Environmental Toxicology

RETRACTED: An innovative predictive model for cervical cancer constructed around a gene profile associated with cholesterol metabolism

Abstract Cholesterol metabolism is crucial for cell survival and cancer progression. The prognostic patterns of genes linked to cholesterol metabolism (CMAGs) in CESC, however, have received very little attention in research. From public databases, TCGA‐CESC cohorts with mRNA expression patterns and the accompanying clinical information of patients were gathered. Consensus clustering was used to find the molecular subtype connected to cholesterol metabolism. In the TCGA‐CESC cohort, a predictive risk model with 28 CMAGs was created using Lasso‐Cox regression. The function enrichment analysis between groups with high‐and low‐risk were investigated by employing GO, KEGG, and GSVA software. The immune cell infiltration was analyzed using ESTIMATE, CIBERSORT, and MCPCOUNTER methods. Finally, we select 7 genes in risk model for further multivariate Cox analysis, and ultimately a hub gene, CHIT1, was identified. Meanwhile, the function of CHIT1 was preliminarily verified in cell and mice tumor model. In conclusion, the abundance of the CHIT1 gene might be beneficial for forecasting the prognosis of CESC, demonstrating that cholesterol metabolism could be a promising treatment target for CESC.

RETRACTED: KIF15 knockdown inhibits the development of endometrial cancer by suppressing epithelial‐mesenchymal transition and stemness through Wnt/β‐catenin signaling

Abstract Endometrial cancer (EC) is one of the most common cancers among women, while the incidence of EC is rising. Many studies have found that Kinesin family member 15 (KIF15) is highly expressed in a series of cancers, but the role of KIF15 in EC is unclear. We detected the expression level of KIF15 in a microarray of EC tissues by immunohistochemical staining (IHC), and analyzed the correlation between the expression level of KIF15 and the pathological characteristics of patients. After inhibit the expression of KIF15 in EC cells with lentivirus, cell proliferation and apoptosis were detected respectively by CCK8 assay, flow cytometry and tunnel assay. Transwell assay and wound healing assay were used to examine the migration ability and invasion ability of EC cells. Spheroid formation assay was used to evaluate cell self‐renewal ability. In vivo tumor xenograft model was used for validation. The expressions of epithelial‐mesenchymal transition, cancer stem cells, and Wnt/β‐catenin signaling molecules were detected by Western blotting. The results showed that the expression of KIF15 in EC tissues was higher than that in normal endometrial tissues, while the expression level of KIF15 in EC was positively correlated with the pathological grade of the tumor. The down‐regulation of KIF15 reduced the proliferation, colony formation, invasion, migration and self‐renewal ability of EC cells, while promoted cell apoptosis. Knockdown of KIF15 inactivates the Wnt/β‐catenin signaling of EC cells, inhibitors of Wnt signaling can counteract the enhanced self‐renewal ability caused by KIF15 overexpression. Therefore, KIF15 may be a new potential target for diagnosis and treatment of EC.

REG3A promotes proliferation and DDP resistance of ovarian cancer cells by activating the PI3K/Akt signaling pathway

AbstractThis study explored the effect of Regenerating Islet‐Derived 3‐Alpha (REG3A) on ovarian cancer (OC) progression. REG3A expression was scrutinized in clinical tissues of 97 OC cases by quantitative real‐time polymerase chain reaction (qRT‐PCR). REG3A expression in OC cells and cisplatin (DDP) resistance OC cells was regulated by transfection. LY294002 (10 μM, inhibitor of the PI3K/Akt signaling pathway) was used to treat OC cells and DDP resistance OC cells. Cell counting kit‐8 and methyl‐thiazolyl‐tetrazolium assays were applied for proliferation and DDP resistance detection. Flow cytometry was utilized for cell cycle and apoptosis analysis. The effect of REG3A on the OC cell in vivo growth was researched by establishing xenograft tumor model via using nude mice using nude mice. The expression of genes in clinical samples, cells and xenograft tumor tissues was investigated by qRT‐PCR, Western blot and immunohistochemistry. As a result, REG3A was over‐expressed in OC patients and cells, associating with dismal prognosis of patients. REG3A knockdown repressed proliferation, DDP resistance, induced cell cycle arrest and apoptosis of OC cells, and reduced the expression MDR‐1, Cyclin D1, Cleaved caspase 3 proteins and the PI3K/Akt signaling pathway activity in OC cells. LY294002 treatment abrogated the promotion effect of REG3A on OC cell proliferation, apoptosis inhibition and DDP resistance. REG3A knockdown suppressed the in vivo growth of OC cells. Thus, REG3A promoted proliferation and DDP resistance of OC cells by activating the PI3K/Akt signaling pathway. REG3A might be a promising target for the clinical treatment of OC.

FAM83A has a pro‐tumor function in ovarian cancer by affecting the Akt/Wnt/β‐catenin pathway

AbstractFamily with sequence similarity 83, member A (FAM83A) is a tumor‐exclusive gene that has a vital role in numerous tumors. However, its role in tumorigenesis remains controversial. This work is dedicated to the study of the role of FAM83A in ovarian cancer. We observed elevated levels of FAM83A in ovarian cancer specimens and cells. Kaplan–Meier survival curves revealed that elevated FAM83A levels predicted a worse overall survival in ovarian cancer patients. The inhibition of FAM83A caused remarkable suppressive effects on the proliferation and invasion of ovarian cancer cells, and enhanced their chemosensitivity. On the contrary, the upregulation of FAM83A had opposite effects. Mechanistically, FAM83A had an effect on the Akt and Wnt/β‐catenin pathways in ovarian cancer cells. The repression of Akt could cancel the regulatory effect of FAM83A overexpression on the Wnt/β‐catenin pathway. Moreover, reactivation of the Wnt/β‐catenin pathway abolished FAM83A‐inhibition‐evoked antitumor effects. Additionally, FAM83A inhibition weakened the tumorigenic potential of ovarian cancer in vivo. Taken together, this work shows that FAM83A exerts a pro‐tumor function in ovarian cancer by affecting the Akt/Wnt/β‐catenin pathway and proposes FAM83A as an effective and possible treatment target for ovarian cancer.

