Migration Of Ovarian Cancer Cells Research Articles

ATP6V1B1 regulates ovarian cancer progression and cisplatin sensitivity through the mTOR/autophagy pathway.

Early detection and effective chemotherapy for ovarian cancer, a serious gynecological malignancy, require further progress. This study aimed to investigate the molecular mechanism of ATPase H+-Transporting V1 Subunit B1 (ATP6V1B1) in ovarian cancer development and chemoresistance. Our data show that ATP6V1B1 is upregulated in ovarian cancer and correlated with decreased progression-free survival. Gain- and loss-of-function experiments demonstrated that ATP6V1B1 promotes the proliferation, migration, and invasion of ovarian cancer cells in vitro, while ATP6V1B1 knockout inhibits tumor growth in vivo. In addition, knocking down ATP6V1B1 increases the sensitivity of ovarian cancer cells to cisplatin. Mechanistic studies showed that ATP6V1B1 regulates the activation of the mTOR/autophagy pathway. Overall, our study confirmed the oncogenic role of ATP6V1B1 in ovarian cancer and revealed that ATP6V1B1 promotes ovarian cancer progression via the mTOR/autophagy axis.

Cell-cycle related centromere protein F deficiency suppresses ovarian cancer cells growth by inducing ferroptosis.

This study aimed to investigate the involvement of the cell cycle-related protein centriole protein F (CENPF) in the development of ovarian cancer (OC) and explored its relationship with ferroptosis. The databases were analyzed to identify differential expression of cell cycle-related proteins between individuals with ovarian cancer and normal individuals. Immunohistochemistry and statistical analysis were conducted on ovarian tissues obtained from 40 patients with epithelial ovarian cancer and 20 normal individuals. In vitro experiments were performed using SKOV3 and HEY epithelial ovarian cancer cell lines. The mRNA microarray data set, consisting of GSE14001, GSE54388, GSE40595, and GSE14407, was downloaded from the Gene Expression Omnibus (GEO) database to investigate the genes associated with cell cycle regulation in ovarian cancer cells. CENPF was selected as the subject of study through differential analysis. Assessed the expression of CENPF in both ovarian cancer (OC) patients and normal ovarian tissues using immunohistochemistry. Lentivirus infection was employed to downregulate CENPF expression, and subsequent experiments including Cell Counting Kit-8 (CCK-8) assay, cell cycle analysis, transwell assay, and wound-healing assay were conducted to investigate the effects of CENPF on proliferation, invasion, migration, and cell cycle regulation in OC cells. The Reactive oxygen species (ROS) and the malondialdehyde (MDA) assays were performed to assess the involvement of CENPF in cellular redox reactions. Western blot analysis was conducted to examine the expression levels of ferroptosis-related proteins (GPX4, SLC7A11, DMT1, and P53). By querying and integrating cell cycle-related genes from the GEO database, in silico analyses using The Cancer Genome Atlas (TCGA) database combined with immunohistochemical studies, we discovered that CENPF is upregulated in ovarian cancer tissues and is related to survival. Downregulation of CENPF inhibited biological function of OC cells, increased intracellular ROS and MDA levels, and downregulated the GPX4 protein and the SLC7A11/xCT protein, but upregulated the DMT1 protein and the tumor protein 53(P53) protein expression to induce ferroptosis. This study did not investigate ferroptosis-related studies following CENPF overexpression, and the findings have not been validated in animal studies. Our findings demonstrated that the deficiency of CENPF played a crucial anti-oncogenic role in the progression of OC through the mechanism of ferroptosis.

PITPNA-AS1 Inhibits Cell Proliferation and Migration in Ovarian Cancer by Regulating the MIR-223-3p/RHOB Axis

PITPNA-AS1 Inhibits Cell Proliferation and Migration in Ovarian Cancer by Regulating the MIR-223-3p/RHOB Axis

Knockdown of CENPM activates cGAS-STING pathway to inhibit ovarian cancer by promoting pyroptosis.

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

Retracted] MicroRNA‑19b promotes the migration and invasion of ovarian cancer cells by inhibiting the PTEN/AKT signaling pathway.

[This retracts the article DOI: 10.3892/ol.2018.8695.].

Tumour-derived exosome SNHG17 induced by oestrogen contributes to ovarian cancer progression via the CCL13-CCR2-M2 macrophage axis.

