Ovarian Progression Research Articles

Mutant p53 Misfolding and Aggregation Precedes Transformation into High-Grade Serous Ovarian Carcinoma.

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.

Activated PARP1/FAK/COL5A1 signaling facilitates the tumorigenesis of cholesterol-resistant ovarian cancer cells through promoting EMT

Cancer cells require plentiful cholesterol for membrane biogenesis and other functional needs due to fast proliferating, leading to the interaction of cholesterol or its metabolites with cancer-related pathways. However, the impact of long-lasting high cholesterol concentrations on tumorigenesis and its underlying mechanisms remains largely unexplored. To the best of our knowledge, this study is the first to establish a cholesterol-resistant ovarian cancer cells, whose intracellular total cholesterol level up to 6–8 mmol/L. We confirmed that high cholesterol facilitated the progression of ovarian cancer in vitro and in vivo. Notably, our findings revealed significant upregulation of collagen type V alpha 1 chain (COL5A1) expression in cholesterol-resistant ovarian cancer cells and human ovarian cancer tissue, which was depended on FAK/Src activation. Mechanistically, PARP1 directly bound to FAK in response to activate FAK/Src/COL5A1 signaling. Intriguingly, COL5A1 depletion significantly impeded the tumorigenesis of these cells, concomitant with a decrease in epithelial-mesenchymal transition (EMT) progression. In conclusion, PARP1/FAK/COL5A1 signaling activation facilitated progression of cholesterol-resistant ovarian cancer cells by promoting EMT, thereby broadening a new therapeutic opportunity.

FHOD3 shows clinical significance in progression of ovarian cancer through regulation of caspase-3 signaling pathway

Ovarian cancer is a malignant disease threatening women’s life. Traditional therapies bring little benefits for the patients with distant metastasis or recurrence. FHOD3 gene was reported to promote progression in cancer. However, the role of FHOD3 in ovarian cancer is not known yet. To investigate the role of FHOD3 gene in the progression of ovarian cancer and its molecular mechanism, FHOD3 gene was successfully knocked down in ovarian cancer cell lines. Then cell behaviors includes proliferation, migration, invasion, and apoptosis were detected. The data demonstrated that cell proliferation, migration, and invasion ability were suppressed after FHOD3 knockdown. Cell apoptosis was induced reversely. Moreover, caspase-3-mediated signaling pathway was activated after FHOD3 knockdown, and activity of caspase-3 further supported this finding. In addition, PARP inhibitor, Olaparib showed much more potent inhibition in ovarian cancer cells with FHOD3 knockdown. In clinical ovarian cancer tissues, FHOD3 gene showed increased expression compared to adjacent normal tissues. And FHOD3 gene expression level was negatively correlated to the patients’ survival. Overall, these findings shed light on the significance of FHOD3 gene in progression of ovarian cancer. This study showed that FHOD3 gene might be exploited as a new target to improve the clinical outcome of ovarian cancer.

Screening of potential targets and small-molecule drugs related to lipid metabolism in ovarian cancer based on bioinformatics

