Development Of Ovarian Cancer Research Articles

Retracted: DDTC Suppresses Ovarian Cancer Development via the PI3K/AKT/mTOR Signaling Pathway.

[This retracts the article DOI: 10.1155/2022/1941077.].

ELK3 Targeting AEG1 Promotes Migration and Invasion of Ovarian Cancer Cells under Hypoxia.

Ovarian cancer (OC) is one of the most common tumors in female reproductive organs with a five-year survival rate of less than 45%. Metastasis is a crucial contributor to OC development. ETS transcription factor (ELK3), as a transcriptional factor, have been involved in multiple tumor development. However, its role in OC remains elusive. In this study, we observed high expression of ELK3 and AEG1 in human OC tissues. OVCAR-3 and SKOV3 cells were treated with hypoxia to mimic tumor microenvironment in vivo. We found that the expression of ELK3 was significantly increased in cells under hypoxia compared with normoxia. ELK3 knockdown inhibited cell migration and invasion abilities under hypoxia. Moreover, ELK3 knockdown decreased β-catenin expression and inhibited the activation of Wnt/β-catenin pathway in SKOV3 cells under hypoxia. Astrocyte-elevated gene-1 (AEG1) has been reported to promote OC progression. Our results showed that the mRNA level of AEG1 was decreased when ELK3 knockdown under hypoxia. Dural luciferase assay confirmed that ELK3 bound to gene AEG1 promoter (-2005-+15) and enhanced its transcriptional activity under hypoxia. Overexpression of AEG1 increased the migration and invasion abilities of SKOV3 cell with ELK3 knockdown. In the absence of ELK3, the activation of β-catenin was recovered by AEG1 overexpression. To sum up, we conclude that ELK3 promotes AEG1 expression by binding to its promoter. ELK3 could promote migration and invasion of OC cells by targeting AEG1, which provides a potential basis for therapeutic approaches to OC.

Scutellaria baicalensis Georgi and Their Natural Flavonoid Compounds in the Treatment of Ovarian Cancer: A Review

Ovarian cancer (OC) is one of the most common types of cancer in women with a high mortality rate, and the treatment of OC is prone to high recurrence rates and side effects. Scutellaria baicalensis (SB) is a herbal medicine with good anti-cancer activity, and several studies have shown that SB and its flavonoids have some anti-OC properties. This paper elucidated the common pathogenesis of OC, including cell proliferation and cell cycle regulation, cell invasion and metastasis, apoptosis and autophagy, drug resistance and angiogenesis. The mechanisms of SB and its flavonoids, wogonin, baicalein, baicalin, Oroxylin A, and scutellarein, in the treatment of OC, are revealed, such as wogonin inhibits proliferation, induces apoptosis, inhibits invasion and metastasis, and increases the cytotoxicity of the drug. Baicalein also inhibits vascular endothelial growth factor (VEGF) expression etc. Analyzing their advantages and disadvantages in treating OC provides a new perspective on the role of SB and its flavonoids in OC treatment. It serves as a resource for future OC research and development.

The Clinical Significance of Genetic Variation in Ovarian Cancer.

Genetic variation is a well-known contributor to the onset and progression of cancer. The goal of this study is to provide a comprehensive examination of the nucleotide and chromosomal variation associated with the onset and progression of serous ovarian cancer. Using a variety of computational and statistical methods, we examine the exome sequence profiles of genetic variants present in the primary tumors of 432 ovarian cancer patient samples to compute: (1) the tumor mutational burden for all genes and (2) the chromosomal copy number alterations associated with the onset/progression of ovarian cancer. Tumor mutational burden is reduced in the late vs. early stages, with the highest levels being associated with loss-of-function mutations in DNA-repair genes. Nucleotide variation and copy number alterations associated with known cancer driver genes are selectively favored over ovarian cancer development. The results indicate that genetic variation is a significant contributor to the onset and progression of ovarian cancer. The measurement of the relative levels of genetic variation associated with individual ovarian cancer patient tumors may be a clinically valuable predictor of potential tumor aggressiveness and resistance to chemotherapy. Tumors found to be associated with high levels of genetic variation may help in the clinical identification of high-risk ovarian cancer patients who could benefit from more frequent monitoring.

Domatinostat Targets the FOXM1-Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents.

The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1-survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.

