Ovarian Progression Research Articles

ZFHX2-AS1 interacts with DKC1 to regulate ARHGAP5 pseudouridylation and suppress ovarian cancer progression

Ovarian cancer (OCa) remains a highly lethal disease, largely due to late-stage diagnosis and limited treatment options for recurrent metastatic tumors. Long non-coding RNAs (lncRNAs) have been recognized as key regulators of cancer hallmarks, yet their specific roles in driving OCa progression are not fully understood. In this study, we employed an integrated approach combining clinical correlation, functional assays, and mechanistic investigations to reveal that lncRNA ZFHX2-AS1 is significantly downregulated in OCa tissues and cells, with its reduced expression associated with poor clinical outcomes. Using in vitro and in vivo models, we demonstrated that overexpression of ZFHX2-AS1 suppresses OCa cell proliferation, migration and invasion, whereas ZFHX2-AS1 knockdown enhances these malignant phenotypes. Mechanistically, we defined that ZFHX2-AS1 interacts with and attenuates the enzymatic activity of the pseudouridine synthase DKC1, thereby reducing pseudouridylation and stabilizing the oncogenic ARHGAP5 mRNA. Re-expression of ARHGAP5 could partially reverse the tumor-suppressive effects of ZFHX2-AS1. Further, we found that ARHGAP5 promotes epithelial-mesenchymal transition (EMT) by regulating Rho GTPases activities, and that ZFHX2-AS1 inhibits EMT in OCa by downregulating ARHGAP5 expression and suppressing the Rho GTPase signaling pathway. Taken together, our findings identify ZFHX2-AS1 as a potent tumor suppressor in OCa, acting through the modulation of DKC1-mediated pseudouridylation of ARHGAP5 and the inhibition of the Rho GTPase pathway, thus offering a potential therapeutic target for combating OCa progression.

YKL40/Integrin β4 Axis Induced by the Interaction between Cancer Cells and Tumor-Associated Macrophages Is Involved in the Progression of High-Grade Serous Ovarian Carcinoma.

Macrophages in the tumor microenvironment, termed tumor-associated macrophages (TAMs), promote the progression of various cancer types. However, many mechanisms related to tumor-stromal interactions in epithelial ovarian cancer (EOC) progression remain unclear. High-grade serous ovarian carcinoma (HGSOC) is the most malignant EOC subtype. Herein, immunohistochemistry was performed on 65 HGSOC tissue samples, revealing that patients with a higher infiltration of CD68+, CD163+, and CD204+ macrophages had a poorer prognosis. We subsequently established an indirect co-culture system between macrophages and EOC cells, including HGSOC cells. The co-cultured macrophages showed increased expression of the TAM markers CD163 and CD204, and the co-cultured EOC cells exhibited enhanced proliferation, migration, and invasion. Cytokine array analysis revealed higher YKL40 secretion in the indirect co-culture system. The addition of YKL40 increased proliferation, migration, and invasion via extracellular signal-regulated kinase (Erk) signaling in EOC cells. The knockdown of integrin β4, one of the YKL40 receptors, suppressed YKL40-induced proliferation, migration, and invasion, as well as Erk phosphorylation in some EOC cells. Database analysis showed that high-level expression of YKL40 and integrin β4 correlated with a poor prognosis in patients with serous ovarian carcinoma. Therefore, the YKL40/integrin β4 axis may play a role in ovarian cancer progression.

Chemotherapy Enriches for Proinflammatory Macrophage Phenotypes that Support Cancer Stem-Like Cells and Disease Progression in Ovarian Cancer.

High-grade serous ovarian cancer remains a poorly understood disease with a high mortality rate. Although most patients respond to cytotoxic therapies, a majority will experience recurrence. This may be due to a minority of drug-resistant cancer stem-like cells (CSC) that survive chemotherapy and are capable of repopulating heterogeneous tumors. It remains unclear how CSCs are supported in the tumor microenvironment (TME) particularly during chemotherapy exposure. Tumor-associated macrophages (TAM) make up half of the immune population of the ovarian TME and are known to support CSCs and contribute to cancer progression. TAMs are plastic cells that alter their phenotype in response to environmental stimuli and thus may influence CSC maintenance during chemotherapy. Given the plasticity of TAMs, we studied the effects of carboplatin on macrophage phenotypes using both THP1- and peripheral blood mononuclear cell (PBMC)-derived macrophages and whether this supports CSCs and ovarian cancer progression following treatment. We found that carboplatin exposure induces an M1-like proinflammatory phenotype that promotes SOX2 expression, spheroid formation, and CD117+ ovarian CSCs, and that macrophage-secreted CCL2/MCP-1 is at least partially responsible for this effect. Depletion of TAMs during carboplatin exposure results in fewer CSCs and prolonged survival in a xenograft model of ovarian cancer. This study supports a role for platinum-based chemotherapies in promoting a transient proinflammatory M1-like TAM that enriches for CSCs during treatment. Improving our understanding of TME responses to cytotoxic drugs and identifying novel mechanisms of CSC maintenance will enable the development of better therapeutic strategies for high-grade serous ovarian cancer. Significance: We show that chemotherapy enhances proinflammatory macrophage phenotypes that correlate with ovarian cancer progression. Given that macrophages are the most prominent immune cell within these tumors, this work provides the foundation for future translational studies targeting specific macrophage populations during chemotherapy, a promising approach to prevent relapse in ovarian cancer.