CRABP2 accelerates epithelial mesenchymal transition in serous ovarian cancer cells by promoting TRIM16 methylation via upregulating EZH2 expression

AbstractRecently, it was covered that cellular retinoic acid‐binding protein 2 (CRABP2) is upregulated in ovarian cancer and participates in tumor progression, however, the specific mechanism remains to be explored. The pcDNA‐CRABP2 or si‐CRABP2 was transfected into SKOV3 and OVCAR3 ovarian cancer cells, respectively, and we observed that overexpression of CRABP2 inhibited cell apoptosis, promoted cell invasion and expression of epithelial mesenchymal transition (EMT) marker proteins, and transfection of si‐CRABP2 had the opposite effect. Furthermore, we predicted that EZH2 interacted with CRABP2, and overexpression of CRABP2 promoted EZH2 expression, knockdown of CRABP2 inhibited EZH2 expression, and co‐immunoprecipitation assay confirmed their binding relationship. The SKOV3 and OVCAR3 cells were then incubated with pcDNA‐CRABP2 alone together with si‐EZH2, and we found that si‐EZH2 reversed the effect of pcDNA‐CRABP2 on promotion of EZH2 expression, cell invasion and EMT maker protein levels. Next, we found that EZH2 could bind to DNMT1, and overexpression of EZH2 inhibited TRIM16 expression and knockdown of EZH2 promoted TRIM16 expression. Moreover, the promoter of TRIM16 contains the CpG island, and ChIP assay observed enriched DNMT1 on the promoter of TRIM16, and overexpression of EZH2 increased the promoter methylation level of TRIM16 and knockdown of EZH2 suppressed the methylation. The SKOV3 cells were incubated with si‐EZH2 alone or combined with si‐TRIM16, and we found that si‐TRIM16 reversed the effect of si‐EZH2. In vivo studies showed that knockdown of CRABP2 inhibited tumor volume and weight, suppressed the expression of EZH2 and EMT related proteins vimentin and snail, and increased the expression of TRIM16 and E‐cadherin.

TRIP13 exerts a cancer‐promoting role in cervical cancer by enhancing Wnt/β‐catenin signaling via ACTN4

AbstractIncreasing evidence has indicated that thyroid hormone receptor interacting protein 13 (TRIP13) exerts a cancer‐promoting role in a broad spectrum of cancers. However, the detailed relevance and function of TRIP13 in cervical cancer remain undefined. The goal of this work was to evaluate the functional significance and mechanism of TRIP13 in cervical cancer. Our data demonstrated that TRIP13 expression was markedly increased in cervical cancer tissue, and high expression of TRIP13 predicted a low survival rate in cervical cancer patients. Knockdown of TRIP13 caused a significant reduction in the proliferation and invasion of cervical cancer cells. By contrast, over‐expression of TRIP13 accelerated the proliferation and invasion of cervical cancer cells. Further data revealed that TRIP13 enhanced the activation of Wnt/β‐catenin signaling associated with modulation of α‐Actinin‐4 (ACTN4). Knockdown of ACTN4 markedly reversed TRIP13‐mediated activation of Wnt/β‐catenin signaling. In addition, inhibition of Wnt/β‐catenin signaling reversed TRIP13‐induced cancer‐promoting effects in cervical cancer cells. Knockdown of TRIP13 markedly retarded the tumor formation and growth of cervical cells in vivo in nude mice. Taken together, the data of this work indicate that TRIP13 accelerates the proliferation and invasion of cervical cancer by enhancing Wnt/β‐catenin signaling via regulation of ACTN4. These findings underscore a relevance of the TRIP13/ACTN4/Wnt/β‐catenin signaling axis in the progression of cervical cancer and suggest TRIP13 as a potential target for treatment of cervical cancer.

Inhibition of the notch signaling pathway overcomes resistance of cervical cancer cells to paclitaxel through retardation of the epithelial–mesenchymal transition process

AbstractUse of paclitaxel as monotherapy or in combination with other therapeutic agents is a widely employed front‐line chemotherapeutic strategy for cervical cancer. However, previous reports have shown that approximately 70% of the patients with cervical cancer develop resistance to paclitaxel. Epithelial–mesenchymal transition (EMT) contributes to the occurrence of chemoresistance in several types of cancer, including cervical cancer. Identification of the critical signaling pathway that regulates the EMT process may provide a novel strategy for avoiding or delaying the emergence of paclitaxel resistance during the treatment of cervical cancer. Herein, we established a paclitaxel‐resistant cervical cancer cell line (HeLa‐229PTR cells) by culturing parental HeLa‐229 cells with increasing concentrations of paclitaxel. We observed elevated expression of Notch1 in HeLa‐229PTR cells compared with their parental HeLa‐229 cells, indicating its potential involvement in the EMT phenotype of the paclitaxel‐resistant cells. Furthermore, silencing of the NOTCH1 gene, as well as treatment with a γ‐secretase inhibitor (DAPT) partially reversed the EMT phenotype and significantly enhanced the sensitivity of HeLa‐229PTR cells to paclitaxel. Moreover, we found that DAPT could significantly inhibit invasiveness, reduce colony formation activity, and promote apoptosis of HeLa‐229PTR cells. Taken together, these results indicated that HeLa‐229PTR cells develop the EMT phenotype partly through activation of Notch1 signaling. Thus, inhibition of Notch1 signaling can be a strategy for the reversal of the EMT phenotype and may increase the sensitivity of cervical cancer cells to treatment with paclitaxel.

Dioscorea nipponicaMakino suppressesTPA‐induced migration and invasion through inhibition of matrix metalloproteinase‐9 in human cervical cancer cells

AbstractDioscorea nipponicaMakino has been used for the treatment of chronic bronchitis, rheumatoid arthritis, cough, and asthma. Several studies have established the antitumor effect ofD. nipponicaMakino extract (DNE). However, no investigations have considered the antimetastatic potential of DNE in cervical cancer cells. The present study examined the effects of DNE on cervical cancer cells treated with 12‐O‐tetradecanoylphorbol‐13‐acetate and characterized the possible molecular mechanisms. MTT assay results indicated that DNE exhibited very low cytotoxicity, and DNE significantly reduced the invasion and migration abilities of cervical cancer cells. Gelatin zymography analysis revealed that DNE significantly inhibited matrix metalloproteinase‐9 (MMP‐9) activity. Reverse transcription‐polymerase chain reaction assay results revealed that DNE treatment inhibited the MMP‐9 mRNA levels of HeLa and SiHa cells. Western blot results revealed that DNE significantly diminished the ERK1/2 phosphorylation. In conclusion, we revealed that the antimetastatic effects of DNE on cervical cancer cells are due to its inhibition of MMP‐9 expression through the ERK1/2 pathway.

