Clinical Treatment Of Ovarian Cancer Research Articles

Network pharmacology-based strategy to reveal the mechanism of pinocembrin against ovarian cancer.

Ovarian cancer stands as the foremost cause of mortality among gynaecological diseases globally, characterized by high morbidity and mortality. Pinocembrin, a flavonoid from natural plant sources, exhibits diverse pharmacological properties. Despite its known pharmacological activities, its specific role in ovarian cancer treatment remains scarcely reported, and its precise molecular mechanism remains elusive. This study integrates network pharmacology and molecular docking techniques to explore pinocembrin's potential mechanism in ovarian cancer treatment. The targets of pinocembrin were compiled from the several online databases. Ovarian cancer targets were identified using the GeneCards database, with common target genes determined by data aggregation. Protein-protein interactions were analysed using the STRING platform. Subsequent Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed. Molecular docking assessed the binding affinity between potential targets and active compounds. Finally, target validity was verified through in vitro experiments. We identified 163 potential pinocembrin targets for ovarian cancer treatment. GO and KEGG analyses revealed pinocembrin's involvement in protein kinase activity, protein phosphorylation, protein kinase complexes and cancer pathways in ovarian cancer treatment. Molecular docking demonstrated strong binding affinity between pinocembrin and most potential target active sites. In vitro experiments suggested pinocembrin's potential to induce apoptosis in ovarian cancer cells through the AKT1-mTOR signalling pathway. This study comprehensively elucidates pinocembrin's potential targets and mechanisms against ovarian cancer, aiming to provide promising candidates for developing novel and effective alternative and/or complementary nutritional supplements for the clinical treatment of ovarian cancer.

Design, Biological Characterization, and Discovery of Novel Cyclohexenyl Derivatives as Kinesin KIF18A Inhibitors for the Treatment of Ovarian Cancer.

A novel class of kinesin KIF18A inhibitors were discovered through modification of the clinical compound AMG650. Structure-activity relationship (SAR) study led to the discovery of compound 16 with an alkenyl motif, a highly potent KIF18A inhibitor, which displayed a favorable pharmacological profile and excellent efficacy in a mouse model of an OVCAR-3 xenograft tumor. Oral administration of 16 can induce a dose-dependent antitumor efficacy in the OVCAR-3 model without significant reduction in body weight. Compound 16 showed potential as a candidate for the clinical treatment of ovarian cancer.

Methotrexate-modified docetaxel liposome targeting with ginsenoside Rh2 as a membrane stabilizer for the treatment of ovarian cancer

At present, nano-agent-targeted therapy has become the main means of clinical treatment for ovarian cancer. Conventional liposomes, while commonly used as drug carriers, often suffer from stability issues that reduce drug bioavailability. Cholesterol, a frequent component in liposome membranes, may cause adverse effects such as dyspnea and shortness of breath when accumulated excessively. To address these challenges, we employed G-Rh2 as an alternative to cholesterol in liposome membranes as it acts as a membrane stabilizer to increase the stability of the liposome system. We prepared methotrexate-modified docetaxel liposomes (MTX@DTX-Rh2-Lips), characterized their properties and evaluated their stability. The ability of MTX@DTX-Rh2-Lips to target SKOV3 cells and loaded mice was confirmed. Assessments through CCK-8, EDU proliferation, and wound healing assay demonstrated the in vitro antitumor effects of MTX@DTX-Rh2-Lips. The in vivo antitumor effects of MTX@DTX-Rh2-Lips were evaluated by immunohistochemistry and immunofluorescence staining. Our findings revealed that MTX@DTX-Rh2-Lips was uniformly spherical and stable, effectively targeting the tumor site, inhibiting the proliferation, invasion, metastasis, and angiogenesis of SKOV3 cells, and affecting the expression of tumor-associated proteins, with a good safety profile. In conclusion, the successful establishment of MTX@DTX-Rh2-Lips introduces promising avenues for the clinical treatment of ovarian cancer.

