, and 86.5%). "CTC or CA125" showed increased sensitivity (91.0%) and "CTC and CA-125" revealed increased specificity (77.8%), comparable to CT/MRI. CTC detection rates in stage I/II and stage III/IV ovarian cancers were 69.6% and 81.4%, respectively. The sensitivity to detect high-grade serous (HGS) cancer from benign tumors (84.6%) was higher than that to detect non-HGS cancers (68.0%). CONCLUSION: Although the diagnostic performance of the TSF platform to differentiate between ovarian cancer and benign tumors did not yield significant results, the combination of CTC and CA-125 showed promising potential in the diagnostic accuracy of ovarian cancer.


Assuntos
Antígeno Ca-125 , Células Neoplásicas Circulantes , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Células Neoplásicas Circulantes/patologia , Pessoa de Meia-Idade , Diagnóstico Diferencial , Adulto , Antígeno Ca-125/sangue , Idoso , Sensibilidade e Especificidade , Separação Celular/métodos , Separação Celular/instrumentação , Estudos Prospectivos , Idoso de 80 Anos ou mais , Adulto Jovem
13.
J Ovarian Res ; 17(1): 96, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720349

RESUMO

OBJECTIVE: To describe the characteristics of children and adolescents with borderline ovarian tumors (BOTs) and evaluate the efficacy and safety of fertility-sparing surgery (FSS) in these patients. METHODS: Patients with BOTs younger than 20 years who underwent FSS were included in this study. RESULTS: A total of 34 patients were included, with a median patient age of 17 (range, 3-19) years; 97.1% (33/34) of cases occurred after menarche. Of the patients, 82.4% had mucinous borderline tumors (MBOTs), 14.7% had serous borderline tumors (SBOTs), and 2.9% had seromucinous borderline tumor (SMBOT). The median tumor size was 20.4 (range, 8-40)cm. All patients were at International Federation of Gynecology and Obstetrics stage I and all underwent FSS: cystectomy (unilateral ovarian cystectomy, UC, 14/34, 41.2% and bilateral ovarian cystectomy, BC, 1/34, 2.9%), unilateral salpingo-oophorectomy (USO; 18/34; 52.9%), or USO + contralateral ovarian cystectomy (1/34; 2.9%). The median follow-up time was 65 (range, 10-148) months. Recurrence was experienced by 10 of the 34 patients (29.4%). One patient with SBOT experienced progression to low-grade serous carcinoma after the third relapse. Two patients had a total of four pregnancies, resulting in three live births. The recurrence rate of UC was significantly higher in MBOTs than in USO (p = 0.005). The 5-year disease-free survival rate was 67.1%, and the 5-year overall survival rate was 100%. CONCLUSIONS: Fertility-sparing surgery is feasible and safe for children and adolescents with BOTs. For patients with MBOTs, USO is recommended to lower the risk of recurrence.


Assuntos
Preservação da Fertilidade , Neoplasias Ovarianas , Humanos , Feminino , Adolescente , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Preservação da Fertilidade/métodos , Criança , Estudos Retrospectivos , Adulto Jovem , Pré-Escolar , Resultado do Tratamento , Tratamentos com Preservação do Órgão/métodos , Recidiva Local de Neoplasia
14.
Int J Biol Sci ; 20(7): 2454-2475, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725854

RESUMO

The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3ß signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.


Assuntos
Diosgenina/análogos & derivados , Glicólise , Neovascularização Patológica , Neoplasias Ovarianas , Saponinas , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Linhagem Celular Tumoral , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Camundongos Nus , Camundongos , Angiogênese
15.
Sci Rep ; 14(1): 10427, 2024 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714753