Oestrogen is known to be strongly associated with ovarian cancer. There was much work to show the importance of lncRNA SNHG17 in ovarian cancer. However, no study has revealed the molecular regulatory mechanism and functional effects between oestrogen and SNHG17 in the development and metastasis of ovarian cancer. In this study, we found that SNHG17 expression was significantly increased in ovarian cancer and positively correlated with oestrogen treatment. Oestrogen could promote M2 macrophage polarization as well as ovarian cancer cells SKOV3 and ES2 cell exosomal SNHG17 expression. When exposure to oestrogen, exosomal SNHG17 promoted ovarian cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) invitro, and tumour growth and lung metastasis invivo by accelerating M2-like phenotype of macrophages. Mechanically, exosomal SNHG17 could facilitate the release of CCL13 from M2 macrophage via the PI3K-Akt signalling pathway. Moreover, CCL13-CCR2 axis was identified to be involved in ovarian cancer tumour behaviours driven by oestrogen. There results demonstrate a novel mechanism that exosomal SNHG17 exerts an oncogenic effect on ovarian cancer via the CCL13-CCR2-M2 macrophage axis upon oestrogen treatment, of which SNHG17 may be a potential biomarker and therapeutic target for ovarian cancer responded to oestrogen.

Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition

BackgroundCartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, is vital in preserving cartilage integrity. Further, its overexpression is associated with the aggressiveness of several types of solid cancers. This study investigated COMP’s role in ovarian cancer, exploring clinicopathological links and mechanistic insights.MethodsTo study the association of COMP expression in cancer cells and stroma with clinicopathological features of ovarian tumor patients, we analyzed an epithelial ovarian tumor cohort by immunohistochemical analysis. Subsequently, to study the functional mechanisms played by COMP, an in vivo xenograft mouse model and several molecular biology techniques such as transwell migration and invasion assay, tumorsphere formation assay, proximity ligation assay, and RT-qPCR array were performed.ResultsBased on immunohistochemical analysis of epithelial ovarian tumor tissues, COMP expression in the stroma, but not in cancer cells, was linked to worse overall survival (OS) of ovarian cancer patients. A xenograft mouse model showed that carcinoma-associated fibroblasts (CAFs) expressing COMP stimulate the growth and metastasis of ovarian tumors through the secretion of COMP. The expression of COMP was upregulated in CAFs stimulated with TGF-β. Functionally, secreted COMP by CAFs enhanced the migratory capacity of ovarian cancer cells. Mechanistically, COMP activated the Notch3 receptor by enhancing the Notch3-Jagged1 interaction. The dependency of the COMP effect on Notch was confirmed when the migration and tumorsphere formation of COMP-treated ovarian cancer cells were inhibited upon incubation with Notch inhibitors. Moreover, COMP treatment induced epithelial-to-mesenchymal transition and upregulation of active β-catenin in ovarian cancer cells.ConclusionThis study suggests that COMP secretion by CAFs drives ovarian cancer progression through the induction of the Notch pathway and epithelial-to-mesenchymal transition.

Patient-Derived Exosomes as siRNA Carriers in Ovarian Cancer Treatment.

RNA interference is a powerful gene-silencing tool with potential clinical applications. However, its therapeutic use is challenging because suitable carriers are unavailable. Exosomes are stable small endogenous vesicles that can transport functional molecules to target cells, making them ideal small interfering RNA (siRNA) carriers. Herein, we elucidated the therapeutic potential of patient-derived exosomes as an siRNA carrier for ovarian cancer (OC) treatment. The exosomes were extracted from the culture medium of primary fibroblasts collected from the omentum of patients with OC during surgery. MET proto-oncogene, receptor tyrosine kinase (MET) was selected for gene silencing, c-Met siRNAs were synthesized and loaded into the exosomes (Met-siExosomes) via electroporation, and the treatment effect of the Met-siExosomes was assessed in vitro and in vivo. The Met-siExosomes downregulated the c-Met protein levels and inhibited OC cell proliferation, migration, and invasion. In xenograft experiments using SKOV3-13 and ES-2 cells, Met-siExosomes were selectively extracted from peritoneally disseminated tumors. Intraperitoneal treatment suppressed the c-Met downstream targets in cancer cells and prolonged mouse survival. The synthesized siRNAs were successfully and selectively delivered via the exosomes to intraperitoneally disseminated tumors. As patients with OC routinely undergo omentectomy and abundant fibroblasts can be easily collected from the omentum, patient-derived exosomes may represent a promising therapeutic siRNA carrier to treat OC.