G2 and S phase‐expressed‐1 acts as a putative tumor promoter in cervical cancer by enhancing Wnt/β‐catenin signaling via modulation of GSK‐3β

AbstractG2 and S phase‐expressed‐1 (GTSE1) is currently identified as a key regulator of carcinogenesis. However, the involvement of GTSE1 in cervical cancer is unclear. The aims of this work were to explore the relationship between GTSE1 and cervical cancer. Our data elucidated high GTSE1 expression in cervical cancer tissue, which predicted a poor prognosis in cervical cancer patients. GTSE1 knockdown had tumor‐suppressive effects in cervical cancer cells by inhibiting cell proliferative and invasive abilities. GTSE1 knockdown decreased the level of phosphorylated glycogen synthase kinase‐3β (GSK‐3β) and active β‐catenin, resulted in inactivation of Wnt/β‐catenin signaling. Suppression of GSK‐3β remarkably abolished the GTSE1‐knockdown‐induced inhibitory effects on Wnt/β‐catenin signaling. Suppression of Wnt/β‐catenin signaling abolished the GTSE1‐overexpression‐induced oncogenic effects. Notably, GTSE1 knockdown impeded the in vivo tumorigenicity of cervical cancer cells. In short, this work demonstrates that GTSE1 is overexpressed in cervical cancer and GTSE1 suppression exerts a tumor‐inhibiting role in cervical cancer by down‐regulating Wnt/β‐catenin signaling. Our work underlines a crucial relevance between GTSE1 and cervical cancer progression and suggests GTSE1 as a promising therapeutic target for cervical cancer.

EF‐24 inhibits TPA‐induced cellular migration and MMP‐9 expression through the p38 signaling pathway in cervical cancer cells

AbstractDiphenyl difluoroketone (EF‐24), a synthetic curcumin analog, has enhanced bioavailability over curcumin. EF‐24 acts more powerful bioactivity for anti‐inflammatory and anti‐cancer activity. However, the effects and mechanism of EF‐24 on cervical cancer has not been fully investigated. Herein, this study evaluated the effects of EF‐24 on TPA‐induced cellular migration of cervical cancer. The results showed that EF‐24 substantially reduced the cellular migration and cellular invasion of the HeLa and SiHa cells. Moreover, gelatin zymography, western blotting analyses and real‐time PCR revealed that EF‐24 suppressed Matrix metalloproteinase‐9 (MMP‐9) activity, protein expression and mRNA levels. Mechanistically, EF‐24 inhibited the phosphorylation of the p38 signaling pathway. In conclusion, EF‐24 inhibited TPA‐induced cellular migration and cellular invasion of cervical cancer cell lines through modulating MMP‐9 expression via downregulating signaling p38 pathway and EF‐24 may have potential to serve as a chemopreventive agent of cervical cancer.

Antitumor activity of pachymic acid in cervical cancer through inducing endoplasmic reticulum stress, mitochondrial dysfunction, and activating the AMPK pathway

AbstractPachymic acid has various pharmacological effects, including anti‐inflammatory, antioxidant, immunomodulatory, and antitumor. However, the role of pachymic acid in cervical cancer remains unclear. So, we investigated the effects of pachymic acid in cervical cancer and elucidated the underlying mechanisms. We treated HeLa cells and normal cervical epithelial cells (HUCECs) with pachymic acid (0, 10, 20, 40, 80, or 160 μM) for 72 h, and found the cell activity was decreased in cells treated with 160 μM pachymic acid for 48 h or 80 μM pachymic acid for 72 h, while HUCECs viability without effect. Next, we observed that endoplasmic reticulum (ER) related gene expression, mitochondrial membrane potential (MMP) changes, ATP depletion, reactive oxygen species (ROS) generation and apoptosis were increased. Moreover, we observed that cytochrome C (Cytc) expression was increased and apoptosis‐inducing factor (AIF) was decreased in the cytoplasm of pachymic acid‐treated HeLa cells. Tauroursodeoxycholic acid (TUDCA) of ER stress inhibitor reversed the effects of pachymic acid on HeLa cells. Phosphorylation of AMPK and acetyl‐CoA carboxylase (ACC) of the AMPK pathway key protein was upregulated in pachymic acid‐induced HeLa cells. Finally, we subcutaneously implanted HeLa cells into female nude mice and treated them with pachymic acid (50 mg/kg) for 3 weeks (5 days/week), and observed in pachymic acid induced xenograft mice, tumor growth was suppressed, cell apoptosis, ER‐related gene expression, and ROS levels in tumor tissues were increased. Therefore, these findings demonstrated that pachymic acid plays an anti‐tumor activity in cervical cancer through inducing ER stress, mitochondrial dysfunction, and activating the AMPK pathway.

RETRACTED: Machine learning analysis of oxidative stress‐related phenotypes for specific gene screening in ovarian cancer

AbstractBackgroundOxidative stress serves a crucial role in tumor development. However, the relationship between ovarian cancer and oxidative stress remains unknown. We aimed to create an oxidative stress‐related prognostic signature to enhance the prognosis prediction of CC patients using bioinformatics.MethodsThe genes differentially expressed and associated with oxidative stress were extracted with the help of “limma” packages. The model for prognosis was created using Multivariate Cox regression analysis to determine the risk related to the genes related to oxidative stress. Patients were categorized as low‐risk or high‐risk based on the median score. The receiver operation characteristic (ROC) and survival curves were used to evaluate the predictive effect of the prognostic signature. We utilized quantitative real‐time PCR to assess the expression levels of key genes associated with oxidative stress in ovarian cancer cell lines (SKOV3, OVCAR3, and HeyA8) and normal ovarian epithelial cells (HOSEpiC).ResultsA signature comprising seven genes associated with oxidative stress was developed to prognosticate patients with ovarian cancer. Overall survival (OS) of the patient having CC was determined using Kaplan–Meier analysis. It was found that patient with a higher risk score had lower OS than the low‐risk score. The signature of genes associated with oxidative stress was found to be independently prognostic for 1, 2, and 3 years. Further research found that the expression levels of nine hub genes had a strong association with patient outcomes. Our analysis revealed a higher expression of CX3CR1 in ovarian cancer cell lines compared with normal cells.ConclusionsTo deploy a novel oxidative stress‐related prognostic signature as an independent biomarker in cervical cancer, we developed and validated it.