Mechanistic analyses reveal that Pueraria montana var. lobata (Willd.) is effective in inhibiting ovarian cancer progression.

Ovarian cancer (OC) is a common malignancies of the female genitalia. P. montana var. lobata (Willd.), a herb with anti-tumor effects, is widely used in the clinical treatment of ovarian cancer (OC), but the ingredients and molecular mechanism of action remains to be explored. In this study, we extracted the main active ingredients of P. montana var. lobata (Willd.) from the TCMSP database, and predicted its potential targets of action against OC from the DisGeNET and GeneCards databases. Protein-protein interaction (PPI) was constructed using the STRING database, while pathway enrichment analyses were performed using the DAVID database. Next, we generated an Ingredient-Target-Pathway network using Cytoscape 3.7.2, then processed the key targets of action and main active ingredients for molecular docking.The results showed that seven active ingredients of P montana var. lobata (Willd.) were associated with treating for OC, namely beta-sitosterol, coumestrol, daidzein, formononetin, genistein, puerarin and scoparone, two important targets Casp3 and Jun, and signaling pathways of P. montana var. lobata (Willd.) against the progression of OC. TUNEL staining, enzyme-linked immunosorbent assay (ELISA), and Western blot assays, the pharmacodynamic effect of puerarin in the treatment of OC and the major targets were verified. Animal experiment demonstrated that application of puerarin at different times of modeling not only upregulated expression of Casp3, Smac, and c-jun proteins, but also promoted apoptosis in tumor cells, hence inhibiting progression of OC. This study demonstrates that P. montana var. lobata (Willd.) can thereby induce apoptosis in tumor cells and inhibit malignant progression through activating expression of Casp3, smac, and c-jun proteins to regulate related apoptosis pathways, as validated by network pharmacology predictions and animal experiments, and can be verifed by large-scale clinical trials in the future. This study also provides theoretical support and new research perspectives for this disease.

VNP20009-Abvec-Igκ-MIIP suppresses ovarian cancer progression by modulating Ras/MEK/ERK signaling pathway.

Ovarian cancer poses a significant threat to women's health, with conventional treatment methods encountering numerous limitations, and the emerging engineered bacterial anti-tumor strategies offer newfound hope for ovarian cancer treatment. In this study, we constructed the VNP20009-Abvec-Igκ-MIIP (VM) engineered strain and conducted initial assessments of its in vitro growth performance and the expression capability of migration/invasion inhibitory protein (MIIP). Subsequently, ID8 ovarian cancer cells and mouse cancer models were conducted to investigate the impact of VM on ovarian cancer. Our results revealed that the VM strain demonstrated superior growth performance, successfully invaded ID8 ovarian cancer cells, and expressed MIIP, consequently suppressing cell proliferation and migration. Moreover, VM specifically targeted tumor sites and expressed MIIP which further reduced the tumor volume of ovarian cancer mice (p < 0.01), via the downregulation of epidermal growth factor receptor (EGFR), Ras, p-MEK, and p-ERK. The downregulation of the PI3K/AKT signaling pathway and the decrease in Bcl-2/Bax levels also indicated VM's apoptotic potency on ovarian cancer cells. In summary, our research demonstrated that VM exhibits promising anti-tumor effects both in vitro and in vivo, underscoring its potential for clinical treatment of ovarian cancer. KEY POINTS: • This study has constructed an engineered strain of Salmonella typhimurium capable of expressing anticancer proteins • The engineered bacteria can target and colonize tumor sites in vivo • VM can inhibit the proliferation, migration, and invasion of ovarian cancer cells.

Machine learning-assisted analysis of epithelial mesenchymal transition pathway for prognostic stratification and immune infiltration assessment in ovarian cancer.