Effects of silencing hsa_circ_0015326 on proliferation, migration, invasion, and apoptosis of epithelial ovarian cancer cells.

Although the treatment of ovarian cancer has made great progress, there are still many patients who are not timely detected and given targeted therapy due to unknown pathogenesis. Recent studies have found that hsa_circ_0015326 is upregulated in ovarian cancer and is involved in the proliferation, invasion, and migration of ovarian cancer cells. However, whether hsa_circ_0015326 can be used as a new target of ovarian cancer needs further investigation. Therefore, the effect of hsa_circ_0015326 on epithelial ovarian cancer was investigated in this study. At first, si-hsa_circ_0015326 lentivirus was transfected into epithelial ovarian cancer cells. Then real-time fluorescence quantitative PCR (qRT-PCR) was used to detect hsa_circ_0015326 level. The proliferation of ovarian cancer cells was detected by CCK-8 assay. The horizontal and vertical migration abilities of the cells were detected by wound-healing assay and Transwell assay, respectively. Transwell assay was also used to determine the invasion rate. As for the apoptosis rate, it was assessed by flow cytometry. As a result, the expression level of hsa_circ_0015326 in A2780 and SKOV3 was found to be higher than that in IOSE-80. However, after transfecting si-hsa_circ_0015326 and si-NC into the cells, the proliferation, migration, and invasion abilities of A2780 and SKOV3 cells in the si-hsa_circ_0015326 group were significantly reduced in comparison to those in the si-NC and mock groups, while their apoptosis rates were elevated. Collectively, silencing hsa_circ_0015326 bears the capability of inhibiting the proliferation, migration, and invasion of ovarian cancer cells while increasing apoptosis rate. It can be concluded that hsa_circ_0015326 promotes the malignant biological activities of epithelial ovarian cancer cells.

Contribution of sphingomyelin phosphodiesterase acid-like 3B to the proliferation, migration, and invasion of ovarian cancer cells.

Cancer has the highest mortality rate among gynecological cancers and poses a serious threat to women's lives. However, the treatment options for ovarian cancer are still limited, and exploring effective targeted biomarkers is particularly important for predicting and treating ovarian cancer. Therefore, it is necessary to explore the molecular mechanisms of the occurrence and development of ovarian cancer. This investigation encompassed the analysis of gene expression profiles, measurement of transcription levels of potential target genes in peripheral blood samples from ovarian cancer patients and characterization of the ovarian cancer-related secretory protein sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B). Through bioinformatics analysis, potential target genes were identified, and their association with overall survival (OS) and progression-free survival (PFS) in ovarian cancer patients was assessed utilizing relevant databases. Subsequently, differences in target gene expression in ovarian cancer tissue samples were validated through protein blotting and quantitative real-time PCR (qRT-qPCR). Cell proliferation assays using the cell count kit-8 (CCK-8) method, as well as transwell chamber assay and pre coated matrix gel chamber assay were employed to elucidate the role of SMPDL3B in ovarian cancer cell migration and invasion. This study revealed a substantial upregulation of SMPDL3B in the serum of ovarian cancer patients, correlating with an unfavorable prognosis. High SMPDL3B expression was linked not only to increased proliferation of ovarian cancer cells, but also enhanced migration and invasion. Remarkably, the knockdown the human alkaline ceramidase 2 (ACER2) gene in cancer cells with heightened SMPDL3B expression significantly inhibited cell proliferation, migration, and invasion induced by SMPDL3B activation (P<0.05), highlighting the functional interplay between ACER2 and SMPDL3B in ovarian cancer. In summary, this study proposes SMPDL3B as a prognostic marker for ovarian cancer, with implications for potential therapeutic intervention targeting the ACER2-SMPDL3B axis.