RESUMO

This study aimed to synchronously determine epitranscriptome-wide RNA N6-methyladenosine (m6A) modifications and mRNA expression profile in high grade serous ovarian cancer (HGSOC). The methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to comprehensively examine the m6A modification profile and the RNA-sequencing (RNA-seq) was performed to analyze the mRNA expression profile in HGSOC and normal fallopian tube (FT) tissues. Go and KEGG analyses were carried out in the enrichment of those differentially methylated and expressed genes. MeRIP-seq data showed 53,794 m6A methylated peaks related to 19,938 genes in the HGSOC group and 51,818 m6A peaks representing 19,681 genes in the FT group. RNA-seq results revealed 2321 upregulated and 2486 downregulated genes in HGSOC. Conjoint analysis of MeRIP-seq and RNA-seq data identified differentially expressed genes in which 659 were hypermethylated (330 up- and 329 down-regulated) and 897 were hypomethylated (475 up- and 422 down-regulated). Functional enrichment analysis indicated that these differentially modulated genes are involved in pathways related to cancer development. Among methylation regulators, the m6A eraser (FTO) expression was significantly lower, but the m6A readers (IGF2BP2 and IGF2BP3) were higher in HGSOC, which was validated by the subsequent real-time PCR assay. Exploration through public databases further corroborated their possible clinical application of certain methylation regulators and differentially expressed genes. For the first time, our study screens the epitranscriptome-wide m6A modification and expression profiles of their modulated genes and signaling pathways in HGSOC. Our findings provide an alternative direction in exploring the molecular mechanisms of ovarian pathogenesis and potential biomarkers in the diagnosis and predicting the prognosis of the disease.


Assuntos
Adenosina , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas , RNA Mensageiro , Humanos , Feminino , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Projetos Piloto , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Perfilação da Expressão Gênica , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/metabolismo , Gradação de Tumores , Pessoa de Meia-Idade , Transcriptoma , Metilação de DNA
16.
Nat Commun ; 15(1): 3771, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38704377

RESUMO

Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.


Assuntos
Biomarcadores Tumorais , Mutação , Neoplasias Ovarianas , Paclitaxel , Neoplasias Gástricas , Paclitaxel/uso terapêutico , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Biomarcadores Tumorais/genética , Claudinas/genética , Claudinas/metabolismo , Evolução Molecular , Animais , Pessoa de Meia-Idade , Prognóstico , Linhagem Celular Tumoral , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Idoso , Antineoplásicos Fitogênicos/uso terapêutico
17.
BMC Cancer ; 24(1): 565, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38711015

RESUMO

BACKGROUND: Recent studies showed heterogeneity in stage IVB patients. However, few studies focused on the prognosis of supraclavicular metastatic ovarian cancer. This study aimed to explore the prognostic factors and the role of primary debulking in IVB ovarian cancer patients with supraclavicular lymph node metastasis. METHODS: We retrospectively analyzed patients newly diagnosed as primary epithelial ovarian cancer with supraclavicular lymph node metastasis from January 2015 to July 2020. Supraclavicular lymph node metastasis was defined as either the pathological diagnosis by supraclavicular lymph node biopsy, or the radiological diagnosis by positron emission tomography-computed tomography (PET-CT). RESULTS: In 51 patients, 37 was diagnosed with metastatic supraclavicular lymph nodes by histology, 46 by PET-CT, and 32 by both methods. Forty-four (86.3%) with simultaneous metastatic paraaortic lymph nodes (PALNs) by imaging before surgery or neoadjuvant chemotherapy were defined as "continuous-metastasis type", while the other 7 (13.7%) defined as "skip-metastasis type". Nineteen patients were confirmed with metastatic PALNs by histology. Thirty-four patients were investigated for BRCA mutation, 17 had germline or somatic BRCA1/2 mutations (g/sBRCAm). With a median follow-up of 30.0 months (6.3-63.4 m), 16 patients (31.4%) died. The median PFS and OS of the cohort were 17.3 and 48.9 months. Survival analysis showed that "continuous-metastasis type" had longer OS and PFS than "skip-metastasis type" (OS: 50.0/26.6 months, PFS: 18.5/7.2months, p=0.005/0.002). BRCA mutation carriers also had longer OS and PFS than noncarriers (OS: 57.4 /38.5 m, p=0.031; PFS: 23.6/15.2m, p=0.005). Multivariate analysis revealed only metastatic PALNs was independent prognostic factor for OS (p=0.040). Among "continuous-metastasis type" patients, 22 (50.0%) achieved R0 abdominopelvic debulking, who had significantly longer OS (55.3/42.3 months, p =0.034) than those with residual abdominopelvic tumors. CONCLUSIONS: In stage IVB ovarian cancer patients with supraclavicular lymph nodes metastasis, those defined as "continuous-metastasis type" with positive PALNs had better prognosis. For them, optimal abdominopelvic debulking had prognostic benefit, although metastatic supraclavicular lymph nodes were not resected. Higher BRCA mutation rate than the general population of ovarian cancer patients was observed in patients with IVB supraclavicular lymph node metastasis, leading to better survival as expected.