Decision-analytic evaluation of the comparative effectiveness and cost-effectiveness of strategies to prevent breast and ovarian cancer in German women with BRCA-1/2 mutations

BackgroundWomen with inherited mutations in the BRCA1 or BRCA2 genes have increased lifetime risks for developing breast and/or ovarian cancer and may develop these cancers around the age of 30 years. Therefore, prevention of breast and ovarian cancer in these women may need to start relatively early in life. In this study we systematically evaluate the long-term effectiveness and cost effectiveness of different prevention strategies for breast and ovarian cancer in women with BRCA-1/2 mutation in Germany.MethodsA decision-analytic Markov model simulating lifetime breast and ovarian cancer development in BRCA-1/2 carriers was developed. Different strategies including intensified surveillance (IS), prophylactic bilateral mastectomy (PBM), and prophylactic bilateral salpingo-oophorectomy (PBSO) alone or in combination at different ages were evaluated. German clinical, epidemiological, and economic (in 2022 Euro) data were used. Outcomes included cancer incidences, mortality, life years (LYs), quality-adjusted life years (QALYs), and discounted incremental cost-effectiveness ratios (ICER). We adopted the German health-care system perspective and discounted costs and health effects with 3% annually.ResultsAll intervention strategies are more effective and less costly than IS alone. Prevention with PBM plus PBSO at age 30 maximizes life expectancy with 6.3 LYs gained, whereas PBM at age 30 with delayed PBSO at age 35 improves quality of life with 11.1 QALYs gained, when compared to IS alone. A further delay of PBSO was associated with lower effectiveness. Both strategies are cost effective with ICERs significantly below 10,000 EUR/LYG or QALY.ConclusionBased on our results, PBM at age 30 plus PBSO between age 30 and 40 prolongs life and is cost effective in women with BRCA-1/2 mutations in Germany. Serial preventive surgeries with delayed PBSO potentially improve quality of life for women. However, delaying PBM and/or PBSO further may lead to increased mortality and reduced QALYs.

Detection of human papillomavirus in archival bladder and ovarian cancer samples

ProblemHuman papillomavirus (HPV) is a well-established causative agent of cervical cancer. However, its role in the development of bladder and ovarian cancer is under debate. Current study evaluated the role of high-risk HPV genotypes 16 and 18 in triggering bladder and ovarian carcinomas. MethodsA total of 80 formalin-fixed and paraffin-embedded (FFPE) archival tissue specimens of both bladder (n = 40) and ovarian carcinoma (n = 40) were tested for the presence of HPV integrants and HPV 16 genotype and HPV 18 genotype. Results and conclusionThe PCR results showed that 5% (2/40) of bladder cancer samples were HPV positive with equal prevalence of HPV 16 in both sexes (1:1) while 22.5% (9/40) of ovarian cancer samples came positive for HPV with only one positive for HPV 16. These results indicate association of HPV with bladder and ovarian carcinomas, HPV 16 genotype being more prevalent than 18. The study emphasizes that HPV is a serious issue in low- and middle-income countries where existing methods of prevention are still inadequate or costly. Timely HPV screening can help lower the burden of HPV-induced carcinomas. Furthermore, systematic HPV vaccination program among the young population is paramount.

O-248 Treatment with antifibrotic targets decreases accumulation of pro-fibrotic myofibroblasts and fibrotic collagen in cultured cryopreserved-thawed human cortical tissue