Backgroundabout 70 % of ovarian cancer (OC) patients with postoperative chemotherapy relapse within 2–3 years due to drug resistance and metastasis, and the 5-year survival rate is only about 30 %. Lipid metabolism plays an important role in OC. We try to explore the potential targets and drugs related to lipid metabolism to provide clues for the treatment of OC. Methodsthe gene expression profiles of OC and normal ovarian tissue samples were obtained from the cancer genome atlas (TCGA) and genotype-tissue expression databases (GTEx). The differentially expressed genes (DEGs) were analyzed. Lipid metabolism related genes (LMRGs) were downloaded from MSigDB database. The DEGs related to lipid metabolism in OC was obtained by intersection. And gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses were performed. The protein-protein interaction (PPI) network of lipid metabolism related DEGs was constructed, and seven algorithms were used to screen core potential target genes. Its expression in OC and prognostic ability were analyzed by Univariate Cox. Cmap database mining OC lipid metabolism related potential small-molecular drugs and docking. CCK8, scratch assay, transwell test and free fatty acid (FFA) assay, fluorescence detection of cellular fatty acid uptake, and the reactivity assay of CPT1A were used to detect the biological effects of drugs on OC cell.Rreverse transcription PCR(RT-qPCR) and WesternBlot were performed to measure the expression of core targets. Results437 DEGs related to lipid metabolism of OC were screened. GO and KEGG analysis showed that these DEGs were lipid metabolism, fatty acid metabolism, sphingolipid metabolism, PPAR signal pathway and so on. The PPI network based on lipid metabolism DEGs consists of 301 nodes and 1107 interaction pairs, and 6 core target genes were screened. ROC curve analysis showed that all of the 6 genes could predict the prognosis of OC. Three small molecular drugs Cephaeline, AZD8055 and GSK-1059615 were found by cmap and molecular docking showed that they all had good binding ability to target gene. Cephaeline has the strongest inhibitory effect on SKOV3 cells of OC, and could significantly inhibit cell migration and invasion regulate the mRNA and protein expression of some targets, and inhibit lipid metabolism process in ovarian cancer cells. Conclusionsix OC potential genes related to lipid metabolism were identified and verified, which can be used as potential biomarkers and therapeutic targets to evaluate the prognostic risk of OC patients. In addition, three small-molecular drugs that may be effective in the treatment of OC were unearthed, among which Cephaeline has the most potential. We speculate that Cephaeline may target six genes to inhibit progression of OC by affecting lipid metabolism.

USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2.

Post-translational modifications of proteins play a pivotal role in both the initiation and progression of ovarian cancer. Despite the recognition of USP33 as a significant factor in various cancers, its specific function and underlying mechanisms in ovarian cancer remain elusive. Proteomics and ubiquitinomics approaches were coupled to screen novel substrate proteins directly regulated by USP33. Our findings unveil that USP33 was observed to eliminate K27- and K48-linked ubiquitin chains from CBX2 at the K277 position. Notably, acetylation of CBX2 at K199, catalyzed by lysine acetyltransferase GCN5, was found to enhance its interaction with USP33, subsequently promoting further deubiquitination and stabilization. Functionally, our experiments demonstrate that USP33 significantly enhances ovarian cancer proliferation and metastasis in a CBX2-dependent manner. Furthermore, analysis revealed a direct positive correlation between the expression levels of USP33 and CBX2 proteins in human specimens, with elevated levels being associated with reduced survival rates in ovarian cancer patients. These findings elucidate the mechanism by which USP33 augments ovarian cancer progression through the stabilization of CBX2, underscoring the USP33-CBX2 axis as a promising therapeutic target in ovarian cancer management.

Hsa_circ_0000129 targets miR-383-5p/tropomyosin 3 axis to facilitate ovarian cancer progression.

Ovarian cancer is one of the most prevalent malignancies among women. CircRNAs play key roles in the progression of ovarian cancer. This study aimed to investigate the mechanism of action of hsa_circ_0000129 and its effects on ovarian cancer. Expression of hsa_circ_0000129, tropomyosin 3 (TPM3), and miR-383-5p in ovarian cancer cell lines and tissue specimens was detected using qRT-PCR or western blotting. Cell counting kit-8 (CCK-8), colony formation, and transwell assays were performed to assess viability, proliferation, and migration of ovarian cancer cells. A xenograft model was used to study tumorigenicity of ovarian cancer cells in vivo. Luciferase and RNA immunoprecipitation assays were performed to determine binding between miR-383-5p and hsa_circ_0000129 or TPM3. Upregulation of hsa_circ_0000129 and TPM3 and downregulation of miR-383-5p were observed in ovarian cancer. Low hsa_circ_0000129 and TPM3 expression repressed viability, migration, and proliferation of ovarian cancer cells. Inhibition of miR-383-5p had a contrary effect. Furthermore, knockdown of hsa_circ_0000129 restricted the tumorigenicity of ovarian cancer cells. Mechanistically, hsa_circ_0000129 has a sponging effect on miR-383-5p, which targets TPM3. Hsa_circ_0000129 stimulated development of the malignant ovarian cancer phenotype by sponging miR-383-5p and releasing TPM3.