RETRACTED: Refining molecular subtypes and risk stratification of ovarian cancer through multi‐omics consensus portfolio and machine learning

AbstractOvarian cancer (OC), known for its pronounced heterogeneity, has long evaded a unified classification system despite extensive research efforts. This study integrated five distinct multi‐omics datasets from eight multicentric cohorts, applying a combination of ten clustering algorithms and ninety‐nine machine learning models. This methodology has enabled us to refine the molecular subtyping of OC, leading to the development of a novel Consensus Machine Learning‐driven Signature (CMLS). Our analysis delineated two prognostically significant cancer subtypes (CS), each marked by unique genetic and immunological signatures. Notably, CS1 is associated with an adverse prognosis. Leveraging a subtype classifier, we identified five key genes (CTHRC1, SPEF1, SCGB3A1, FOXJ1, and C1orf194) instrumental in constructing the CMLS. Patients classified within the high CMLS group exhibited a poorer prognosis and were characterized by a “cold tumor” phenotype, indicative of an immunosuppressive microenvironment rich in MDSCs, CAFs, and Tregs. Intriguingly, this group also presented higher levels of tumor mutation burden (TMB) and tumor neoantigen burden (TNB), factors that correlated with a more favorable response to immunotherapy compared to their low CMLS counterparts. In contrast, the low CMLS group, despite also displaying a “cold tumor” phenotype, showed a favorable prognosis and a heightened responsiveness to chemotherapy. This study's findings underscore the potential of targeting immune‐suppressive cells, particularly in patients with high CMLS, as a strategic approach to enhance OC prognosis. Furthermore, the redefined molecular subtypes and risk stratification, achieved through sophisticated multi‐omics analysis, provide a framework for the selection of therapeutic agents.

OTU deubiquitinase 7B facilitates the hyperthermia‐induced inhibition of lung cancer progression through enhancing Smac‐mediated mitochondrial dysfunction

AbstractHyperthermia, as an adjuvant therapy, has shown promising anti‐tumor effects. Ovarian tumor domain‐containing 7B (OTUD7B) is a deubiquitinating enzyme that is frequently found in a variety of cancers. The aim of this study is to investigate the role of OTUD7B in lung cancer hyperthermia and the underlying mechanism. A549 and CALU‐3 cells were respectively exposed to 42 or 44°C for the indicated times (0, 1, 3, or 6 h) followed by incubation at 37°C for 24 h. We found a temperature‐ and time‐dependent decrease in cell viability and an increase in apoptosis levels. Compared with 0 h, heat treatment for 3 h inhibited the proliferation and invasion of A549 cells, reduced the expression levels of mitochondrial membrane potential, IAP family members (cIAP‐1 and XIAP) proteins and ubiquitination of Smac, and increased Smac protein expression. Treatment with 10 μM Smac mimic BV6 further enhanced the anti‐tumor effect of hyperthermia. Next, co‐IP validation showed that OTUD7B interacted with Smac and stabilized Smac through deubiquitination. OTUD7B overexpression induced damage in A549 and CALU‐3 cells, while silencing OTUD7B caused opposite effects. Overexpressing OTUD7B enhanced the anti‐cancer effect of hyperthermia, while si‐OTUD7B reversed the anti‐cancer effect of hyperthermia, which was verified in the xenograft tumor model in nude mice. Taken together, OTUD7B may serve as a potential anticancer factor with potential clinical efficacy in the thermotherapeutic treatment of lung cancer.

Long noncoding RNA VPS9D1 ‐ AS1 promotes the progression of endometrial cancer via regulation of the miR‐187‐3p / S100A4 axis

Abstract VPS9D1‐AS1 functions as an oncogene in many cancers. However, its role and potential mechanism in the progression of endometrial cancer (EC) are not fully understood. VPS9D1‐AS1 levels in EC and adjacent normal tissues were investigated using the TCGA‐UCEC cohort and 24 paired clinical samples. The roles of VPS9D1‐AS1 and miR‐187‐3p in cell cycle, proliferation, and apoptosis were evaluated by loss‐ and gain‐of‐function experiments. In addition, the effect of VPS9D1‐AS1 on tumor growth was further investigated in vivo. Rescue experiments were performed to investigate the involvement of the miR‐187‐3p/S100A4 axis in VPS9D1‐AS1 knockdown‐mediated antitumor effects. VPS9D1‐AS1 was highly expressed in EC tissues. VPS9D1‐AS1 knockdown, similar to miR‐187‐3p overexpression, significantly inhibited cell proliferation, inhibited colony formation, induced cell cycle arrest, and facilitated apoptosis of KLE cells. MiR‐187‐3p bound directly to VPS9D1‐AS1 and the 3′UTR of S100A4. Furthermore, VPS9D1‐AS1 negatively regulated miR‐187‐3p while positively regulating S100A4 expression in EC cells. MiR‐187‐3p knockdown or S100A4 overexpression partially reversed the tumor suppressive function of VPS9D1‐AS1 knockdown. The results suggest that VPS9D1‐AS1 affects EC progression by regulating the miR‐187‐3p/S100A4 axis. This may provide a promising therapeutic target to help treat EC.

Licochalcone A induces endoplasmic reticulum stress‐mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression

Abstract Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC‐7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER‐related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER‐stress mediated cell apoptosis and decreased expression of ER‐ and apoptosis‐related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78‐mediated ER‐stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

RETRACTED: Research on the toxicological prognostic significance of age‐related genes in endometrial cancer unveiling key factors in patient prognosis

Abstract This study investigates the influence of aging‐related genes on endometrial cancer, a prominent gynecological malignancy with rising incidence and mortality. By analyzing gene expression differences between cancerous and normal endometrial tissues, 42 aging‐related genes were identified as differentially expressed. Utilizing the TCGA‐UCEC sample, consensus clustering divided the samples into two molecular subgroups, Aging low and Aging high, based on their expression profiles. These subgroups showed distinct prognoses and survival rates, with the Aging high group associated with DNA repair and cell cycle pathways, and the Aging low group showing suppressed metabolic pathways and increased immune cell infiltration, suggesting a potential for better immunotherapy outcomes. Mutation analysis did not find significant differences in mutation frequencies between the groups, but a high Tumor Mutation Burden (TMB) correlated with better prognosis. A risk score model was also developed, showcasing significant prognostic power. Further analysis of the SIX1 gene revealed its overexpression in cancer cells. Drug sensitivity tests indicated that the low‐risk group might respond better to chemotherapy. This research underscores the significance of aging‐related genes in endometrial cancer, offering insights into their prognostic value and therapeutic potential, which could lead to personalized treatment approaches and enhanced patient management.