Abstract Study question Could the excess deposition of fibrotic collagen and the presence of myofibroblast be reversed by in vitro culture of human cortical tissue with antifibrotic targets? Summary answer The in vitro treatment of fibrotic ovarian stroma with Metformin, Pirfenidone or Mitoquinone proved effective in decreasing collagen accumulation and the presence of myofibroblasts. What is known already Tissue fibrosis is characterized by an excessive accumulation of extracellular matrix proteins, leading to organ dysfunction. The ovary is the first organ to show fibrosis related to ageing, creating permissive conditions for ovarian cancer development. Due to this, there is an urgent need for ovarian fibrosis treatments. The clinically approved treatment with Metformin has shown efficacy in preventing fibrosis progression from post-menopausal ovaries obtained from diabetic patients, while Pirfenidone is used to treat pulmonary fibrosis. Transmasculine people exposed to prolonged androgen therapy show early signs of ovarian fibrosis, providing a suitable model to study ovarian fibrosis management strategies Study design, size, duration duration Fresh and cryopreserved-thawed human ovarian samples obtained from 9 cisgender women (cOVA) and 9 transgender and gender diverse people (tOVA) were included for histological analysis of collagen content and fiber organization. Cryopreserved-thawed cortical fragments from 6 tOVAs were cultured for 8 days with or without antifibrotic treatments (Metformin, Pirfenidone and Mitoquinone). Cryopreserved-thawed cortical fragments from 9 tOVAs were used for in vitro culture, followed by metabolic assays. Participants/materials, setting, methods Human ovarian samples were obtained from 9 cisgender women (29,1,3±7,9years) scheduled for gonadotoxic therapy undergoing oophorectomy for fertility preservation and from 24 transgender and gender diverse people (22,7±2,4 years) undergoing gender affirming oophorectomy. Collagen content and organization were visualized by second harmonic generation and polarized light imaging. Collagen type 1 and 4, ACTA2+ myofibroblasts and TUNEL+ apoptotic cells were detected and quantified using immunofluorescence. Mitochondrial respiration and glycolysis were measured using the Seahorse XF analyzer. Main results and the role of chance Histological analysis of collagen content and organization confirmed that tOVA from subjects in fertile age presents characteristics of ovarian fibrosis, such as a higher accumulation and anisotropic (linearized) organization of collagen fibers within the stroma, indicating that long exposure to androgen therapy affects the extracellular matrix composition of the ovary. Furthermore, both tOVA and cOVA cortical tissue showed an increase in anisotropic collagen disposition after being cryopreserved-thawed when compared to its fresh counterpart, indicating cryopreservation could favor fibrotic progression. Additionally, standard in vitro culture of cryopreserved-thawed ovarian cortical fragments promotes an accumulation of collagen 1 and 4 as well as an increase in the number of myofibroblasts and apoptotic cells after 8 days of culture. Treatment with antifibrotics targets such as Pirfenidone, Metformin and Mitoquinone proved to be efficient in reducing both collagen accumulation (P < 0.05), pro-fibrotic myofibroblasts (P < 0.05) and TUNEL+ apoptotic cells (P < 0.05). These results support the evidence that ovarian fibrosis can be prevented or reverted in vitro with anti-oxidants and drugs targeting inflammatory response. As such, these treatments should be considered as therapeutic approaches for women of advancing age and metabolic disorders to prevent pro-tumorigenic fibrotic ovarian stroma. Limitations, reasons for caution Small sample size. There is variation in the type and duration of the androgen treatment in transgender and gender diverse people included in the study. Furthermore, the collagen analysis from the cOVA samples was performed on 1cm2 biopsies that might not represent the general collagen distribution in the complete ovary. Wider implications of the findings Medical treatments affecting the ovarian metabolic cell function, such as androgen therapy for transgender people and gender diverse or lab procedures to cryopreserved human ovarian tissue, can trigger fibrosis progression. Nevertheless, human ovarian fibrosis seems reversible and preventable using drugs targeting mitochondrial metabolism and inflammatory response. Trial registration number not applicable

Identifying miRNA biomarkers for breast cancer and ovarian cancer: a text mining perspective.

microRNA (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing. Numerous studies have demonstrated the critical role of miRNAs in the development of breast cancer and ovarian cancer. To reduce potential bias from individual studies, a more comprehensive approach of exploring miRNAs in cancer research is essential. This study aims to explore the role of miRNAs in the development of breast cancer and ovarian cancer. Abstracts of the publications were tokenized and the biomedical terms (miRNA, gene, disease, species) were identified and extracted for vectorization. Predictive analyses were conducted with four machine learning models: K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Random Forest (RF), and Naïve Bayes. Both holdout validation and cross-validation were utilized. Feature importance will be identified for miRNA-cancer networks construction. We found that miR-182 is highly specific to female cancers. miR-182 targets different genes in regulating breast cancer and ovarian cancer. Naïve Bayesprovided a promising prediction model for breast cancer and ovarian cancer with miRNAs and genes combination, with an accuracy score greater than 60%. Feature importance identified miR-155 and miR-199 are critical for breast cancer and ovarian cancer prediction, with miR-155 being highly related to breast cancer, whereas miR-199 being more associated with ovarian cancer. Our approach effectively identified potential miRNA biomarkers associated with breast cancer and ovarian cancer, providing a solid foundation for generating novel research hypotheses and guiding future experimental studies.