Targeting RAC1 reactivates pyroptosis to reverse paclitaxel resistance in ovarian cancer by suppressing P21-activated kinase 4.

Pyroptosis may play an important role in the resistance of ovarian cancer (OC) to chemotherapy. However, the mechanism by which pyroptosis modulation can attenuate chemotherapy resistance has not been comprehensively studied in OC. Here, we demonstrated that RAS-associated C3 botulinum toxin substrate 1 (RAC1) is highly expressed in OC and is negatively correlated with patient outcomes. Through cell function tests and in vivo tumor formation tests, we found that RAC1 can promote tumor growth by mediating paclitaxel (PTX) resistance. RAC1 can mediate OC progression by inhibiting pyroptosis, as evidenced by high-throughput automated confocal imaging, the release of lactate dehydrogenase (LDH), the expression of the inflammatory cytokines IL-1β/IL-18 and the nucleotide oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Mechanically, RNA-seq, gene set enrichment analysis (GSEA), coimmunoprecipitation (Co-IP), mass spectrometry (MS), and ubiquitination tests further confirmed that RAC1 inhibits caspase-1/gasdermin D (GSDMD)-mediated canonical pyroptosis through the P21-activated kinase 4 (PAK4)/mitogen-activated protein kinase (MAPK) pathway, thereby promoting PTX resistance in OC cells. Finally, the whole molecular pathway was verified by the results of in vivo drug combination tests, clinical specimen detection and the prognosis. In summary, our results suggest that the combination of RAC1 inhibitors with PTX can reverse PTX resistance by inducing pyroptosis through the PAK4/MAPK pathway.

ATUALIZAÇÕES EM BIOMARCADORES PARA DIAGNÓSTICO PRECOCE DE DOENÇAS ÓSSEAS

Introduction: Biomarkers play a crucial role in the early identification of diseases and the assessment of treatment response. This study aims to explore the efficacy of different biomarkers in predicting and monitoring chronic diseases, with a focus on cardiovascular and oncological conditions. Methodology: A systematic review of studies published between 2010 and 2023 was conducted, analyzing the validity and applicability of specific biomarkers such as troponin, BNP (B-type natriuretic peptide), and CA-125. Randomized controlled trials, cohort studies, and meta-analyses were included. The quality of the studies was assessed using the Jadad scale and the Newcastle-Ottawa method. Results: The analyzed biomarkers showed high sensitivity and specificity for early diagnosis and monitoring of diseases. Troponin was particularly effective in detecting myocardial infarction, while BNP performed well in assessing heart failure. CA-125 was useful for monitoring ovarian cancer progression but had limitations in early detection. Discussion: The analysis indicates that biomarkers can provide valuable information for managing chronic diseases, improving diagnosis and treatment follow-up. However, the accuracy of biomarkers may be affected by variables such as comorbidities and individual patient characteristics. Further studies are needed to validate and refine the use of these biomarkers in different clinical contexts. Conclusion: Biomarkers are promising tools for the detection and monitoring of chronic diseases, with the potential to transform clinical practice. The implementation of biomarkers should be accompanied by further studies to ensure their efficacy and accuracy in various clinical scenarios.

SVIL promotes ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions through the TGF-β/Smad pathway