Ovarian cancer is the most lethal gynaecological malignancy, and serous ovarian cancer (SOC) is one of the more important pathological subtypes. Previous studies have reported a significant association of epithelial tomesenchymal transition (EMT) with invasive metastasis and immune modulation of SOC, however, there is a lack of prognostic and immune infiltration biomarkers reported for SOC based on EMT. Gene expression data for ovarian cancer and corresponding patient clinical data were collected from the TCGA database and the GEO database, and cell type annotation and spatial expression analysis were performed on single cell sequencing data from the GEO database. To understand the cell type distribution of EMT-related genes in SOC single-cell data and the enrichment relationships of biological pathways and tumour functions. In addition, GO functional annotation analysis and KEGG pathway enrichment analysis were performed on mRNAs predominantly expressed with EMT to predict the biological function of EMT in ovarian cancer. The major differential genes of EMT were screened to construct a prognostic risk prediction model for SOC patients. Data from 173 SOC patient samples obtained from the GSE53963 database were used to validate the prognostic risk prediction model for ovarian cancer. Here we also analysed the direct association between SOC immune infiltration and immune cell modulation and EMT risk score. and calculate drug sensitivity scores in the GDSC database.In addition, we assessed the specific relationship between GAS1 gene and SOC cell lines. Single cell transcriptome analysis in the GEO database annotated the major cell types of SOC samples, including: T cell, Myeloid, Epithelial cell, Fibroblast, Endothelial cell, and Bcell. cellchat revealed several cell type interactions that were shown to be associated with EMT-mediated SOC invasion and metastasis. A prognostic stratification model for SOC was constructed based on EMT-related differential genes, and the Kapan-Meier test showed that this biomarker had significant prognostic stratification value for several independent SOC databases. The EMT risk score has good stratification and identification properties for drug sensitivity in the GDSC database. This study constructed a prognostic stratification biomarker based on EMT-related risk genes for immune infiltration mechanisms and drug sensitivity analysis studies in SOC. This lays the foundation for in-depth clinical studies on the role of EMT in immune regulation and related pathway alterations in SOC. It is also hoped to provide effective potential solutions for early diagnosis and clinical treatment of ovarian cancer.

CRTC2 promotes paclitaxel resistance by inducing autophagy in ovarian cancer in part via the PI3K-AKT signaling axis.

Background: Ovarian cancer is the most malignant gynecological disease, which seriously threatens female physical and mental health. Paclitaxel is a first-line chemotherapy drug in the clinical treatment of ovarian cancer, but drug resistance has become an important factor affecting the survival of ovarian cancer patients. However, the main mechanism of chemotherapy resistance in ovarian cancer remains unclear. In this study, we analyzed the Integrated Gene Expression Database (GEO) dataset using comprehensive bioinformatics tools to provide new therapeutic strategies and search for prognostic targets for ovarian cancer. Methods: Ovarian cancer related genes were extracted from GSE18520 by bioinformatics method. Differentially expressed genes (DEGs) were obtained by differential analysis, and related genes and functions were elucidated. The key gene CRTC2 was identified by prognostic analysis. Immunohistochemistry was used to detect the expression of CRTC2 in chemotherapy-resistant and chemotherapy-sensitive ovarian cancer tissues. Functional analysis (cell assay) confirmed the role of CRTC2 in paclitaxel resistance. Autophagy related proteins were detected by Western blot. Autophagy flux analysis was performed using the GFP/RFP-LC3 adenovirus reporter. Results: A total of 3,852 DEGs were identified in the GEO microarray dataset. Key genes were screened by prognostic analysis. We found that CRTC2 was highly expressed in chemoresistant tissues of ovarian cancer. In 110 patients with ovarian cancer, high expression of CRTC2 was associated with poorer prognostic factors and shorter survival. At the same time, we found that CRTC2 can promote the proliferation and invasion ability of ovarian cancer cells. In addition, CRTC2 can affect the expression of PI3K, AKT, autophagic flux and sensitivity to paclitaxel chemotherapy in ovarian cancer. Conclusion: CRTC2 can affect autophagy partially through PI3K-AKT signaling pathway, and then affect the sensitivity of ovarian cancer to paclitaxel chemotherapy. CRTC2 may be a potential predictor or target for ovarian cancer therapy.

Identification of a ferroptosis-related long non-coding RNA signature for prognosis prediction of ovarian cancer.