Justification of the choice of hormone therapy for ovarian cancer

BACKGROUND. Hormonal dependence of ovarian cancer remains a debatable issue in modern oncogynecology. Its decision will allow not only to clarify the pathogenesis of the development of ovarian cancer, its prognosis, but also to substantiate the indications for hormone therapy as a component of complex treatment.
 OBJECTIVE. To study the experience of domestic and foreign specialists regarding the pathogenetic rationale for prescribing hormone therapy to patients with ovarian cancer and its effectiveness.
 MATERIALS AND METHODS. Generalization and analysis of scientific publications on the research topic.
 RESULTS. The article summarizes data on the pathogenetic rationale for the appointment of hormone therapy, as well as the effectiveness of antiestrogens and aromatase inhibitors in the treatment of primary ovarian cancer and recurrences of the disease.
 CONCLUSIONS. To date, indications for the appointment and criteria for the use of hormone therapy in the complex treatment of ovarian cancer are not developed. The question of the reliability of the factors of the disease prognosis, taking into account the hormonal receptor status of ovarian cancer, remains open.

Hsa_circ_0001741 Suppresses Ovarian Cancer Cell Proliferations Through Adsorption of miR-188-5p and Promotion of FOXN2 Expression.

Ovarian cancer (OC) is among several general malignant gynecological cancers associated with high mortality rates on a global scale. Earlier investigations have revealed a critical role of circular RNAs (circRNAs) in OC development, which is a new class of endogenous non-coding RNA (ncRNA) that reported to mediate progression of diverse tumor types. At present, the precise involvement of circRNAs and associated regulatory mechanisms in OC remain unknown. In this study, hsa_circ_0001741 expression patterns in OC cells and tissues were tested. The underlying regulatory pathways and targets were further explored with the aid of bioinformatics, luciferase reporter, 5-ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) analyses. Further investigation of the hsa_circ_0001741 effects on tumor growth in vivo revealed abnormal circRNA expression in OC. hsa_circ_0001741 expression reduced in OC cells and tissues, indicative of activity in OC progression. hsa_circ_0001741 upregulation resulted in OC proliferation inhibitions. The luciferase reporter outputs verified miR-188-5p and FOXN2 as hsa_circ_0001741 downstream targets. FOXN2 silencing or miR-188-5p upregulations reversed inhibitory effects regarding hsa_circ_0001741 on OC cell proliferation. Therefore our data suggested that hsa_circ_0001741 upregulation inhibited proliferation of OC through modulatory effects on miR-188-5p/FOXN2 signaling.

An immune related signature inhibits the occurrence and development of serous ovarian cancer by affecting the abundance of dendritic cells

Serous ovarian cancer is one of the major causes of cancer related death among women worldwide. The advanced diagnosis worsens the prognosis of patients with serous ovarian cancer. The immune system has an important impact on the progression of ovarian cancer. Herein, we aimed to establish an immune related prognostic signature to assist in the early diagnosis, treatment, and prognostic evaluation of patients with serous ovarian cancer. Multiple public data sets and immune related genes were obtained from various online public databases, and immune related prognostic signatures were developed through differential expression analysis, univariate Cox proportional hazard regression analysis, and the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model. The nomogram model, Kaplan–Meier survival curve analysis, receiver operating characteristic (ROC) curve analysis, and decision curve analysis showed that this signature had a good prediction potential. In conclusion, an immune related signature with good prediction efficiency was established through systematic bioinformatics analysis, which may play a tumor inhibition role by affecting the abundance of activated dendritic cells.

MOB kinase activator 1A acts as an oncogene by targeting PI3K/AKT/mTOR in ovarian cancer

BackgroundTo illuminate the precise roles of MOB Kinase Activator 1 A (MOB1A) in the development of ovarian cancer (OC).MethodsMOB1A expression and clinical data of OC were obtained from the public database on gene expression and proteomics. Meanwhile, verification of expression was carried out in Gene Expression Omnibus, the Human Protein Atlas, and OC cell lines. The prognosis of MOB1A was explored in the Kaplan-Meier plotter. RNA interference and lentivirus vectors were applied to construct knockdown and overexpressed cell models. Changes in the malignant behaviors of OC cells were detected by cholecystokinin octopeptide cell counting kit, wound healing, colony formation assay, transwell, flow cytometry assays, and in vivo experiments. Changes in proteins in the PI3K and autophagy-related makers were detected by western blot analysis.ResultsThe expression of MOB1A was significantly upregulated and accompanied by an inferior survival rate in OC. Knockdown of MOB1A inhibited the proliferation, invasion, migration, and cell cycle of OC cells, whereas induced cell autophagy. MOB1A upregulation had the opposite effects. In addition, bioinformatics analysis and western blot experiments showed that MOB1A plays an important role in the PI3K/AKT/mTOR pathway.ConclusionsOur findings indicated that MOB1A is highly expressed and related to poor prognosis in OC. MOB1A plays a role in promoting the malignant biological behavior of tumor cells through PI3K/AKT/mTOR signaling pathway.