ObjectiveOvarian cancer is the malignant tumor with the highest mortality rate in gynecology. We aimed to identify novel genes that promote ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions. MethodsWe screened SVIL as a hypoxia-associated target in ovarian cancer and explored the related molecular mechanisms. We assessed the effects of SVIL on ovarian cancer progression and metastasis in clinical samples and cellular hypoxia models. Further, we investigated the relevant pathways of SVIL and confirmed the effects of SVIL on ovarian cancer progression by using nude mouse in situ tumor models. ResultsWe found that SVIL was significantly highly expressed in the hypoxic environment of ovarian cancer, and SVIL expression correlated with patient prognosis.CCK8, Wound-healing assay, Transwell assay, Western Blot, and apoptosis assays revealed that knockdown of SVIL inhibited the activation of the TGFβ1/smad2/3 pathway, which attenuated the progression and epithelial-mesenchymal transition(EMT) of ovarian cancer and alleviated cisplatin resistance by increasing cisplatin-induced apoptosis. Furthermore, in a nude mouse ovarian cancer in situ model, we found that the knockdown of SVIL significantly inhibited tumor growth and metastasis. ConclusionSVIL highly expressed in the hypoxic microenvironment can increase ovarian cancer progression and cisplatin resistance by activating TGFβ1/smad2/3 pathway. Our study demonstrated that SVIL may be a novel target for the treatment of ovarian cancer.

Platelet and epithelial cell interations can be modeled in cell culture, and are not affected by dihomo-gamma-linolenic acid.

Increasing evidence is implicating roles for platelets in the development and progression of ovarian cancer, a highly lethal disease that can arise from the fallopian tubes, and has no current method of early detection or prevention. Thrombosis is a major cause of mortality of ovarian cancer patients suggesting that the cancer alters platelet behavior. The objective of this study was to develop a cell culture model of the pathological interactions of human platelets and ovarian cancer cells, using normal FT epithelial cells as a healthy control, and to test effects of the anti-platelet dihomo-gamma-linolenic acid (DGLA) in the model. Both healthy and cancer cells caused platelet aggregation, however platelets only affected spheroid formation by cancer cells and had no effect on healthy cell spheroid formation. When naturally-formed spheroids of epithelial cells were exposed to platelets in transwell inserts that did not allow direct interactions of the two cell types, platelets caused increased size of the spheroids formed by cancer cells, but not healthy cells. When cancer cell spheroids formed using magnetic nanoshuttle technology were put in direct physical contact with platelets, the platelets caused spheroid condensation. In ovarian cancer cells, DGLA promoted epithelial-to-mesenchymal (EMT) transition at doses as low as 100 μM, and inhibited metabolic viability and induced apoptosis at doses ≥150 μM. DGLA doses ≤150 μM used to avoid direct DGLA effects on cancer cells, had no effect on the pathological interactions of platelets and ovarian cancer cells in our models. These results demonstrate that the pathological interactions of platelets with ovarian cancer cells can be modeled in cell culture, and that DGLA has no effect on these interactions, suggesting that targeting platelets is a rational approach for reducing cancer aggressiveness and thrombosis risk in ovarian cancer patients, however DGLA is not an appropriate candidate for this strategy.

Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-β/SMADs signaling pathway

Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25–2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-β/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-β/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

Retracted] miR‑148a‑3p suppresses epithelial ovarian cancer progression primarily by targeting c‑Met.

[This retracts the article DOI: 10.3892/ol.2018.8110.].

Ovarian cancer derived extracellular vesicles promote the cancer progression and angiogenesis by mediating M2 macrophages polarization

BackgroundExtracellular vesicles (EVs) are mediators between cancer cells and other types of cells, such as tumor-associated macrophages (TAMs), in the tumor microenvironment. EVs can remodel the tumor microenvironment and regulate tumor progression. However, the underlying molecular mechanism of these interactions remains unclear.MethodsFirst, we explored the effect of TAMs on the survival prognosis of patients with ovarian cancer. Next, we isolated EVs derived from ovarian cancer cells (OV-EVs) through ultracentrifugation and analyzed the capacity of OV-EVs to regulate macrophage polarization in ovarian tumors and in whole peripheral blood. Moreover, we explored the roles of OV-EVs-induced macrophages in tumor progression through in vitro and in vivo assays.ResultsOV-EVs were encapsulated by macrophages and induced the polarization of macrophages toward the M2 phenotype. Moreover, OV-EVs-induced M2 macrophages promoted angiogenesis and cancer progression both in vitro and in vivo. In addition, OV-EVs-induced macrophages increased the expression level of VEGF and increased the expression level of VEGFR in tumors, which resulted in angiogenesis in ovarian cancer.ConclusionsThe present study demonstrated that OV-EVs induce M2 polarization in macrophages and promote the progression of ovarian cancer. This study provides novel insight into the mechanism of ovarian cancer progression.