DLGAP5 knockdown inactivates the Wnt/β‐catenin signal to repress endometrial cancer cell malignant activities

AbstractHuman discs large‐associated protein 5 (DLGAP5), a microtubule‐associated protein, has been reported to be upregulated in several tumors. However, the role of DLGAP5 in endometrial cancer (EC) progression and the related underlying mechanism were still unknown. A bioinformatics analysis was performed to analyze the expression and prognostic significance of DLGAP5 in EC tissues using TCGA, CPTAC, Human Protein Atlas, and GSE63678 databases, UALCAN web tool, and the Kaplan–Meier plotter. Effects of DLGAP on EC cell malignant properties were evaluated by CCK‐8, flow cytometry analysis, TUNEL assay, caspase‐3 activity assay, and Transwell invasion assay. The expression of DLGAP5, Wnt3, c‐Myc, Ki67, and cleaved caspase‐3 was detected by western blot analysis. DLGAP5 was highly expressed and correlated with poor prognosis in EC patients. DLGAP5 knockdown inhibited proliferation and invasion, triggered apoptosis, and increased caspase‐3 activity in EC cells. Additionally, DLGAP5 knockdown inactivated the Wnt/β‐catenin signaling pathway in EC cells. Moreover, β‐catenin overexpression abolished the effects of DLGAP5 knockdown on the malignant phenotypes of EC cells. DLGAP5 silencing suppressed the malignant properties in EC cells by inactivating the Wnt/β‐catenin pathway.

Revolutionizing prognosis: Introducing cell death index (CDI) as a powerful prognostic tool for CSCC patients

AbstractBackgroundCervical squamous cell carcinoma (CSCC) threatens the body health of women worldwide. This study aimed to foster a new concept of prognostic indicator named cell death index (CDI).MethodsRNA‐seq and scRNA‐seq datasets were downloaded from the GEO and TCGA database as the training and validation cohorts. Programmed cell death (PCD)‐related gene signatures were obtained from published research. The construction of prognostic model was performed based on CDI value. Patients with CSCC were divided into high‐ and low‐CDI groups. We explored the differences in overall survival time, immune infiltration, mutation status, and drug sensitivity between high and low CDI groups by R software.ResultsWe constructed prognostic model to calculate the CDI value with 23 genes. Patients with high CDI have shorter survival time than those with low CDI. CDI was considered a risk factor compared to other characteristics. The nomogram model estimated overall survival (OS) at 1, 3, and 6 years, with age, Stage, and CDI, indicating the accuracy of the model in predicting 1‐, 3‐, and 6‐year survival rates. CDI values were negatively correlated with most immune checkpoint genes. We measured the significant drug sensitivity of Mitoxantrone, Sabutoclax, Sepantronium bromide, Topotecan, BI‐2536, and BMS‐754807 between high‐ and low‐CDI groups with significant correlation.ConclusionThis investigation constructed a novel effective prognostic indicator of CDI in patients with CSCC and identified potential genes associated with cell death that could be targeted for prognosis and treatment of CSCC.

Functional mechanism of hypoxia‐like conditions mediating resistance to ferroptosis in cervical cancer cells by regulating KDM4A SUMOylation and the SLC7A11 / GPX4 pathway

Abstract The discovery of ferroptosis has unveiled new perspectives for cervical cancer (CC) management. We elucidated the functional mechanism of hypoxia‐like conditions in CC cell ferroptosis resistance. CC cells were subjected to normoxia or hypoxia‐like conditions, followed by erastin treatment to induce ferroptosis. The assessment of cell viability/ferroptosis resistance was performed by MTT assay/Fe 2+ , MDA, and glutathione measurement by colorimetry. KDM4A/SUMO1/Ubc9/SENP1 protein levels were determined by Western blot. Interaction and binding sites between KDM4A and SUMO1 were analyzed and predicted by immunofluorescence/co‐immunoprecipitation and GPS‐SUMO 1.0 software, with the target relationship verified by mutation experiment. SLC7A11/GPX4/H3K9me3 protein levels, and H3K9me3 level in the SLC7A11 gene promoter region were determined by RT‐qPCR and Western blot/chromatin immunoprecipitation. H3H9me3/SLC7A11/GPX4 level alterations, and ferroptosis resistance after KDM4A silencing or KDM4A K471 mutation were assessed. Hypoxia‐like conditions increased CC cell ferroptosis resistance and KDM4A, SUMO1, and Ubc9 protein levels, while it decreased SENP1 protein level. KDM4A and SUMO1 were co‐localized in the nucleus, and hypoxia‐like conditions promoted their interaction. Specifically, the K471 locus of KDM4A was the main locus for SUMO1ylation. Hypoxia‐like conditions up‐regulated SLC7A11 and GPX4 expression levels and decreased H3K9me3 protein level and H3K9me3 abundance in the SLC7A11 promoter region. KDM4A silencing or K471 locus mutation resulted in weakened interaction between KDM4A and SUMO1, elevated H3K9me3 levels, decreased SLC7A11 expression, ultimately, a reduced CC cell ferroptosis resistance. CoCl 2 ‐stimulated hypoxia‐like conditions enhanced SUMO1 modification of KDM4A at the K471 locus specifically, repressed H3K9me3 levels, and up‐regulated SLC7A11/GPX4 to enhance CC cell ferroptosis resistance.

Deoxyshikonin triggers apoptosis in cervical cancer cells through p38 MAPK ‐mediated caspase activation

Abstract Deoxyshikonin (DSK) is a biological component derived from Lithospermum erythrorhizon . Although DSK possesses potential anticancer activities, whether DSK exerts anticancer effects on cervical cancer cells is incompletely explored. This study was aimed to investigate the anticancer activity of DSK against cervical cancer cells and its molecular mechanisms. Cell viability was evaluated by MTT assay. Level of phosphorylation and protein was determined using Western blot. Involvement of signaling kinases was assessed by specific inhibitors. Our results revealed that DSK reduced viability of human cervical cell in a dose‐dependent fashion. Meanwhile, DSK significantly elicited apoptosis of HeLa and SiHa cells. Apoptosis microarray was used to elucidate the involved pathways, and the results showed that DSK dose‐dependently diminished cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and XIAP, and induced cleavage of poly(ADP‐ribose) polymerase (PARP) and caspase‐8/9/3. Furthermore, we observed that DSK significantly triggered activation of ERK, JNK, and p38 MAPK (p38), and only inhibition of p38 diminished the DSK‐mediated pro‐caspases cleavage. Taken together, our results demonstrate that DSK has anti‐cervical cancer effects via the apoptotic cascade elicited by downregulation of IAPs and p38‐mediated caspase activation. This suggests that DSK could act as an adjuvant to facilitate cervical cancer management.