The lncRNA TPTEP1 suppresses PI3K/AKT signalling and inhibits ovarian cancer progression by interacting with PTBP1.

The expression of the long noncoding RNA (lncRNA) TPTE pseudogene 1 (TPTEP1) is significantly downregulated in ovarian cancer (OC). However, the function and mechanism of the lncRNA TPTEP1 in OC have not been identified. To investigate the expression of the lncRNA TPTEP1, we analysed a publicly available dataset and 20 pairs of OC and normal ovarian samples tissue from the First Affiliated Hospital of Anhui Medical University. Functional assays were used to determine the role of the lncRNA TPTEP1 in OC progression. Furthermore, Western blot, FISH, RNA pull-down, mass spectrometry and RNA immunoprecipitation approaches were used to determine the mechanism by which the lncRNA TPTEP1 affects OC progression. Animal experiments were used to determine the role of the lncRNA TPTEP1 in ovarian tumorigenicity invivo. The expression of the lncRNA TPTEP1 in OC tissues was significantly lower than that in normal tissues and low expression of the lncRNA TPTEP1 was significantly correlated with advanced FIGO stage and the presence of malignant ascites in OC patients. Invitro and invivo, regulation of the expression of the lncRNA TPTEP1 caused changes in OC cell proliferation, migration, invasion and apoptosis. Mechanistically, we found that TPTEP1 directly binds to the polypyrimidine tract-binding protein 1 (PTBP1) protein and inhibits PI3K/AKT signalling. The lncRNA TPTEP1 inhibits PI3K/AKT signalling by directly binding PTBP1, possibly indicating the molecular mechanism underlying its biological function. With further research, these findings may aid in the development of clinically useful strategies for the treatment of OC.

Exosomal AHSG in ovarian cancer ascites inhibits malignant progression of ovarian cancer by p53/FAK/Src signaling.

The primary cause of mortality in patients with ovarian cancer (OC) is tumor metastasis. A comprehensive understanding of the mechanisms underlying metastasis in OC is essential for accurate prognosis prediction and the development of targeted therapeutic agents. Our findings indicate that alpha-2 Heremans Schmid glycoprotein (AHSG) is downregulated in OC exosomes. Consequently, the objective of this study was to identify novel prognostic markers and potential therapeutic targets for OC. Exosomes derived from OC cells and patient ascites were purified and applied to OC cells to assess their migratory ability using wound-healing and transwell assays. AHSG expression was enhanced by overexpressing lentivirus, and the resulting exosomes were isolated and co-cultured with OC cells to verify their effect on the migration ability of OC. Exosomes in ovarian malignant ascites have been demonstrated to promote OC metastasis. However, our findings indicate that AHSG is down-regulated in OC tissues and ascites exosomes. Furthermore, overexpression of AHSG in OC cells has been shown to markedly decrease their migratory ability, as well as reduce the migratory ability of cancer cells after co-culture of its exosomes with cancer cells. The low expression of AHSG in exosomes derived from OC tissues and ascites is associated with metastatic progression in OC patients. Additionally, cancer-derived AHSG can be transported to OC cells via exosomes, where it inhibits OC migration in vitro and in vivo by regulating the p53/FAK/Src signaling pathway. The present study demonstrated that AHSG, derived from cancer cells, exerts a negative regulatory effect on OC cell motility, migration, and metastasis. These findings suggest that AHSG is a potential candidate for OC treatment.

HDAC7 promotes ovarian cancer malignancy via AKT/mTOR signalling pathway.

Ovarian cancer is of the most lethal malignancy and causes serious threat to women health worldwide. A deep understanding of molecular mechanisms underlying ovarian cancer progression is critical for the development of promising therapeutic strategies. In this study, we aimed to employ immunohistochemistry to determine the protein level of HDAC7 in patient tissues, our data showed HDAC7 levels are upregulated in tumour tissues. In addition, we also performed Kaplan-Meier survival analysis to investigate the association between HDAC7 expression and clinical prognosis, and found that HDAC7 expression was associated with poor prognosis in ovarian cancer patients. Inhibition of HDAC7 cells resulted in lower cell proliferation, invasion and colony formation. Furthermore, we also found that HDAC7 inhibition suppressed PI3K/AKT/mTOR pathway. In contrast, exogenous HDAC7 expression activated the PI3K/AKT/mTOR pathway in HDAC7 knockout cells and rescued the cell proliferation, invasion and colony formation. However, inhibition of p-AKT induced lower cell proliferation, metastasis and colony formation abilities. In murine model, HDAC7 KO significantly decreased the tumour burden. These data indicate that HDAC7 is involved in regulation of PI3K/AKT/mTOR pathway and targeting of HDAC7 could be potential therapeutic strategy in the treatment of ovarian cancer.