LGALS1 regulates cell adhesion to promote the progression of ovarian cancer.

The present study aimed to explore the significance and molecular mechanisms of galectin-1 (LGALS1) in ovarian cancer (OC). Using the Gene Expression Omnibus database and The Cancer Genome Atlas database, the results of the present study demonstrated that LGALS1 mRNA expression was markedly increased in OC and associated with advanced tumor, lymphatic metastasis and residual lesions. In Kaplan-Meier analysis, patients who expressed LGALS1 highly had a poor prognosis. Furthermore, using The Cancer Genome Atlas database, differentially expressed genes that are potentially regulated by LGALS1 in OC were determined. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to build a biological network of upregulated differentially expressed genes. The results of the enrichment analysis revealed that the upregulated differentially expressed genes were primarily associated with 'ECM-receptor interaction', 'cell-matrix adhesion' and 'focal adhesion', which are closely associated with the metastasis of cancer cells. Subsequently, cell adhesion was selected for further analysis. The results demonstrated that LGALS1 was co-expressed with the candidate genes. Subsequently, the elevated expression levels of candidate genes were verified in OC tissues, and survival analysis indicated that high expression of candidate genes was associated with shortened overall survival of patients with OC. In the present study, OC samples were also collected to verify the high protein expression levels of LGALS1 and fibronectin 1. The results of the present study highlighted that LGALS1 may regulate cell adhesion and participate in the development of OC. Therefore, LGALS1 exhibits potential as a therapeutic target in OC.

Stability Characterization of the Novel Anti-Cancer HM-10/10 HDL-Mimetic Peptide.

Epithelial adenocarcinoma of the ovary and colon are associated with the highest rates of cancer-related deaths in women in the U.S. The literature supports the role of HDL-associated apolipoproteins in the treatment of cancer and other pro-inflammatory diseases. Previously, we developed a novel 20-amino acid mimetic peptide, HM-10/10, which potently inhibits tumor development and growth in colon and ovarian cancer. Here, we report the properties of HM-10/10 relative to its stability in vitro. The results demonstrated that HM-10/10 had the highest half-life in human plasma compared to plasma from other species tested. HM-10/10 demonstrated stability in human plasma and simulated gastric environment, increasing its promise as an oral pharmaceutical. However, under conditions modeling the small intestine, HM-10/10 demonstrated significant degradation, likely due to the peptidases encountered therein. Furthermore, HM-10/10 demonstrated no evidence of time-dependent drug-drug interactions, although it demonstrated CYP450 induction slightly above cutoff. As proteolytic degradation is a common limitation of peptide-based therapeutics, we are pursuing strategies to improve the stability properties of HM-10/10 by extending its bioavailability while retaining its low toxicity profile. HM-10/10 holds promise as a new agent to address the international women's health crisis of epithelial carcinomas of the ovary and colon.

MiR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway.

The miR-141-3p has been reported to participate in regulating autophagy and tumor-stroma interactions in ovarian cancer (OC). We aim to investigate whether miR-141-3p accelerates the progression of OC and its effect on macrophage 2 polarization by targeting the Kelch-like ECH-associated protein1-Nuclear factor E2-related factor2 (Keap1-Nrf2) pathway. SKOV3 and A2780 cells were transfected with miR-141-3p inhibitor and negative control to confirm the regulation of miR-141-3p on OC development. Moreover, the growth of tumors in xenograft nude mice treated by cells transfected with miR-141-3p inhibitor was established to further testify the role of miR-141-3p in OC. The expression of miR-141-3p was higher in OC tissue compared with non-cancerous tissue. Downregulation of miR-141-3p inhibited the proliferation, migration, and invasion of ovarian cells. Furthermore, miR-141-3p inhibition also suppressed M2-like macrophage polarization and in vivo OC progression. Inhibition of miR-141-3p significantly enhanced the expression of Keap1, the target gene of miR-141-3p, and thus downregulated Nrf2, while activation of Nrf2 reversed the reduction in M2 polarization by miR-141-3p inhibitor. Collectively, miR-141-3p contributes to tumor progression, migration, and M2 polarization of OC by activating the Keap1-Nrf2 pathway. Inhibition of miR-141-3p attenuates the malignant biological behavior of ovarian cells by inactivating the Keap1-Nrf2 pathway.