Integrative analysis from multi‐center studies identifies a weighted gene co‐expression network analysis‐based Tregs signature in ovarian cancer

AbstractOvarian cancer (OC) is a malignancy associated with poor prognosis and has been linked to regulatory T cells (Tregs) in the immune microenvironment. Nevertheless, the association between Tregs‐related genes (TRGs) and OC prognosis remains incompletely understood. The xCell algorithm was used to analyze Tregs scores across multiple cohorts. Weighted gene co‐expression network analysis (WGCNA) was utilized to identify potential TRGs and molecular subtypes. Furthermore, we used nine machine learning algorithms to create risk models with prognostic indicators for patients. Reverse transcription‐quantitative polymerase chain reaction and immunofluorescence staining were used to demonstrate the immunosuppressive ability of Tregs and the expression of key TRGs in clinical samples. Our study found that higher Tregs scores were significantly correlated with poorer overall survival. Recurrent patients exhibited increased Tregs infiltration and reduced CD8+ T cell. Moreover, molecular subtyping using seven key TRGs revealed that subtype B exhibited higher enrichment of multiple oncogenic pathways and had a worse prognosis. Notably, subtype B exhibited high Tregs levels, suggesting immune suppression. In addition, we validated machine learning‐derived prognostic models across multiple platform cohorts to better distinguish patient survival and predict immunotherapy efficacy. Finally, the differential expression of key TRGs was validated using clinical samples. Our study provides novel insights into the role of Tregs in the immune microenvironment of OC. We identified potential therapeutic targets derived from Tregs (CD24, FHL2, GPM6A, HOXD8, NAP1L5, REN, and TOX3) for personalized treatment and created a machining learning‐based prognostic model for OC patients, which could be useful in clinical practice.

The immune landscape and prognostic analysis of CXCL8 immune‐related genes in cervical squamous cell carcinoma

AbstractCervical squamous cell carcinoma (CESC), one of the most common malignancies in women, imposes a significant burden on women's health worldwide. Despite extensive research, the molecular and pathogenic mechanisms of cervical squamous cell carcinoma and CESC remain unclear. This study aimed to explore the immune‐related genes, immune microenvironment infiltration, and prognosis of CESC, providing a theoretical basis for guiding clinical treatment. Initially, by mining four gene sets and immune‐related gene sets from public databases, 14 immune‐related genes associated with CESC were identified. Through univariate and multivariate COX regression analyses, as well as lasso regression analysis, four CESC‐independent prognostic genes were identified, and a prognostic model was constructed, dividing them into high and low‐risk groups. The correlation between these genes and immune cells and immune functions were explored through ssGSEA enrichment analysis, revealing a close association between the high‐risk group and processes such as angiogenesis and epithelial–mesenchymal transition. Furthermore, using public databases and qRT‐PCR experiments, significant differences in CXCL8 expression between normal cervical cells and cervical cancer cells were discovered. Subsequently, a CXCL8 knockdown plasmid was constructed, and the efficiency of CXCL8 knockdown was validated in two CESC cell lines, MEG‐01 and HCE‐1. Through CCK‐8, scratch, and Transwell assays, it was confirmed that CXCL8 knockdown could inhibit the proliferation, invasion, and migration abilities of CESC cells. Targeting CXCL8 holds promise for personalized therapy for CESC, providing a strong theoretical basis for achieving clinical translation.

RETRACTED: Development of gene panel for predicting recurrence in early‐stage cervical cancer patients

Abstract Cervical cancer (CC) is a common malignancy affecting women worldwide. Our objective was to develop a consensus‐based gene panel using multi‐omics data that could effectively predict recurrence in early‐stage cervical cancer patients. We utilized the “Multi‐Omics Consensus Integration Analysis (MOVICS)” package for consensus clustering design to integrate multiple omics datasets and improve the molecular classification landscape of early‐stage CC. We identified the “resting and naive” tumor microenvironment (TME) as cancer subtype (CS) 2. Leveraging the feature genes from the CS classifier, we employed machine learning algorithms to identify a gene panel, including ALDH1A1, CLDN10, MUC13, and C10orf99, which could generate a consensus machine learning‐driven score (CMLS) for each patient. Stratifying patients into high and low CMLS groups resulted in Kaplan–Meier curves demonstrating a significant difference in recurrence rates between the two groups. This difference remained significant even after adjusting for clinical features in multivariate Cox regression analysis, with the risk ratio of CMLS surpassing that of clinical characteristics. Furthermore, the TME exhibited notable differences between the different CMLS groups, suggesting that patients with low CMLS may exhibit a better response to immunotherapy. This study highlights the potential of the CMLS approach in predicting recurrence in early‐stage cervical cancer patients and provides a screening model for selecting patients suitable for immunotherapy.

RETRACTED: USP14 promotes the proliferation of cervical cancer via upregulating β‐catenin

Abstract In recent years, the ubiquitin–proteasome system (UPS) has become a hot spot in medical research in cervical cancer (CC) and has received extensive attention. Among them, ubiquitin‐specific protease 14 (USP14) is involved in a wide variety of typical cell signaling pathways and is recognized to be involved in the progression of most known tumors. However, the expression and significance of USP14 in CC have not been directly studied. Through database analysis, we found that USP14 was overexpressed in CC, which influenced the FIGO stage and prognosis of CC patients, and it was positively correlated with the expression level of β‐catenin. In this study, USP14 promoted the G1‐S phase transition of Hela and Siha cells and inhibited cell apoptosis, thereby promoting the proliferation, migration, and invasion of CC cells. In addition, USP14 also significantly promoted the growth of subcutaneous tumor in nude mice. We also found that overexpression of USP14 significantly upregulated β‐catenin expression and increased the activity of Wnt/β‐catenin signaling pathway. While knockdown of USP14 resulted in the opposite. These results suggest that USP14 may promote the proliferation of CC by up‐regulating the expression of β‐catenin, contributing to a deeper understanding of the mechanisms of CC and providing a potential therapeutic target.