BBOX1 mediates metabolic reprogramming driven by hypoxia and participates in the malignant progress of high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer that causes great threats to women's health. Therefore, we performed RNA-sequencing technology in clinical samples to explore the molecular mechanisms underlying the progression of HGSOC. We then noticed BBOX1, a kind of 2-oxoglutarate-dependent enzyme that is highly expressed in HGSOC tumor tissues. Functional studies showed that BBOX1 promotes cell survival and growth of HGSOC cells in vitro and in vivo. Overexpression of the wild-type BBOX1 promoted cell proliferation, but the Asn191 and Asn292 mutation (key amino acid for the enzymatic activity of BBOX1) counteracted this effect (P < 0.05), which indicated that the promotion effect of BBOX1 on HGSOC cell proliferation was related to its catalytic activity. Downregulation of BBOX1 reduced the activity of the mTORC1 pathway, and decreased protein expression of IP3R3 and phosphorylation level of S6KThr389. Metabolomics analysis revealed that BBOX1 is implicated in the glucose metabolism, amino acid metabolism, and nucleotide metabolism of HGSOC cells. In addition, inhibition of BBOX1 suppressed HGSOC cell glycolysis and decreased glucose consumption, lactate production, and the expression of key factors in glycolysis. Finally, we found hypoxia induced the expression of BBOX1 in HGSOC cells and confirmed that BBOX1 could be transcriptionally activated by hypoxia-inducible factor-1α, which could directly bind to the BBOX1 promoter. In summary, BBOX1 mediated the metabolic reprogramming driven by hypoxia, and affected cell metabolism through the mTORC1 pathway, thus acting as an oncogene during HGSOC development.

Hsa_circ_0020093 suppresses ovarian cancer progression by modulating LRPPRC activity and miR-107/LATS2 signaling

A substantive body of evidence has demonstrated the significant roles of circular RNA (circRNA) in cancer. However, the contribution of dysregulated circRNAs to ovarian cancer (OC) remains elusive. We aim to elucidate the critical roles and mechanisms of hsa_circ_0020093, which was demonstrated to be downregulated in OC tissues in our previous study. In this study, we confirmed the decreased expression of hsa_circ_0020093 in OC tissues and cell lines and demonstrated the negative correlation between its expression and FIGO stage, abdominal implantation and CA125 level of OC patients. Through gain and loss of function studies, we confirmed the inhibitory role of hsa_circ_0020093 in ovarian tumor growth in vitro and in vivo. Mechanistically, based on the peri-nuclear accumulation of hsa_circ_0020093, we discovered the interaction between hsa_circ_0020093 and the mitochondrial protein LRPPRC by RNA pull-down, mass spectrometry, RNA Binding Protein Immunoprecipitation. As a result, qRT-PCR and transmission electron microscopy results showed that the mitochondria mRNA expression and mitochondria abundance were decreased upon hsa_circ_0020093-overexpression. Meanwhile, we also unearthed the hsa_circ_0020093/miR-107/LATS2 axis in OC according to RNA-sequencing, RIP and luciferase reporter assay data. Furthermore, LRPPRC and LATS2 are both reported as the upstream regulators of YAP, our study also studied the crosstalk between hsa_circ_0020093, LRPPRC and miR-107/LATS2, and unearthed the up-regulation of phosphorylated YAP in hsa_circ_0020093-overexpressing OC cells and xenograft tumors. Collectively, our study indicated the novel mechanism of hsa_circ_0020093 in suppressing OC progression through both hsa_circ_0020093/LRPPRC and hsa_circ_0020093/miR-107/LATS2 axes, providing a potential therapeutic target for OC patients.