PDK1 promotes epithelial ovarian cancer progression by upregulating BGN

PDK1 promotes epithelial ovarian cancer progression by upregulating BGN

Actin-related protein 2/3 complex subunit 1B promotes ovarian cancer progression by regulating the AKT/PI3K/mTOR signaling pathway.

Actin-related protein 2/3 complex subunit 1B (ARPC1B) is an essential subunit of the actin-related protein 2/3 (Arp2/3) complex. While there have been numerous research reports on Arp2/3 in relation to tumors, there needs to be more research on ARPC1B and its role in tumors, particularly at the pan-cancer level. Utilizing data from the cancer genome atlas (TCGA) and genotype-tissue expression (GTEx) databases, we analyzed ARPC1B expression differences in normal, tumor, and adjacent tissues, investigating its correlation with prognosis and clinical stages in various cancers. We conducted gene enrichment analysis and explored ARPC1B's connection to the tumor immune microenvironment and its impact on anti-tumor drug resistance. In addition, in vivo and in vitro experiments have also been carried out to find the mechanism of ARPC1B on ovarian cancer (OV) proliferation and invasion. ARPC1B was highly expressed in 33 tumor types, suggesting its role as a tumor-promoting factor. Its expression correlated with poor prognosis and served as a clinical staging marker in over 10 tumor types. ARPC1B is implicated in various biological processes and signaling pathways, uniquely associated with tumor immunity, indicating immunosuppressive conditions in high-expression cases. High ARPC1B expression was linked to resistance to six anti-tumor drugs. Further experiments showed that ARPC1B can affect the proliferation, apoptosis, migration, and invasion of OV cells through the AKT/PI3K/mTOR pathway. ARPC1B is a biomarker for immune suppression, prognosis, clinical staging, and drug resistance, providing new insights for cancer therapeutics.

Exploring Molecular Drivers of PARPi Resistance in BRCA1-Deficient Ovarian Cancer: The Role of LY6E and Immunomodulation.

Approximately 50% of patients diagnosed with ovarian cancer harbor tumors with mutations in BRCA1, BRCA2, or other genes involved in homologous recombination repair (HR). The presence of homologous recombination deficiency (HRD) is an approved biomarker for poly-ADP-ribose polymerase inhibitors (PARPis) as a maintenance treatment following a positive response to initial platinum-based chemotherapy. Despite this treatment option, the development of resistance to PARPis is common among recurrent disease patients, leading to a poor prognosis. In this study, we conducted a comprehensive analysis using publicly available datasets to elucidate the molecular mechanisms driving PARPi resistance in BRCA1-deficient ovarian cancer. Our findings reveal a central role for the interferon (IFN) pathway in mediating resistance in the context of BRCA1 deficiency. Through integrative bioinformatics approaches, we identified LY6E, an interferon-stimulated gene, as a key mediator of PARPi resistance, with its expression linked to an immunosuppressive tumor microenvironment (TME) encouraging tumor progression and invasion. LY6E amplification correlates with poor prognosis and increased expression of immune-related gene signatures, which is predictive of immunotherapy response. Interestingly, LY6E expression upon PARPi treatment resistance was found to be dependent on BRCA1 status. Gene expression analysis in the Orien/cBioPortal database revealed an association between LY6E and genes involved in DNA repair, such as Rad21 and PUF60, emphasizing the interplay between DNA repair pathways and immune modulation. Moreover, PUF60, Rad21, and LY6E are located on chromosome 8q24, a locus often amplified and associated with the progression of ovarian cancer. Overall, our study provides novel insights into the molecular determinants of PARPi resistance and highlights LY6E as a promising prognostic biomarker in the management of HRD ovarian cancer. Future studies are needed to fully elucidate the molecular mechanisms underlying the role of LY6E in PARPi resistance.

Egfl6 promotes ovarian cancer progression by enhancing the immunosuppressive functions of tumor-associated myeloid cells.

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a new regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cells migration and promotes their differentiation towards an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intra-tumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10 and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to a-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of a-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression co-localized with myeloid cell infiltration. scRNAseq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the onco-immunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential novel therapeutic target to enhance immunotherapy in OvCa patients.

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.