A novel mechanism of cannabidiol in suppressing ovarian cancer through LAIR ‐1 mediated mitochondrial dysfunction and apoptosis

Abstract Cannabidiol (CBD) is a nonpsychoactive cannabinoid compound. It has been shown that CBD can inhibit the proliferation of ovarian cancer cells, but the underlying specific mechanism is unclear. We previously presented the first evidence for the expression of leukocyte‐associated immunoglobulin‐like receptor 1 (LAIR‐1), a member of the immunosuppressive receptor family, in ovarian cancer cells. In the present study, we investigated the mechanism by which CBD inhibits the growth of SKOV3 and CAOV3 ovarian cancer cells, and we sought to understand the concurrent role of LAIR‐1. In addition to inducing ovarian cancer cell cycle arrest and promoting cell apoptosis, CBD treatment significantly affected the expression of LAIR‐1 and inhibited the PI3K/AKT/mTOR signaling axis and mitochondrial respiration in ovarian cancer cells. These changes were accompanied by an increase in ROS, loss of mitochondrial membrane potential, and suppression of mitochondrial respiration and aerobic glycolysis, thereby inducing abnormal or disturbed metabolism and reducing ATP production. A combined treatment with N ‐acetyl‐ l ‐cysteine and CBD indicated that a reduction in ROS production would restore PI3K/AKT/mTOR pathway signaling and ovarian cancer cell proliferation. We subsequently confirmed that the inhibitory effect of CBD on the PI3K/AKT/mTOR signal axis and mitochondrial bioenergy metabolism was attenuated by knockdown of LAIR‐1. Our animal studies further support the in vivo anti‐tumor activity of CBD and suggest its mechanism of action. In summary, the present findings confirm that CBD inhibits ovarian cancer cell growth by disrupting the LAIR‐1‐mediated interference with mitochondrial bioenergy metabolism and the PI3K/AKT/mTOR pathway. These results provide a new experimental basis for research into ovarian cancer treatment based on targeting LAIR‐1 with CBD.

RETRACTED: Protective effect of tretinoin on cervical cancer growth and proliferation through downregulation of pFAK2 expression

Abstract Background Cervical cancer, a life‐threatening disease, is the seventh most commonly detected cancer among women throughout the world. The present study investigated the effect of tretinoin on cervical cancer growth and metastasis in vitro and in vivo in the mice model. Materials and Methods Cell Counting Kit‐8, clonogenic survival, and transwell chamber assays were used for determination cells proliferation, colony formation, and invasiveness. Western blotting assay was used for assessment of protein expression whereas AutoDock Vina and Discovery studio software for in silico studies. Results Tretinoin treatment significantly ( p  < .05) reduced the proliferation of HT‐3 and Caski cells in concentration‐based manner. Incubation with tretinoin caused a significant decrease in clonogenic survival of HT‐3 and Caski cells compared with the control cultures. The invasive potential of HT‐3 cells was decreased to 18%, whereas that of Caski cells to 21% on treatment with 8 μM concentration of tretinoin. In HT‐3 cells, tretinoin treatment led to a prominent reduction in p‐focal adhesion kinase (FAK), matrix metalloproteinases (MMP)‐2, and MMP‐9 expression in HT‐3 cells. Treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. The metastasis of tumor in model cervical cancer mice group was effectively inhibited in spleen, intestines, and peritoneal cavity. In silico studies showed that tretinoin interacts with alanine, proline, isoleucine, and glycine amino acid residues of FAK protein to block its activation. The 2‐dimensional diagram of interaction of tretinoin with FAK protein revealed that tretinoin binds to alanine and glycine amino acids through conventional hydrogen bonding. Conclusion In summary, tretinoin suppressed the proliferation, colony formation, and invasiveness of cervical cancer cells in vitro. It decreased the expression of activated focal adhesion kinase, MMP‐2, and MMP‐9 in HT‐3 cells in dose‐dependent manner. In silico studies showed that tretinoin interacts with alanine and glycine amino acids through conventional hydrogen bonding. In vivo data demonstrated that treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. Therefore, tretinoin can be developed as an effective therapeutic agent for cervical cancer treatment.

RETRACTED: Pathogenomics model for personalized medicine in cervical cancer: Cross‐talk of gene expressions and pathological images related to oxidative stress

Abstract An increasing number of studies have shown that oxidative stress plays an important role in the development and progression of cancer. Cervical cancer (CC) is a disease of unique complexity that tends to exhibit high heterogeneity in molecular phenotypes. We aim here to characterize molecular features of cervical cancer by developing a classification system based on oxidative stress‐related gene expression profiles. In this study, we obtained gene expression profiling data for cervical cancer from the TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) (GSE44001) databases. Oxidative stress‐related genes used for clustering were obtained from GeneCards. Patients with cervical cancer were divided into two subtypes (C1 and C2) by non‐negative matrix factorization (NMF) classification. By performing Kaplan–Meier survival analysis, differential expression analysis, and gene set enrichment analysis (GSEA) between the two subtypes, we found that subtype C2 had a worse prognosis and was highly enriched for immune‐related pathways as well as epithelial‐mesenchymal transition (EMT) pathways. Subsequently, we performed metabolic pathway analysis, gene mutation landscape analysis, immune microenvironment analysis, immunotherapy response analysis, and drug sensitivity analysis of the two isoforms. The results showed that the isoforms were significantly different between metabolic pathway enrichment and the immune microenvironment, and the chromosomes of subtype C1 were more unstable. In addition, we found that subtype C2 tends to respond to treatment with anti‐CTLA4 agents, a conclusion that coincides with high chromosomal variation in C1, as well as C2 enrichment of immune‐related pathways. Then, we screened 10 agents that were significantly susceptible to C2 subtype. Finally, we constructed pathogenomics models based on pathological features and linked them to molecular subtypes. This study establishes a novel CC classification based on gene expression profiles of oxidative stress‐related genes and elucidates differences between immune microenvironments between CC subtypes, contributing to subtype‐specific immunotherapy and drug therapy.