CDCA5 promoted cell invasion and migration by activating TGF-β1 pathway in human ovarian cancer cells

BackgroundThe gene cell division cycle associated 5 (CDCA5), also called sororin, has oncogenic characteristics and is upregulated in various carcinomas. Nevertheless, the involvement of CDCA5 in ovarian cancer (OC), a highly aggressive form of cancer, and the underlying mechanism of metastasis remain inadequately investigated.ResultsThe bioinformatics data revealed a negative correlation between the patient’s survival and CDCA5 expression, which was overexpressed in OC. Functional assays also confirmed high expression levels of CDCA5 in OC tissues and cells. This suggests that CDCA5 may potentially enhance the motility, migration, and proliferation of OC cells invitro. It impedes DNA damage and apoptosis in OC cells, inhibiting xenograft development in nude mice. The RNA sequencing results suggest CDCA5 is majorly associated with biological functions related to the extracellular matrix (ECM) and influences the transforming growth factor (TGF) signaling pathway. Moreover, subsequent functional investigations elucidated that CDCA5 facilitated the migration and invasion of OC cells viathe TGF-β1/Smad2/3 signaling pathway activation.ConclusionsCDCA5 may be a strong potential therapeutic target for the treatment and management of OC.

Anlotinib Inhibits Ovarian Cancer and Enhances Cisplatinum Sensitivity via Suppressing NOTCH2 Expression and Stemness.

The prognosis of ovarian cancer (OC) patients is especially poor for patients with chemotherapy resistance. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor, has shown encouraging clinical efficacy in several tumor types. The aim of the present study was to examine the inhibitory efficacy and mechanism of anlotinib on the proliferation and chemosensitivity of OC cells. The inhibitory effects of Anlotinib on SKOV3 and OVCAR3 OC cells were examined using CCK-8 cell-viability, colony-formation, flow-cytometry, transwell-migration and sphere-formation assays. A xenograft mouse model was used for in vivo studies. RT-qPCR and western blotting were used to detect gene expression. Molecular targets of anlotinib were elevated in OC patient tumors. Anlotinib significantly inhibited ovarian cancer cell proliferation and migration in vitro. Anlotinib enhanced the sensitivity of ovarian cancer cells to cisplatinum both in vitro and in vivo. Anlotinib suppressed sphere formation and the stemness phenotype of OC cells by inhibiting NOTCH2 expression. Anlotinib inhibits ovarian cancer and enhances cisplatinum sensitivity, suggesting its future clinical promise.

Abstract 4569: APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC)

Abstract Ovarian cancer is the leading cause of cancer-related death in women and most cases are diagnosed at later stages, with distant metastasis. Standard-of-care therapy is surgery followed by platinum and paclitaxel; however, most patients who initially respond to therapy eventually relapse after developing metastatic disease and chemoresistance. FAK overexpression or activation occurs in a substantial proportion of EOCs and is predictive of poor clinical outcomes. Recent studies have reported that FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer. Four EOC cell lines (OVCAR-3, SK-OV-3, A2780, and Kuramochi) were used for in vitro experiments. Cell proliferation was measured by CellTiter-Glo assays. Cell migration ability was assessed by wound healing assays. OVCAR-3 xenograft and luciferase-tagged ID8 (ID8-Luc) peritoneal syngeneic models were established to evaluate the synergistic antitumor efficacy of combined APG-2449 and PLD in vivo. APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant (OVCAR-3 and SK-OV-3) and platinum-sensitive (A2780 and Kuramochi) cell lines. In wound healing assays, FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells (SK-OV-3, OVCAR-3, and ID8-Luc) in a dose-dependent manner. In the OVCAR-3 xenograft model, combined APG-2449 and PLD demonstrated enhanced antitumor effects compared with either APG-2449 or PLD monotherapy (synergistic index, 1.33). In the ID8-Luc peritoneal syngeneic model, the combination regimen outperformed PLD or APG-2449 monotherapy in tumor growth inhibition. This inhibitory effect persisted more than 1 month after stopping combination treatment, whereas the monotherapy groups experienced rapid disease relapse. The combination group also exhibited the longest ascites-free and survival times compared with PLD or APG-2449 monotherapy groups. Overall, our data suggest that inhibition of FAK by APG-2449 enhances the antitumor effect of PLD in EOC cell lines and the OVCAR-3 xenograft mouse model. The combination regimen can also prolong ascites-free and survival times, as shown in the ID8-Luc peritoneal syngeneic model. These promising results support future clinical development of this combination treatment for ovarian cancer. Citation Format: Zhou Yu, Eric Liang, Daojie Liu, Bingxing Wu, Xinyi Yao, Yanqiu Ji, Dajun Yang, Yifan Zhai. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4569.