Ovarian cancer is one of the deadliest malignant tumors. Ferroptosis is closely related to various cancers, including ovarian cancer, but the genes involved in regulating ferroptosis in ovarian cancer are still unclear. The aim of this study is to construct a long non-coding RNA (lncRNA) signature related to ferroptosis and evaluate its relationship with the prognosis and clinicopathological characteristics of patients with ovarian cancer. In this study, a prognostic risk model comprising 18 lncRNAs related to ferroptosis was obtained. Compared to the low-risk group, the high-risk group based on the FerRLSig score had significantly poorer overall survival (P < 0.001). The receiver operating characteristics curve supported the accuracy of the model, established a prognostic nomogram combining FerRLSig and clinical characteristics, and showed a good prognosis and survival risk stratification predictive power. In addition, Gene Set Enrichment Analysis (GSEA) showed that FerRLSig was involved in many malignant tumor-related immunomodulatory pathways. Based on the risk model, we found that immune status and immunotherapy, chemotherapy, and targeted therapy were significantly different between the high-risk and low-risk groups. This study provided a more in-depth understanding of the molecular and signaling pathways of ferroptosis in ovarian cancer and showed the impact of tumor microenvironment on ovarian cancer, as well as provided a prognostic model for ovarian cancer patients to guide the clinical treatment of ovarian cancer.

Herpesvirus entry mediator regulates the transduction of Tregs via STAT5/Foxp3 signaling pathway in ovarian cancer cells.

The ratio of regulatory T cells (Treg) in peripheral blood of cancer patients has a closely correlation to the occurrence and development of ovarian cancer. In this study, our aim to explore the expression of herpesvirus entry mediator (HVEM) in ovarian cancer and its correlation with Tregs. The expression of HVEM in peripheral blood of ovarian cancer patients was detected by ELISA, and the ratio of CD4+ CD25 + Foxp3 positive Tregs cells was detected by flow cytometry. Ovarian cancer cell lines with high- and low-HVEM expression were constructed. CD4+ cells were co-cultured with ovarian cancer (OC) cells, and the expressions of IL-2 and TGF-β1 in the supernatant of cells were detected by ELISA, and western blot was used to detect the expressions of STAT5, p-STAT5, and Foxp3. The results indicated that the number of Treg cells in the peripheral blood of OC patients increased, and the expression of HVEM increased, the two have a certain correlation. At the same time, the overexpression of HVEM promoted the expression of cytokines IL-2 and TGF- β1, promoted the activation of STAT5 and the expression of Foxp3, leading to an increase in the positive rate of Treg, while the HVEM gene silence group was just the opposite. Our results showed that the expression of HVEM in OC cells has a positive regulation effect on Tregs through the STAT5/Foxp3 signaling pathway. To provide experimental basis and related mechanism for the clinical treatment of ovarian cancer.

The effects of REG4 expression on chemoresistance of ovarian cancer

Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan–Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENT What is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway. What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment. What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

Icaritin Inhibits Migration and Invasion of Human Ovarian Cancer Cells via the Akt/mTOR Signaling Pathway.

Ovarian cancer (OC) is the most lethal of all gynecologic malignancies with poor survival rates. Although surgical treatment and chemotherapy had advanced to improve survival, platinum-based chemoresistance remains a major hurdle in the clinical treatment of OC. The search for novel active ingredients for the treatment of drug-resistant OC is urgently needed. Here, we demonstrated that icaritin, the main active ingredient derived from the traditional Chinese herb Epimedium genus, significantly suppressed the proliferation, migration, and invasion of both drug-susceptible and cisplatin-resistant OC cells in vitro. Mechanistically, icaritin at 20 μM significantly inhibited the phosphorylation of Akt and mTOR, as well as decreased the expression of vimentin and increased the expression of E-cadherin. Our data indicate that icaritin, a prenylated flavonoid natural product, could serve as a potential inhibitor of cisplatin-resistant OC by inhibiting the Akt/mTOR signaling pathway.