RBM15 m6A modification‐mediated OTUB2 upregulation promotes cervical cancer progression via the AKT/mTOR signaling

AbstractCervical cancer (CC) is a deadly gynecological tumor worldwide. Otubain 2 (OTUB2) has been recently identified as an oncogene in human malignancies. However, its expression and function remain unclear. This work aims to explore the role of OTUB2 in CC progression. Herein, The Cancer Genome Atlas data revealed that OTUB2 expression was significantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and gradually increased with CESC progression; moreover, OTUB2 expression predicted poor outcomes of CESC patients. Then, RT‐qPCR and Western blotting were applied to determine mRNA and protein expression in CC and normal cells. Our results confirmed that OTUB2 was highly expressed in CC cell lines. As indicated by CCK‐8, Transwell, and flow cytometry results, OTUB2 silencing attenuated proliferative and metastatic capacities of CC cells but promoted CC cell apoptosis. Then, RBM15, an N6‐methyladenosine (m6A) methyltransferase “writer,” was also demonstrated to be upregulated in CESC and CC cells. Mechanistically, m6A RNA immunoprecipitation (Me‐RIP) results showed that RBM15 inhibition reduced the m6A methylation level of OTUB2 in CC cells, leading to the decline of OTUB2 expression. In addition, OTUB2 inhibition deactivated the AKT/mTOR signaling in CC cells. Furthermore, SC‐79 (AKT/mTOR activator) partially abated the inhibitory effects of OTUB2 knockdown on the AKT/mTOR signaling pathway and the malignant phenotypes of CC cells. In summary, this work showed that RBM15‐mediated m6A modification led to OTUB2 upregulation, thereby promoting malignant behaviors of CC cells via the AKT/mTOR signaling pathway.

Ursolic acid reduces Adriamycin resistance of human ovarian cancer cells through promoting the HuR translocation from cytoplasm to nucleus

AbstractUrsolic acid (UA) has been shown to suppress various tumor progression, however, its roles in Adriamycin resistance of human ovarian cancer (OC) cells are still unclear. This work aims to investigate the effects of UA on the Adriamycin resistance of human OC cells. Here, we constructed Adriamycin‐resistant OC SKOV3‐Adr cells and found that UA attenuated Adriamycin resistance in SKOV3‐Adr cells. Additionally, UA enhanced Adriamycin sensitivity in the parental SKOV3 and another OC cell line A2780 cells. Mechanistic studies showed that HuR mRNA level was similar between SKOV3 and SKOV3‐Adr cells, but the cytoplasmic expression of HuR protein was increased in SKOV3‐Adr cells compared with that in SKOV3 cells, and subsequently enhancing the mRNA stability of multidrug resistance gene 1 (MDR1). Moreover, UA had no effects on HuR expression, but promoted the cytoplasm‐nucleus translocation of HuR protein, decreased MDR1 mRNA stability and thus reduced MDR1 expression. Furthermore, overexpression of MDR1 rescued the effects of UA on Adriamycin resistance and sensitivity. This work reveals a novel HuR/MDR1 axis responsible for UA‐mediated attenuation on Adriamycin resistance in OC cells.

LncRNA PSMA3‐AS1 promotes cell proliferation, migration, and invasion in ovarian cancer by activating the PI3K/Akt pathway via the miR‐378a‐3p/GALNT3 axis

AbstractThe crucial roles of the long noncoding RNAs (lncRNAs) in the development of ovarian cancer (OC) have been extensively studied. According to the prediction result from the Kaplan–Meier Plotter database, high expression of lncRNA proteasome subunit α type‐3 antisense RNA1 (PSMA3‐AS1) is associated with the poor prognosis in patients with OC. Thus, the study aimed to investigate the role of lncRNA PSMA3‐AS1 in OC. Reverse transcription quantitative polymerase chain reaction analysis revealed that PSMA3‐AS1 expression was significantly upregulated in OC cells and tissues. PSMA3‐AS1 silencing inhibited OC cell proliferation, migration, and invasion, as shown by results of cell counting kit‐8, colony formation, wound healing, and Transwell assays, respectively. Additionally, PSMA3‐AS1 deficiency suppressed tumor growth in vivo. Mechanistically, luciferase reporter and RNA pulldown assays implied that PSMA3‐AS1 served as a competing endogenous RNA for miR‐378a‐3p to upregulate the expression of polypeptide N‐acetylgalactosaminyltransferase 3 (GALNT3). GALNT3 was a target gene of miR‐378a‐3p in OC. Moreover, PSMA3‐AS1 activated the PI3K/Akt pathway by upregulating GALNT3 expression. Overall, PSMA3‐AS1 promotes OC cell proliferation, migration, invasion, and xenograft tumor growth by activating the PI3K/Akt pathway via the miR‐378a‐3p/GALNT3 axis.

Cuproptosis‐related lncRNAs ovarian cancer: Multi‐omics analysis of molecular mechanisms and potential therapeutic targets

Abstract Ovarian cancer (OV) is an aggressive malignancy that poses a significant threat to the health and lives of women. Cuproptosis is a newly discovered form of programmed cell death that offers a promising therapeutic target, although its significance in cancer progression remains uncertain. In this study, we established a prognostic model of OV with six cuproptosis‐related long non‐coding RNAs (lncRNAs), including CTC.246B18.8, LINC00337, RP11.568N6.1, RP11.158I9.8, RP11.678G14.3 and CYP4F26P, based on the data of The Cancer Genome Atlas (TCGA). Lower risk scores were associated with favorable prognosis. In addition, a negative outcome was associated with high expression of CTC.246B18.8. According to the ESTIMATE algorithm, CTC.246B18.8 was negatively correlated with the ImmuneScore, and positively with immune checkpoints, immune cell infiltration, and tumor mutation burden (TMB). Moreover, gene set enrichment analysis (GSEA) revealed that pathways related to immunosuppression are likely activated in response to CTC‐246B18.8 overexpression. Furthermore, CTC‐246B18.8 expression was also associated with the sensitivity to various chemotherapy drugs. The expression patterns of the above lncRNAs were verified in ovarian tumor cell lines (SK‐OV‐3, COC1, and A2780) and normal ovarian epithelial cells (IOSE – 80). Six cuproptosis‐related genes (CRGs), including ATP7B, MTF1, SLC31A1, DLD, ATP7A and DLAT, were differentially expressed between CTC‐246B18.8 high and CTC‐246B18.8 low patient groups, and exhibited organ‐specific expression patterns pan‐cancer. Small molecule drugs that target these CRGs were predicted, and potential candidates included DIAMIDE, bathocuproine disulfonate, D‐penicillamine, etc. To summarize, our findings provide molecular insights into the role of cuproptosis in OV, and the signature lncRNAs and CRGs should be investigated further as immunotherapy biomarkers of OV.