Abstract 954: An evaluation of the combination of metformin and Y15 for the treatment of platinum-resistant ovarian cancer

Abstract Ovarian cancer is the fifth leading cause of cancer mortality among women. This high mortality rate is linked to the development of resistance to first-line chemotherapy with platinum compounds which has been attributed in part to increased activity of focal adhesion kinase (FAK). The anti-diabetic drug Metformin was previously shown to inhibit the proliferation and migration of ovarian cancer cells and thus, the combination of a FAK inhibitor, Y15, and Metformin may be a promising treatment for platinum-resistant ovarian cancer (PROC). The objective of this study was to evaluate the combination of Y15 and Metformin on PROC cell viability and the mechanism of cell death. An MTT assay was used to analyze cell viability in PROC OVCAR3 cells after 48 h of treatment by measuring the absorbance at 570 nm with a microplate reader. Western blot was used to determine the protein levels of the apoptosis marker cleaved PARP and the autophagy marker LC3B-II. The exposure of OVCAR3 platinum-resistant ovarian cancer cells to Metformin (4.5 mM) + Y15 (5.5 µM) resulted in a significantly enhanced cytotoxicity (32.6 ± 1.8%) compared to single drug treatment with either Metformin (4.5 mM) (65.0 ± 4.2%) or Y15 (5.5 µM) (66.0 ± 4.8%). A combination of Metformin (7.8 mM) + Y15 (5.5 µM) also resulted in a significantly enhanced cytotoxicity (22.8 ± 1.5%) compared to single drug treatment with either Metformin (7.8 mM) (50.7 ± 3.7%) or Y15 (5.5 µM) (66.0 ± 4.8%). Cells treated with the combination of Metformin and Y15 for 24, 48, and 72-hours showed an increase in cleaved PARP compared to the control, Metformin alone and Y15 alone. For Metformin alone, there was an increase in cleaved PARP compared to the control at all timepoints and increased from 24 hours to 72 hours. For Y15 alone, the amount of cleaved PARP was also higher compared to the control at all time points, however, decreased over time from 24 hours to 72 hours. Cells treated with Metformin, Y15, and a combination of Metformin and Y15 showed no conversion of LC3B-I to LC3B-II, which occurs during autophagy. Thus, it is concluded that the mechanism of cell death for both Metformin and Y15 is through apoptosis and not autophagy and apoptosis is enhanced with the combination of the drugs. The delivery of Metformin and Y15 can result in an additive effect on cell viability through apoptosis and can be further explored as a promising approach for the treatment of PROC. Citation Format: Manuel A. Duarte, Kristal Garcia, Marco A. Arriaga, Sue Anne Chew, Arkene S. Levy, Isabela Mendez. An evaluation of the combination of metformin and Y15 for the treatment of platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 954.

Abstract 389: The role of endoplasmic reticulum stress in immune surveillance and effectiveness of immunotherapy in renal and ovarian carcinoma