Assuntos
Procedimentos Cirúrgicos de Citorredução , Metástase Linfática , Estadiamento de Neoplasias , Neoplasias Ovarianas , Humanos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Prognóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Procedimentos Cirúrgicos de Citorredução/métodos , Adulto , Idoso , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/mortalidade , Linfonodos/patologia , Linfonodos/cirurgia , China/epidemiologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Proteína BRCA1/genética , População do Leste Asiático
19.
Ter Arkh ; 96(3): 266-272, 2024 Apr 16.
Artigo em Russo | MEDLINE | ID: mdl-38713042

RESUMO

AIM: To investigate the antitumor effects of human placenta hydrolysate (HPH) peptides on three hormone-dependent human cell lines: prostate adenocarcinoma, breast carcinoma, and ovarian cancer by metabolic analysis of cell cultures. MATERIALS AND METHODS: The effect of HPH on tumor and control tumor cell lines was evaluated. Study stages: (A) de novo peptide sequencing by collision-induced dissociation mass spectrometry; (B) detection of peptides with anti-tumor properties; (C) expert analysis of the obtained lists of peptides. RESULTS: Dose-dependent cytotoxic effects of HPH on three tumor cell lines are shown: PC-3 (human prostate adenocarcinomas), OAW-42 (human ovarian cancer), BT-474 (human breast carcinomas), and IC50 constants (1.3-2.8 mg/ml) were obtained. The analysis of the HPH peptide fraction showed more than 70 peptides with antitumor properties in the composition of this HPH, including kinase inhibitors: mitogen-activated protein kinases, kappa-bi nuclear factor inhibitor kinase, AKT serine/threonine kinase 1, protein kinase C zeta, interleukin-1 receptor-associated kinase 4 and cyclin-dependent kinase 1. CONCLUSION: The results of the study indicate not only the oncological safety of the HPH used in therapy but also the mild antitumor effects of this HPH at high concentrations.


Assuntos
Neoplasias da Mama , Placenta , Neoplasias da Próstata , Humanos , Feminino , Placenta/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Gravidez , Neoplasias da Próstata/tratamento farmacológico , Masculino , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Células PC-3 , Hidrolisados de Proteína/farmacologia , Relação Dose-Resposta a Droga
20.
BMC Cancer ; 24(1): 551, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693472

RESUMO

OBJECTIVE: We aimed to screen novel gene signatures for ovarian cancer (OC) and explore the role of biomarkers in OC via regulating pyroptosis using bioinformatics analysis. METHODS: Differentially expressed genes (DEGs) of OC were screened from GSE12470 and GSE16709 datasets. Hub genes were determined from protein-protein interaction networks after bioinformatics analysis. The role of Centromeric protein M (CENPM) in OC was assessed by subcutaneous tumor experiment using hematoxylin-eosin and immunohistochemical staining. Tumor metastasis was evaluated by detecting epithelial-mesenchymal transition-related proteins. The proliferation, migration, and invasion were determined using cell counting kit and transwell assay. Enzyme-linked immunosorbent assay was applied to measure inflammatory factors. The mRNA and protein expression were detected using real-time quantitative PCR and western blot. RESULTS: We determined 9 hub genes (KIFC1, PCLAF, CDCA5, KNTC1, MCM3, OIP5, CENPM, KIF15, and ASF1B) with high prediction value for OC. In SKOV3 and A2780 cells, the expression levels of hub genes were significantly up-regulated, compared with normal ovarian cells. CENPM was selected as a key gene. Knockdown of CENPM suppressed proliferation, migration, and invasion of OC cells. Subcutaneous tumor experiment revealed that CENPM knockdown significantly suppressed tumor growth and metastasis. Additionally, pyroptosis was promoted in OC cells and xenograft tumors after CENPM knockdown. Furthermore, CENPM knockdown activated cGAS-STING pathway and the pathway inhibitor reversed the inhibitory effect of CENPM knockdown on viability, migration, and invasion of OC cells. CONCLUSION: CENPM was a novel biomarker of OC, and knockdown of CENPM inhibited OC progression by promoting pyroptosis and activating cGAS-STING pathway.


Assuntos
Proteínas de Membrana , Nucleotidiltransferases , Neoplasias Ovarianas , Piroptose , Transdução de Sinais , Humanos , Feminino , Piroptose/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Animais , Camundongos , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Movimento Celular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus
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