Structure-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation of VEGF inhibitors for the clinical treatment of Ovarian Cancer.

Vascular endothelial growth factor (VEGF) and its receptor play an important role both in physiologic and pathologic angiogenesis, which is identified in ovarian cancer progression and metastasis development. The aim of the present investigation is to identify a potential vascular endothelial growth factor inhibitor which is playing a crucial role in stimulating the immunosuppressive microenvironment in tumor cells of the ovary and to examine the effectiveness of the identified inhibitor for the treatment of ovarian cancer using various in silico approaches. Twelve established VEGF inhibitors were collected from various literatures. The compound AEE788 displays great affinity towards the target protein as a result of docking study. AEE788 was further used for structure-based virtual screening in order to obtain a more structurally similar compound with high affinity. Among the 80 virtual screened compounds, CID 88265020 explicates much better affinity than the established compound AEE788. Based on molecular dynamics simulation, pharmacophore and comparative toxicity analysis of both the best established compound and the best virtual screened compound displayed a trivial variation in associated properties. The virtual screened compound CID 88265020 has a high affinity with the lowest re-rank score and holds a huge potential to inhibit the VGFR and can be implemented for prospective future investigations in ovarian cancer.

Glaucocalyxin B Attenuates Ovarian Cancer Cell Growth and Cisplatin Resistance In Vitro via Activating Oxidative Stress.

Ovarian cancer is one of the fatal gynecological cancers around the world. Cisplatin is the first-line chemotherapy drug for the clinical treatment of ovarian cancer. However, many patients with ovarian cancer are still suffering from resistance to cisplatin. Therefore, the new drug combinations or treatment strategies for ovarian cancer are urgently needed. Glaucocalyxin B (GLB), a diterpenoid isolated from the aerial parts of Rabdosia japonica, has shown antitumor activity in some tumors. However, the mechanisms by which GLB inhibits ovarian cancer remain unclear. In the present study, we showed that GLB potently inhibits ovarian cancer cell growth in a dose-dependent manner. Furthermore, we found that GLB has a notably synergistic antitumor effect with cisplatin. Mechanistically, we found that GLB enhances the sensitivity of ovarian cancer cells to cisplatin via increasing reactive oxygen species (ROS) levels, the phosphorylation of c-Jun N-terminal kinase (JNK), and DNA damage. Interestingly, a synergistic inhibitory effect of GLB with cisplatin was also observed in the cells which were resistance to cisplatin. Together, these data suggest that GLB can sensitize ovarian cancer cells to cisplatin by increasing ROS levels.

Identification and Validation of Immune-Related Gene for Predicting Prognosis and Therapeutic Response in Ovarian Cancer.

Ovarian cancer (OC) is a devastating malignancy with a poor prognosis. The complex tumor immune microenvironment results in only a small number of patients benefiting from immunotherapy. To explore the different factors that lead to immune invasion and determine prognosis and response to immune checkpoint inhibitors (ICIs), we established a prognostic risk scoring model (PRSM) with differential expression of immune-related genes (IRGs) to identify key prognostic IRGs. Patients were divided into high-risk and low-risk groups according to their immune and stromal scores. We used a bioinformatics method to identify four key IRGs that had differences in expression between the two groups and affected prognosis. We evaluated the sensitivity of treatment from three aspects, namely chemotherapy, targeted inhibitors (TIs), and immunotherapy, to evaluate the value of prediction models and key prognostic IRGs in the clinical treatment of OC. Univariate and multivariate Cox regression analyses revealed that these four key IRGs were independent prognostic factors of overall survival in OC patients. In the high-risk group comprising four genes, macrophage M0 cells, macrophage M2 cells, and regulatory T cells, observed to be associated with poor overall survival in our study, were higher. The high-risk group had a high immunophenoscore, indicating a better response to ICIs. Taken together, we constructed a PRSM and identified four key prognostic IRGs for predicting survival and response to ICIs. Finally, the expression of these key genes in OC was evaluated using RT-qPCR. Thus, these genes provide a novel predictive biomarker for immunotherapy and immunomodulation.