SUGT1 regulates the progression of ovarian cancer through the AKT/PI3K/mTOR signaling pathway

This study investigates the expression and functional roles of SUGT1 in ovarian cancer, utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Our analyses reveal that SUGT1 is significantly upregulated in ovarian cancer tissues compared to normal controls. We further explore the prognostic value of SUGT1, where elevated expression correlates with poorer patient outcomes, particularly in ovarian cancer. The functional implications of SUGT1 in cancer biology were assessed through in vitro and in vivo experiments. Gene Set Enrichment Analysis (GSEA) indicates a significant association between high SUGT1 expression and the activation of glycolytic pathways, suggesting a potential role in metabolic reprogramming. Inhibition of SUGT1 via siRNA in ovarian cancer cell lines results in decreased proliferation and increased apoptosis, along with reduced migration and invasion capabilities. Additionally, our study identifies the transcription factor ELF1 as a significant regulator of SUGT1 expression. Through promoter analysis and chromatin immunoprecipitation, we demonstrate that ELF1 directly binds to the SUGT1 promoter, enhancing its transcription. This regulatory mechanism underscores the importance of transcriptional control in cancer metabolism, providing insights into potential therapeutic targets. Our findings establish SUGT1 as a crucial player in the oncogenic processes of ovarian cancer, influencing both metabolic pathways and transcriptional regulation. This highlights its potential as a biomarker and therapeutic target in managing ovarian cancer.

ETS1 drives EGF-induced glycolytic shift and metastasis of epithelial ovarian cancer cells

Epithelial ovarian cancer (EOC), a leading cause of gynecological cancer-related morbidity and mortality and the most common type of ovarian cancer (OC), is widely characterized by alterations in the Epidermal Growth Factor (EGF) signaling pathways. The phenomenon of metastasis is largely held accountable for the majority of EOC-associated deaths. Existing literature reports substantiate evidence on the indispensable role of metabolic reprogramming, particularly the phenomenon of the ‘Warburg effect’ or aerobic glycolysis in priming the cancer cells towards Epithelial to Mesenchymal transition (EMT), subsequently facilitating EMT. Considering the diverse roles of growth factor signaling across different stages of oncogenesis, our prime emphasis was laid on unraveling mechanistic details of EGF-induced ‘Warburg effect’ and resultant metastasis in EOC cells. Our study puts forth Ets1, an established oncoprotein and key player in OC progression, as the prime metabolic sensor to EGF-induced cues from the tumor microenvironment (TME). EGF treatment has been found to induce Ets1 expression in OC cells predominantly through the Extracellular Signal-Regulated Kinase1/2 (ERK1/2) pathway activation. This subsequently results in pronounced glycolysis, characterized by an enhanced lactate production through transcriptional up-regulation of key determinant genes of the central carbon metabolism namely, hexokinase 2 (HK2) and monocarboxylate transporter 4 (MCT4). Furthermore, this study reports an unforeseen combinatorial blockage of HK2 and MCT4 as an effective approach to mitigate cellular metastasis in OC. Collectively, our work proposes a novel mechanistic insight into EGF-induced glycolytic bias in OC cells and also sheds light on an effective therapeutic intervention approach exploiting these insights.

PPM1F regulates ovarian cancer progression by affecting the dephosphorylation of ITGB1.

PPM1F has been shown to play diverse biological functions in the progression of multiple tumors. PPM1F controls the T788/T789 phosphorylation switch of ITGB1 and regulates integrin activity. However, the impacts of PPM1F and ITGB1 on ovarian cancer (OV) progression remain unclear. Whether there is such a regulatory relationship between PPM1F and ITGB1 in ovarian cancer has not been studied. Therefore, the purpose of this study is to elucidate the function and the mechanism of PPM1F in ovarian cancer. The expression level and the survival curve of PPM1F were analyzed by databases. Gain of function and loss of function were applied to explore the function of PPM1F in ovarian cancer. A tumor formation assay in nude mice showed that knockdown of PPM1F inhibited tumor formation. We tested the effect of PPM1F on ITGB1 dephosphorylation in ovarian cancer cells by co-immunoprecipitation and western blotting. Loss of function was applied to investigate the function of ITGB1 in ovarian cancer. ITGB1-mut overexpression promotes the progression of ovarian cancer. Rescue assays showed the promoting effect of ITGB1-wt on ovarian cancer is attenuated due to the dephosphorylation of ITGB1-wt by PPM1F. PPM1F and ITGB1 play an oncogene function in ovarian cancer. PPM1F regulates the phosphorylation of ITGB1, which affects the occurrence and development of ovarian cancer.

