Ying Wang

HKDC1 promotes ovarian cancer progression through boosting lipid metabolism and immune escape by stabilizing G6PC/G6PC2

Ovarian cancer (OC) is a significant health challenge, yet the mechanisms driving its progression remain unclear. This study explored the role of hexokinase domain-containing protein 1 (HKDC1) in OC, focusing on tumor growth, lipid metabolism, and immune evasion. Human OC cell lines (SKOV3 and HEY) and the murine OC cell line (ID8) were used to knock down and overexpress HKDC1. An ID8-based epithelial OC mouse model was established to validate the in vitro findings. Our results demonstrated that HKDC1 was upregulated in OC and promoted cell proliferation, migration, and invasion. HKDC1 enhanced lipid accumulation by elevating levels of free fatty acids (FFA), triglycerides, phospholipids, cholesterol, and neutral lipid, while upregulating key enzymes (ACC1, FASN, SCD1, HMGCS1, and HMGCR). It promoted immune escape through PD-L1 upregulation, inhibiting T cell proliferation and reducing IFN-γ, granzyme B, and perforin levels while increasing PD-1 levels. HKDC1 knockdown reversed these effects, which were restored by adding FFA. Mechanistically, HKDC1 interacted with and stabilized glucose-6-phosphatase catalytic subunits (G6PC/G6PC2), supporting its tumor-promoting functions. These findings were confirmed in an OC mouse model, highlighting HKDC1 as a key driver of OC progression through lipid biosynthesis and immune suppression, offering potential therapeutic targets.

Expression and clinical significance of HER2/neu, aromatase P450 and adhesion molecule CD24 in endometrial cancer

This study aimed at exploring the expression and clinical significance of aromatase P450, adhesion molecule CD24 and HER2/neu in endometrial cancer. The expression of aromatase P450, adhesion molecule CD24 and HER2/neu was detected by immunohistochemistry in 15 cases of endometrial hyperplasia group, 50 cases of endometrial adenocarcinoma and 3 cases of uterine papillary adenocarcinoma, with 15 cases of normal endometrium as control group. We detected no expression of aromatase P450, adhesion molecule CD24 or HER2/neu in control group. Aromatase P450 positive expression rate was 66.7% in endometrial hyperplasia group and 70.3% in endometrial carcinoma group, without significant difference (p>0.05). There was no significant difference (p>0.05) in the positive expression rate of aromatase P450 between different myometrial invasion groups of endometrial adenocarcinomas. CD24 positive expression rate was 40.0% in endometrial hyperplasia group and 79.6% in endometrial carcinoma group, with significant difference (p<0.05). HER2/neu positive expression rate was 26.7% in the endometrial hyperplasia group and 57% in endometrial carcinoma group, with significant difference (p<0.05). In conclusion, aromatase P450 may be one factor associated with endometrial cancer cell proliferation, while CD24 and HER2/neu may be important factors associated with the invasion and metastasis of endometrial cancer.

Discovery of the Inhibitor Targeting the SLC7A11/xCT Axis through In Silico and In Vitro Experiments

In the development and progression of cervical cancer, oxidative stress plays an important role within the cells. Among them, Solute Carrier Family 7 Member 11 (SLC7A11/xCT) is crucial for maintaining the synthesis of glutathione and the antioxidant system in cervical cancer cells. In various tumor cells, studies have shown that SLC7A11 inhibits ferroptosis, a form of cell death, by mediating cystine uptake and maintaining glutathione synthesis. Additionally, SLC7A11 is also involved in promoting tumor metastasis and immune evasion. Therefore, inhibiting the SLC7A11/xCT axis has become a potential therapeutic strategy for cervical cancer. In this study, through structure-based high-throughput virtual screening, a compound targeting the SLC7A11/xCT axis named compound 1 (PubChem CID: 3492258) was discovered. In vitro experiments using HeLa cervical cancer cells as the experimental cell model showed that compound 1 could reduce intracellular glutathione levels, increase glutamate and reactive oxygen species (ROS) levels, disrupt the oxidative balance within HeLa cells, and induce cell death. Furthermore, molecular dynamics simulation results showed that compound 1 has a stronger binding affinity with SLC7A11 compared to the positive control erastin. Overall, all the results mentioned above indicate the potential of compound 1 in targeting the SLC7A11/xCT axis and treating cervical cancer both in vitro and in silico.

Hsa_circ_0000585 promotes chemoresistance to cis-platin in epithelial cells of ovarian cancer by modulating autophagy

Chemoresistance, i.e., resistance to cisplatin (DDP), has been a major obstacle to ovarian cancer treatment. It has been found that circular RNAs (circRNAs) play vital roles in the tumorigenesis various cancers by regulating autophagy, while few studies focusing on cisplatin-resistance ovarian cancer (CROC). The expressions of the circRNAs were detected by qRT-PCR. Short hairpin RNA targeting circRNA was used to explore the biological functions of the circRNA. Cell viability, autophagic flux, immunofluorescence, and xenograft tumors experiments were performed to further illustrate the underlying mechanisms. Hsa_circ_0000585 was increased in cisplatin-resistant SKOV3/DDP cells. Stably knocking down hsa_circRNA_0000585 expression in SKOV3/DDP cells was established by RNA interference. We found that downregulation of hsa_circ_0000585 significantly enhanced the sensitivity of DDP/SkOV3 cells to DDP. In vivo study, hsa_circRNA_0000585 knockdown significantly decreased tumor volume in nude mice. Under the measurements of western blot and cellular immunofluorescence, hsa_circ_0000585 knockdown significantly inhibited the expression of Beclin1 and P62, indicating the autophagic flux was inhibited. Administrations with autophagic inhibitor "Chloroquine (CQ)" and autophagy activator "QX77" further confirmed that hsa_circ_0000585 knockdown resulted in autophagy inhibition. Overall, this study provided a new insight into the role of circRNAs in the mechanism of DDP-resistance in ovarian cancer. Hsa_circRNA_0000585 may be promising therapeutic targets for the enhancement of the sensitivity of ovarian cancer cells to cisplatin-mediated chemotherapy.