Gemcitabine Nanoparticles Improve the Activity of Ovarian Cancer Cells by Inhibiting CA-125 and Apoptosis-Related Proteins

In recent years, the risk of ovarian cancer (OC) has become increasingly prevalent. Gemcitabine (GE) provides excellent inhibitory action on some solid tumors, but how it affects OC remains elusive. In the present research, we prepared GE nanoparticles (GEN) and analyzed OC cell viability under its intervention, hoping to conceive novel ideas for future clinical treatment of OC. Through experiments, we observed that the encapsulation efficiency and drug loading of GEN were observably higher than those of GE alone, and the release rate presented a stable slow release state. Under GEN intervention, the viability of OC cells was decreased, the apoptosis rate was elevated, and the apoptosis-related proteins were activated, while CA-125 was suppressed. Therefore, we can see that GEN exert favorable inhibitory action on OC cell viability, whose mechanism may be achieved through activating apoptosis-related proteins and inhibiting CA-125, which may be a new scheme for OC treatment in the future.

CREBBP knockdown suppressed proliferation and promoted chemo-sensitivity via PERK-mediated unfolded protein response in ovarian cancer.

CREBBP, in short CBP, has been reported to be involved in tumorigenesis in various cancers, but its role in ovarian cancer remains largely unexplored. In our study, survival analysis of CBP in patients with ovarian cancer was conducted using the Kaplan-Meier Plotter database, then we utilized specific shRNA targeting CREBBP to block the expression of CBP, and detected its effect on cell proliferation and chemo-sensitivity in ovarian cancer cells. The results showed that high expression of CBP was correlated with poor prognosis in ovarian cancer patients. CREBBP knockdown in ovarian cancer cells significantly inhibited tumor proliferation both in vitro and in vivo. Moreover, CREBBP knockdown promoted chemo-sensitivity in ovarian cancer cells. Mechanism research further demonstrated that CREBBP knockdown attenuated unfolded protein response (UPR), which was mediated by PERK/ATF4/STC2 signaling pathway. Our research linked CBP and UPR in ovarian cancer and may provide new strategies for the clinical treatment of ovarian cancer.

LINC00665 promotes Ovarian Cancer progression through regulating the miRNA-34a-5p/E2F3 axis.

Objective: To clarify the role of LINC00665 in ovarian cancer (OC) progression and the possible mechanism.Methods: LINC00665 levels in OC tissues and cell lines were detected by qRT-PCR. The correlation between LINC00665 and clinicopathologic characteristics of OC patients was assessed. Biological functions of OC cell phenotypes influenced by LINC00665 were examined by CCK-8, colony formation and Transwell assay. Dual-luciferase reporter assay and RIP assay were conducted to verify the interaction between LINC00665 and its downstream target.Results: LINC00665 was upregulated in OC and linked to poor prognosis. Knockdown of LINC00665 blocked malignant proliferative, migratory and invasive functions of OC cells. By competitively binding miRNA-34a-5p, LINC00665 abolished the inhibitory effect of miR-34a-3p on its downstream gene E2F3, thus promoting OC progression.Conclusion: LINC00665/miRNA-34a-5p/E2F3 axis is involved in OC progression, providing novel insights into the clinical treatment of OC.

UTMD promoted local delivery of miR-34a-mimic for ovarian cancer therapy

MicroRNA-mediated gene therapy is emerging as a promising method for the treatment of ovarian cancer, but the development of miRNA mimic delivery vectors is still in its infancy, where the safety and efficacy of miR-34a-mimic remain unknown. Ultrasound-targeted microbubble destruction (UTMD) can be an effective and minimally invasive tool for the delivery of miR-34a-mimic in vitro and in vivo. Here, we describe a high-efficiency gene delivery strategy by using miR-34a-mimic loaded folate modified microbubbles (miR-34a-FM) with a portable ultrasonic irradiation system. Ultrasonic parameters, including acoustic intensity (AI), exposure time (ET) and duty cycle (DC), were optimized and the optimal acoustic condition (1.0 W/cm2, 20 s, and 15% DC) was used to deliver miRNA-34a into cells in vitro. MiR-34a mimic was successfully introduced into the cytoplasm and was found to inhibit proliferation and induce apoptosis of SK-OV-3 cells. Next, miR-34a-mimic was delivered to tumor tissue via UTMD, inhibiting tumor growth and prolonging the survival time of mice. In summary, UTMD-mediated miR-34a-mimic delivery has potential application in the clinical treatment of ovarian cancer.