MTCH2 promotes the malignant progression of ovarian cancer through the upregulation of AIMP2 expression levels, mitochondrial dysfunction and by mediating energy metabolism.

Ovarian cancer (OC) is a gynecological malignancy that ranks among the most common female cancers worldwide and notably reduces a patient's quality of life. Mitochondrial carrier homology 2 (MTCH2) is a mitochondrial outer membrane protein that serves a regulatory role in mitochondrial metabolism and cell death. The precise contribution and underlying molecular pathways of MTCH2 in the context of OC development is currently unclear. The present study aimed to investigate the roles of MTCH2 in the energy metabolism, cell proliferation and metastatic potential of OC cells and evaluate the regulatory relationship between MTCH2, aminoacyl transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2) and claudin-3. An analysis of 67 patients with high-grade serous OC demonstrated increased expression levels of MTCH2, AIMP2 and claudin-3 in OC tumor tissue samples compared with in corresponding normal tissues adjacent to OC tissue samples. MTCH2 overexpression was significantly associated with the International Federation of Gynecology and Obstetrics stage and tumor differentiation of the OC tumor samples. In vitro experiments using the SK-OV-3 OC cell line demonstrated that MTCH2 exerts a regulatory effect on the cell proliferation, invasion and migratory capabilities of these cells. Knockdown of MTCH2 reduced ATP production, induced mitochondrial dysfunction and promoted cytoskeleton remodeling and apoptosis in SK-OV-3 OC cells. In addition, MTCH2 knockdown downregulated the expression levels of both claudin-3 and AIMP2 proteins. Knockdown of AIMP2 inhibited the regulatory effect of MTCH2. Co-immunoprecipitation experiments demonstrated that MTCH2 interacts with AIMP2 and claudin-3. The present study provides novel insights into the treatment of OC metastasis, as MTCH2 was demonstrated to serve roles in the progression of OC cells through the regulation of claudin-3 via AIMP2, which could provide novel insights into the treatment of ovarian cancer metastasis.

Salidroside exerts anti-tumor effects in ovarian cancer by inhibiting STAT3/c-Myc pathway-mediated glycolysis.

Salidroside (SAL) is a bioactive substance extracted from the traditional Chinese medicine Rhodiola rosea, which exhibits multiple pharmacological effects, such as anti-inflammatory, antioxidant, and anti-tumor properties. Currently, the effects of SAL on the malignant progression of ovarian cancer (OC) and its specific mechanism of action are not clear. Cell Counting Kit 8 (CCK-8), clone formation, Hoechst 33258 staining, flow cytometry, transwell, western blotting and immunofluorescence assays were performed to determine the impacts of SAL on the biological properties of OC cells (CAOV3 and SKOV3) and human normal ovarian epithelial cells (IOSE80). The binding activity of SAL and proteins was evaluated. Glucose consumption, lactate and ATP production, extracellular acidification rate (ECAR) and related proteins were measured to assess glycolysis. Animal models were established to evaluate the impact of SAL treatment in vivo and the expression levels of STAT3/c-Myc pathway-related proteins were determined to explore the relationship between SAL and OC. The results showed that SAL reduced the viability, clone formation, migration and invasion ability of CAOV3 and SKOV3 cells, and induced apoptosis. SAL inhibited epithelial-mesenchymal transition (EMT) and decreased glucose consumption, lactate and ATP production and ECAR. SAL exhibited good binding activity with STAT3 and c-Myc and reduced the expression levels of STAT3/c-Myc pathway and glycolysis-related proteins in vitro and in vivo. In conclusion, SAL exerted anti-tumor effects by interfering with the malignant biological progression of OC cells by inhibiting STAT3/c-Myc pathway-mediated glycolysis.