Ultrasound-responsive Bi2MoO6-MXene heterojunction as ferroptosis inducers for stimulating immunogenic cell death against ovarian cancer.

BACKGROUND: Ovarian cancer (OC) has the highest fatality rate among all gynecological malignancies, necessitating the exploration of novel, efficient, and low-toxicity therapeutic strategies. Ferroptosis is a type of programmed cell death induced by iron-dependent lipid peroxidation and can potentially activate antitumor immunity. Developing highly effective ferroptosis inducers may improve OC prognosis. RESULTS: In this study, we developed an ultrasonically controllable two-dimensional (2D) piezoelectric nanoagonist (Bi2MoO6-MXene) to induce ferroptosis. A Schottky heterojunction between Bi2MoO6 (BMO) and MXene reduced the bandgap width by 0.44 eV, increased the carrier-separation efficiency, and decreased the recombination rate of electron-hole pairs under ultrasound stimulation. Therefore, the reactive oxygen species yield was enhanced. Under spatiotemporal ultrasound excitation, BMO-MXene effectively inhibited OC proliferation by more than 90%, induced lipid peroxidation, decreased mitochondrial-membrane potential, and inactivated the glutathione peroxidase and cystathionine transporter protein system, thereby causing ferroptosis in tumor cells. Ferroptosis in OC cells further activated immunogenic cell death, facilitating dendritic cell maturation and stimulating antitumor immunity. CONCLUSION: We have succeeded in developing a highly potent ferroptosis inducer (BMO-MXene), capable of inhibiting OC progression through the sonodynamic-ferroptosis-immunogenic cell death pathway.

Bioinformatics Analysis and Experimental Verification Define Different Angiogenesis Subtypes in Endometrial Carcinoma and Identify a Prognostic Signature.

Increasing evidence indicates that peripheral blood vessels play a pivotal role in regulating tumor growth with the presence of new blood vessels facilitating tumor growth and metastasis. Nevertheless, the impact of specific molecule-mediated angiogenesis on the tumor immune microenvironment (TIME) and individual prognosis of uterine corpus endometrial carcinoma (UCEC) remains uncertain. The transcriptome information on 217 prognostic angiogenesis-related genes was integrated, and the angiogenesis patterns of 506 UCEC patients in The Cancer Genome Atlas (TCGA) cohort were comprehensively evaluated. We identified five angiogenic subtypes, namely, EC1, EC2, EC3, EC4, and EC5, which differed significantly in terms of prognosis, clinicopathological features, cancer hallmarks, genomic mutations, TIME patterns, and immunotherapy responses. Additionally, an angiogenesis-related prognostic risk score (APRS) was constructed to enable an individualized comprehensive evaluation. In multiple cohorts, APRS demonstrated a powerful predictive ability for the prognosis of UCEC patients. Likewise, APRS was confirmed to be associated with clinicopathological features, genomic mutations, cancer hallmarks, and TIME patterns in UCEC patients. The predictability of APRS for immune checkpoint inhibitor (ICI) therapy was also salient. Subsequently, the expression levels of four angiogenesis-related hub genes were verified by qRT-PCR, immunohistochemistry, and single-cell sequencing data analysis. The effects of four representative genes on angiogenesis were validated by Wound-Healing and Transwell assays, tube formation assay in vitro, and tumor xenograft model in vivo. This study proffered a new classification of UCEC patients based on angiogenesis. The established APRS may contribute to individualized prognosis prediction and immunotherapy selections that are better suited for UCEC patients.

IGF2BP2-modified circular RNA circCHD7 promotes endometrial cancer progression via stabilizing PDGFRB and activating JAK/STAT signaling pathway.