PolyphyllinVII induces mitochondrial apoptosis by regulating the PP2A/AKT/DRP1 signaling axis in human ovarian cancer.

Ovarian cancer is a gynecological malignancy with high mortality. Adjuvant therapy such as chemoradiotherapy inevitably leads to side effects and drug resistance. In recent years, traditional Chinese medicine has been widely studied for its safety, effectiveness, and unique pharmacological effects. Polyphyllin VII is an important component of Rhizoma paridis saponins, and has cytotoxic effects on many types of cancer cells. The aim of the present study was to evaluate the anti-tumor activity of polyphyllin VII in human ovarian cancer cells. Recent studies found that polyphyllin VII induces mitochondrial pathway apoptosis by increasing mitochondrial division, but the specific mechanism was unclear. The results of this study revealed that polyphyllin VII could effectively induce mitochondrial dysfunction, including increased mitochondrial division and reactive oxygen species (ROS) production. Notably, the mitochondrial location of dynamin-related protein 1 (DRP1) plays an important role in its function. In addition, polyphyllin VII enhanced the mitochondrial localization of DRP1 which is mediated by increased protein phosphatase 2A (PP2A) activity, and decreased AKT activity. A specific PP2A inhibitor, LB100, attenuated mitochondrial division and apoptosis in cells caused by polyphyllin VII, confirming the function of the PP2A/AKT pathway in polyphyllin VII treatment. Additionally, xenotransplantation experiments have also confirmed the anti-tumor effect of polyphyllin VII in vivo. Therefore, interference of the mitochondrial translocation of DRP1 through PP2A/AKT pathway may be an attractive and effective therapeutic approach by polyphyllin VII in ovarian cancer. This may provide new strategies for polyphyllin VII in the clinical treatment of ovarian cancer.

The Nrf2/PGC1α Pathway Regulates Antioxidant and Proteasomal Activity to Alter Cisplatin Sensitivity in Ovarian Cancer.

Drug resistance remains a barrier in the clinical treatment of ovarian cancer. Proteasomal and antioxidant activities play important roles in tumor drug resistance, and increasing evidence suggests the existence of an interaction between antioxidant and proteasomal activities. However, the mechanism of the synergistic effects of proteasomal activity and antioxidation on tumor drug resistance is not completely clear. In this study, we compared two ovarian cancer cells, A2780 and SKOV3 cells. Among them, SKOV3 cell is a human clear cell carcinoma cell line that is resistant to platinum. We found that compared with the findings in A2780 cells, SKOV3 cells were less sensitive to both proteasomal inhibitor and cisplatin. Proteasomal inhibition enhanced the sensitivity of A2780 cells, but not SKOV3 cells, to cisplatin. Notably, the Nrf2-mediated antioxidant pathway was identified as a resistance mechanism in proteasome inhibitor-resistant cells, but this was not the only factor identified in our research. In SKOV3 cells, PGC1α regulated the antioxidant activity of Nrf2 by increasing the phosphorylation of GSK3β, and in turn, Nrf2 regulated the transcriptional activity of PGC1α. Thus, Nrf2 and PGC1α synergistically participate in the regulation of proteasomal activity. Furthermore, the Nrf2/PGC1α pathway participated in the regulation of mitochondrial function and homeostasis, further regulating proteasomal activity in SKOV3 cells. Therefore, exploring the roles of PGC1α and Nrf2 in the regulation of proteasomal activity by antioxidant and mitochondrial functions may provide new avenues for reversing drug resistance in ovarian cancer.