Abstract In complex tumor-host interactions, the immune response has a dual role, with the capacity to both promote and suppress tumor growth, requiring complex interactions of regulatory molecules within the cellular network of the tumor-immune microenvironment (TIME). Various factors in TIME, such as low pH and hypoxia, cause Endoplasmic Reticulum Stress (ERS). Immune cells exposed to ERS lack antigen presentation, exhibit a suppressor phenotype, and can initiate apoptosis. Therefore, relieving ERS can benefit immune surveillance and response to immunotherapy. Our research is focused on tumor-immune cells interaction, specifically in ovarian and renal cancers. We conducted in vitro co-cultures of these cancer cells with peripheral blood mononuclear cells (PBMC) and manipulated ERS using a well-established ERS inducer tunicamycin and a chemical chaperone tauroursodeoxycholic acid (TUDCA). We then employed various techniques such as MTT, RT-qPCR, western blotting, immunofluorescence staining, scratch wound assay, and 3D co-cultures to analyze cellular viability, gene expression, protein levels of ERS markers (e.g., BiP, CHOP, PERK), immune cell activity (e.g., IL-2, INFγ, FoxP3, PD-1), migration, invasiveness, interaction, spheroid formation, and immune cell infiltration. Furthermore, we examined ERS and immune profiles in tumor samples from patients with ovarian and renal cancer who underwent conventional therapy or immunotherapy.Relieving ERS increased the infiltration of PBMC into tumor spheroids and reduced the expression of BiP and PERK in PBMC. In vitro, the viability of ovarian and renal cancer cells increased when cultured alone after ERS alleviation. However, when co-cultured with PBMC, their viability decreased, indicating enhanced immune cell response. Additionally, the growth and migration of ovarian and renal cancer cells were limited in these co-cultures, along with increased expression of BiP and CHOP and an elevated CHOP/BiP ratio. We connected these findings to the molecular background of ERS in patient samples and observed a positive correlation between a favorable clinical outcome, higher lymphocyte infiltration at the tumor site, and increased levels of BiP and CHOP in cancer cells. We further applied these results to OC and RCC in vivo syngeneic mouse models, currently with very promising outcomes.Based on these results we expect ERS alleviation as a suitable approach to improving the survival and effectiveness of immune cell populations within hostile tumor-induced microenvironment with positive effects on anticancer immunotherapy. Supported by Ministry of Health of the Czech Republic, grant nr. NU21-03-00539, and by the Johannes Amos Comenius Programme, project SALVAGE nr. CZ.02.01.01/00/22_008/0004644. All rights reserved. Citation Format: Marek Svoboda, Lukas Moran, Barbora Vavrusakova, Lenka Krejci, Kamila Souckova, Katerina Vasickova, Milos Holanek. The role of endoplasmic reticulum stress in immune surveillance and effectiveness of immunotherapy in renal and ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 389.

Portulaca oleracea L. polysaccharide inhibits ovarian cancer via inducing ACSL4-dependent ferroptosis.

The antitumor effect of Portulaca oleracea L. polysaccharide (POL) has been demonstrated, but whether it curbs the development of ovarian cancer has not been reported. Here, we treated ovarian cancer cells with different concentrations of POL, detected cell activity by CCK-8 assay, and apoptosis rate by flow cytometry. The results showed that SKOV3 and Hey cell survival decreased with increasing POL concentration in a dose-dependent manner. POL significantly inhibited ovarian cancer cell migration and increased cell death compared with the control group. Ferroptosis inhibitors, but not apoptosis, necrosis, and autophagy inhibitors, reversed POL-induced cell death. Further studies revealed that POL promoted the accumulation of lipid reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA), and decreased glutathione (GSH) production. Moreover, POL significantly increased the mortality of ovarian cancer cells. In vivo studies confirmed that POL reduced the volume and weight of tumors and increased the levels of Fe2+ and MDA in mice in vivo. Western blot assay revealed that POL increased the expression of ACSL4 in ovarian cancer cells as well as in tumors in mice in vivo. More importantly, the POL-mediated increase in lipid ROS, Fe2+, MDA, and decrease in GSH were significantly reversed after knocking down ACSL4 in ovarian cancer cells. Thus, POL can effectively inhibit ovarian cancer development, which may be achieved by increasing ACSL4-mediated ferroptosis. These results suggest that POL has the potential to be a potential drug for targeted treatment of ovarian cancer.

Cancer-associated fibroblast-secreted FGF7 as an ovarian cancer progression promoter.

Ovarian cancer (OC) is distinguished by its aggressive nature and the limited efficacy of current treatment strategies. Recent studies have emphasized the significant role of cancer-associated fibroblasts (CAFs) in OC development and progression. Employing sophisticated machine learning techniques on bulk transcriptomic datasets, we identified fibroblast growth factor 7 (FGF7), derived from CAFs, as a potential oncogenic factor. We investigated the relationship between FGF7 expression and various clinical parameters. A series of in vitro experiments were undertaken to evaluate the effect of CAFs-derived FGF7 on OC cell activities, such as proliferation, migration, and invasion. Single-cell transcriptomic analysis was also conducted to elucidate the interaction between FGF7 and its receptor. Detailed mechanistic investigations sought to clarify the pathways through which FGF7 fosters OC progression. Our findings indicate that higher FGF7 levels correlate with advanced tumor stages, increased vascular invasion, and poorer prognosis. CAFs-derived FGF7 significantly enhanced OC cell proliferation, migration, and invasion. Single-cell analysis and in vitro studies revealed that CAFs-derived FGF7 inhibits the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF-1α) via FGFR2 interaction. Activation of the FGF7/HIF-1α pathway resulted in the upregulation of mesenchymal markers and downregulation of epithelial markers. Importantly, in vivo treatment with neutralizing antibodies targeting CAFs-derived FGF7 substantially reduced tumor growth. Neutralizing FGF7 in the medium or inhibiting HIF-1α signaling reversed the effects of FGF7-mediated EMT, emphasizing the dependence of FGF7-mediated EMT on HIF-1α activation. These findings suggest that targeting the FGF7/HIF-1α/EMT axis may offer new therapeutic opportunities to intervene in OC progression.