SRC-3/TRAF4 facilitates ovarian cancer development by activating the PI3K/AKT signaling pathway

Abstract Objective Ovarian cancer is the seventh most common cancer in women, and it causes many deaths in women worldwide. Patients with ovarian cancer have a poor prognosis and low survival rate. This study aimed to explore the role of the SRC-3/TRAF4/PI3K/AKT pathway in ovarian cancer development. Methods SRC-3 and TRAF4 expression in ovarian cancer cell lines were assessed using qRT-PCR and western-blotting. The expression of SRC-3 and TRAF4 in ovarian cancer cells was downregulated by transient transfection with sh-RNAs. An MTT assay was performed to evaluate cell proliferation. Cell migration and invasion were measured using a Transwell assay. Cell stemness was detected using a cell spheroidization assay and western blotting. The expression levels of stem cell factors and PI3K/AKT pathway proteins were determined by qRT-PCR and western blot analysis. Results SRC-3 and TRAF4 were upregulated in ovarian cancer cell lines. TRAF4 is a downstream factor of SRC-3, and the protein level of TRAF4 was regulated by SRC-3. SRC-3 knockdown reduced TRAF4 expression. Silencing SRC-3 or TRAF4 inhibited cell proliferation, migration, and invasion, as well as the expression of stem cell factors. Furthermore, sh-TRAF4 as well as treatment with LY294002, the PI3K/Akt inhibitor, inhibited the phosphorylation of Akt and PI3K, thus repressing the activation of PI3K/AKT signaling pathway in ovarian cancer cell lines. However, TRAF4 overexpression reversed the effect of SRC-3 silencing on cell proliferation, migration, invasion, and stemness. Conclusion Our study demonstrated that SRC-3/TRAF4 promotes ovarian cancer cell growth, migration, invasion, and stemness by activating the PI3K/AKT pathway.

Identification of Core Prognosis‐Related Candidate Genes in Cervical Cancer via Integrated Bioinformatical Analysis

Purposes. Cervical cancer (CC) is one of the highest frequently occurred malignant gynecological tumors with high rates of morbidity and mortality. Here, we aimed to identify significant genes associated with poor outcome. Materials and methods. Differentially expressed genes (DEGs) between CC tissues and normal cervical tissues were picked out by GEO2R tool and Venn diagram software. Database for Annotation, Visualization and Integrated Discovery (DAVID) was performed to analyze gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway. The protein‐protein interactions (PPIs) of these DEGs were visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Afterwards, Kaplan‐Meier analysis was applied to analyze the overall survival among these genes. The Gene Expression Profiling Interactive Analysis (GEPIA) was applied for further validation of the expression level of these genes. Results. The mRNA expression profile datasets of GSE63514, GSE27678, and GSE6791 were downloaded from the Gene Expression Omnibus database (GEO). In total, 76 CC tissues and 35 normal tissues were collected in the three profile datasets. There were totally 73 consistently expressed genes in the three datasets, including 65 up‐regulated genes and 8 down‐regulated genes. Of PPI network analyzed by Molecular Complex Detection (MCODE) plug‐in, all 65 up‐regulated genes and 4 down‐regulated genes were selected. The results of the Kaplan‐Meier survival analysis showed that 3 of the 65 up‐regulated genes had a significantly worse prognosis, while 3 of the 4 down‐regulated genes had a significantly better outcome. For validation in GEPIA, 4 of 6 genes (PLOD2, ANLN, AURKA, and AR) were confirmed to be significantly deregulated in CC tissues compared to normal tissues. Conclusion. We have identified three up‐regulated (PLOD2, ANLN, and AURKA) and a down‐regulated DEGs (AR) with poor prognosis in CC on the basis of integrated bioinformatical methods, which could be regarded as potential therapeutic targets for CC patients.

Integrating Contrast-enhanced US to O-RADS US for Classification of Adnexal Lesions with Solid Components: Time-intensity Curve Analysis versus Visual Assessment.

Purpose To compare the diagnostic performance of time-intensity curve (TIC) analysis and subjective visual assessment of contrast-enhanced US (CEUS) when integrated with the Ovarian-Adnexal Reporting and Data System (O-RADS) US risk stratification system for characterizing adnexal lesions with solid components. Materials and Methods In this prospective multicenter study conducted from September 2021 to December 2022, female individuals with suspected adnexal lesions containing solid components detected at routine US were enrolled. All participants underwent preoperative CEUS examinations. Histopathologic findings were used as the reference standard for diagnosis. Lesions were classified according to the O-RADS US system. Enhancement of solid tissue compared with the outer myometrium was evaluated using both TIC analysis and subjective visual assessment. The diagnostic performance of O-RADS alone and each CEUS assessment method when integrated with the O-RADS US system was assessed and compared using receiver operating characteristic curve analysis. Results A total of 180 lesions (80 malignant and 100 benign histopathologic outcomes) in 175 participants (median age, 47 years [IQR, 33-56]) were analyzed. Incorporating CEUS (assessed through both TIC analysis and subjective visual assessment) with O-RADS US showed significantly improved diagnostic performance over O-RADS US alone, with an area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI: 0.80, 0.91) compared with 0.78 (95% CI: 0.71, 0.84). No evidence of a difference was observed between the AUCs of TIC analysis and subjective visual assessment in the enhancement evaluation of solid tissue with CEUS for adnexal malignancy categorization (