NSAID-Au(I) Complexes Induce ROS-Driven DAMPs and Interpose Inflammation to Stimulate the Immune Response against Ovarian Cancer.

Inflammation contributes to the development of ovarian cancer, and chemoresistance is a principal obstacle in ovarian cancer treatment. Herein, we designed and synthesized a series of gold(I) complexes derived from NSAIDs or their analogues. Among them, complex B3 (Npx-Au) displayed higher antitumor activity than cisplatin and other gold(I) complexes. Npx-Au could induce oxidative stress and the damage-associated molecular patterns (DAMPs) process by the inhibition of TrxR activity. Mechanistic studies revealed that simultaneous downregulation of COX-2 and PD-L1 was observed after Npx-Au treatment. Interestingly, in vivo experiments demonstrated that Npx-Au treatment could stimulate the immune response via reducing the expression of PD-L1, inducing DC maturation and increasing the infiltration of T (CD4+ and CD8+) cells. Collectively, our studies found that the gold(I) complex Npx-Au could elicit immunogenic cell death (ICD) and provide a promising strategy for chemotherapy combined with immunotherapy in the treatment of ovarian cancer.

Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer

Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.

Gut microbiota dysbiosis promotes the development of epithelial ovarian cancer via regulating Hedgehog signaling pathway

ABSTRACT Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, which remains a threat to female health at all ages. Hypotheses for EOC development include the continuous presence of inflammation, in which microbiota and inflammatory cytokines participate in cancer-related signaling pathway activation. Hedgehog (Hh) signaling is prominent for EOC progression, and interacts with inflammation response related to gut microbiota (GM). However, the precise roles of GM during this process are unknown. Here, we showed that the GM from patients with EOC differed from that of healthy women and had GM dysbiosis. We found that EOC modeling may lead to GM changes in mice, and it restored after the administration of GM from healthy controls, while GM from patients with EOC further exacerbated GM dysbiosis. Furthermore, we found that GM from EOC markedly promoted tumor progression and activated Hh signaling; meanwhile, it increased the extent of inflammation and activated NF-κB signaling, but GM from healthy controls improved them. Our results demonstrate how GM dysbiosis promoted EOC progression by activating Hh signaling mediated by TLR4/NF-κB signaling. We anticipate our assay to be a new thought for exploring the role of GM in EOC development. Furthermore, improving GM dysbiosis is a novel therapeutic approach for delaying EOC development.

GLORIOSA: A randomized, open-label, phase 3 study of mirvetuximab soravtansine with bevacizumab vs. bevacizumab as maintenance in platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

TPS5622 Background: Elevated folate receptor-alpha (FRα) expression is a characteristic of epithelial ovarian cancer (EOC), thereby providing a rational target for antibody drug conjugate (ADC) development in ovarian cancer. Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has received accelerated approval for patients with FRα positive platinum resistant ovarian cancer. MIRV in combination with BEV has demonstrated clinically meaningful activity, along with acceptable tolerability, in patients with FRα expressing ovarian cancer.1 Methods: GLORIOSA is a randomized, open-label, phase 3 study designed to evaluate the efficacy of in combination with bevacizumab compared with bevacizumab alone as maintenance for patients with FRα-positive recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancers who have not progressed after second line platinum-based chemotherapy plus bevacizumab (which may be given on protocol for patients with high FRα tumor expression). Confirmation of high FRα positivity by immunohistochemistry using the Ventana FOLR1 CDx Assay (high expression; ≥ 75% of viable tumor cells staining at 2+ intensity) and 1 prior line of therapy is required for inclusion. GLORIOSA is designed to randomize 418 patients, 1:1 receiving intravenous MIRV at a dose of 6 mg/kg adjusted ideal body weight plus bevacizumab 15mg/kg every 3 weeks or receiving bevacizumab 15mg/kg every 3 weeks until disease progression or unacceptable toxicity. Radiological assessments will be conducted every 9 weeks (± 2 weeks) for 72 weeks, and subsequently every 18 weeks (± 3 weeks) until progressive disease (PD), death, the start of new anticancer therapy, or withdrawal of consent from the study (whichever occurs first). The primary efficacy endpoint is progression-free survival by investigator and will also be assessed as a sensitivity analysis. The secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. GLORIOSA is a global study that opened for enrollment in December 2022. Reference: 1. Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023; 170: 241–247 Clinical trial information: NCT05445778 .