Plasma membrane SK2 channel activity regulates migration and chemosensitivity of high-grade serous ovarian cancer cells.

No data are currently available on the functional role of small conductance Ca2+ -activated K+ channels (SKCa) in ovarian cancer. Here, we characterized the role of SK2 (KCa2.2) in ovarian cancer cell migration and chemosensitivity. Using the selective non-cell-permeant SK2 inhibitor Lei-Dab7, we identified functional SK2 channels at the plasma membrane, regulating store-operated Ca2+ entry (SOCE) in both cell lines tested (COV504 and OVCAR3). Silencing KCNN2 with short interfering RNA (siRNA), or blocking SK2 activity with Lei-Dab7, decreased cell migration. The more robust effect of KCNN2 knockdown compared to Lei-Dab7 treatment suggested the involvement of functional intracellular SK2 channels in both cell lines. In cells treated with lysophosphatidic acid (LPA), an ovarian cancer biomarker of progression, SK2 channels are a key player of LPA pro-migratory activity but their role in SOCE is abolished. Concerning chemotherapy, SK2 inhibition increased chemoresistance to Taxol® and low KCNN2 mRNA expression was associated with the worst prognosis for progression-free survival in patients with serous ovarian cancer. The dual roles of SK2 mean that SK2 activators could be used as an adjuvant chemotherapy to potentiate treatment efficacy and SK2 inhibitors could be administrated as monotherapy to limit cancer cell dissemination.

ST14 interacts with TMEFF1 and is a predictor of poor prognosis in ovarian cancer

TMEFF1 is a new protein involved in the physiological functions of the central nervous system, and we previously reported TMEFF1 can promote ovarian cancer. ST14 was determined to be involved in the processes of epidermal differentiation, epithelial cell integrity, and vascular endothelial cell migration, etc. The relationship between ST14 and TMEFF1 in the ovary remains unknown. In this study, we detected the expression of ST14 and TMEFF1 in 130 different ovarian cancer tissues through immunohistochemistry. We determined ST14 and TMEFF1 were highly expressed in ovarian cancer, indicating a higher degree of tumor malignancy and a worse prognosis. Tissues significantly expressing ST14 also highly expressed TMEFF1, and the expression of the two proteins was positively correlated. Consistently, immunofluorescence double staining demonstrated the co-localization of ST14 and TMEFF1 in the same region, and immunoprecipitation confirmed the interaction between ST14 and TMEFF1. TMEFF1 expression was also reduced after knocking down ST14 through Western blot. MTT, wound healing and Transwell assays results determined that knockdown of ST14 inhibited proliferation, migration and invasion of ovarian cancer cells in vitro, but the inhibitory effect was restored after adding TMEFF1 exogenous protein. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis showed that ST14 and its related genes were enriched in the processes of epithelial formation, intercellular adhesion, protein localization, and mitosis regulation. We also clarified the kinase, microRNA, and transcription factor target networks and the impact of genetic mutations on prognosis. Overall, high expression of ST14 and TMEFF1 in ovarian cancer predicts higher tumor malignancy and a worse prognosis. ST14 and TMEFF1 co-localize and interact with each other in ovarian cancer. ST14 can regulate TMEFF1 expression to promote proliferation, migration and invasion of ovarian cancer cells. We speculate that the relationship between ST14 and TMEFF1 in ovarian cancer could become a potential target for anti-cancer therapy.

Statement of Retraction: Two Cu(II) complexes: inhibitory activity on ovarian cancer cell proliferation, migration, and invasion ability via increasing miRNA16 expression

Statement of Retraction: Two Cu(II) complexes: inhibitory activity on ovarian cancer cell proliferation, migration, and invasion ability via increasing miRNA16 expression