Circular RNAs (circRNAs) represent a class of covalently closed, single-stranded RNAs and have been linked to cancer progression. N6-methyladenosine (m6A) methylation is a ubiquitous RNA modification in cancer cells. Increasing evidence suggests that m6A can mediate the effects of circRNAs in cancer biology. In contrast, the post-transcriptional systems of m6A and circRNA in the progression of endometrial cancer (EC) remain obscure. The current study identified a novel circRNA with m6A modification, hsa_circ_0084582 (circCHD7), which was upregulated in EC tissues. Functionally, circCHD7 was found to promote the proliferation of EC cells. Mechanistically, circCHD7 interacted with insulin-like growth factor 2 mRNA-binding protein (IGF2BP2) to amplify its enrichment. Moreover, circCHD7 increased the mRNA stability of platelet-derived growth factor receptor beta (PDGFRB) in an m6A-dependent manner, thereby enhancing its expression. In addition, the circCHD7/IGF2BP2/PDGFRB axis activated the JAK/STAT signaling pathway and promoted EC cell proliferation. In conclusion, these findings provide new insights into the regulation of circRNA-mediated m6A modification, and the new "circCHD7-PDGFRB" model of regulation offers new perspectives on circCHD7 as a potential target for EC therapy.

lncRNA UCA1 promotes tumor progression by targeting SMARCD3 in cervical cancer.

Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been identified as a key molecule in human cancers. However, its functional implications remain unspecified in the context of cervical cancer (CC). This research aims to identify the regulatory mechanism of UCA1 in CC. UCA1 was identified through microarray and confirmed through a quantitative real-time polymerase chain reaction. Proteins that bind with UCA1 were recognized using RNA pull-down assays along with RNA immunoprecipitation. Ubiquitination assays and coimmunoprecipitation were performed to explore the molecular mechanisms of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 3 (SMARCD3) downregulated in CC. The effects of UCA1 and SMARCD3 on the progression of CC were investigated through gain- and loss-of-function assays and xenograft tumor formation in vivo. In this study, UCA1 was found to be upregulated in CC cells as well as in human plasma exosomes for the first time. Functional studies indicated that UCA1 promotes CC progression. Mechanically, UCA1 downregulated the SMARCD3 protein stabilization by promoting SMARCD3 ubiquitination. Taken together, we revealed that the UCA1/SMARCD3 axis promoted CC progression, which could provide a new therapeutic target for CC.

Lactate metabolism-related genes to predict the clinical outcome and molecular characteristics of endometrial cancer.

BACKGROUND: Metabolic reprogramming is one of hallmarks of cancer progression and is of great importance for the tumor microenvironment (TME). As an abundant metabolite, lactate has been found to play a critical role in cancer development and immunosuppression of TME. However, the potential role of lactate metabolism-related genes in endometrial cancer (EC) remains obscure. METHODS: RNA sequencing data and clinical information of EC were obtained from The Cancer Genome Atlas (TCGA) database. Lactate metabolism-related genes (LMRGs) WERE from Molecular Signature Database v7.4 and then compared the candidate genes from TCGA to obtain final genes. Univariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression were performed to screen prognostic genes. A lactate metabolism-related risk profile was constructed using multivariate Cox regression analysis. The signature was validated by time-dependent ROC curve analysis and Kaplan-Meier analysis. The relationship between the risk score and age, grade, stage, tumor microenvironmental characteristics, and drug sensitivity was as well explored by correlation analyses. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional analysis between the high and low-risk groups were performed. CCK8, EdU, and clone formation assays were applied to detect the proliferation ability of EC cells, Transwell assay was performed to detect the migration ability of EC cells, and intracellular lactate and glucose content was used to asses lactate metabolism. RESULTS: We constructed a risk signature based on 18 LMRGs. Kaplan-Meier curves confirmed that the high-risk group had poorer prognosis compared to the low-risk group. A nomogram was then constructed to predict the probability of EC survival. We also performed GO enrichment analysis and KEGG pathway functional analysis between the high and low-risk groups, and the outcome revealed that the features were significantly associated with energy metabolism. There was a significant correspondence between LMRGs and tumor mutational load, checkpoints and immune cell infiltration. C1, C2, and C4 were the most infiltrated in the high-risk group. The high-risk group showed increased dendritic cell activation, while the low-risk group showed increased plasma cells and Treg cells. Drug sensitivity analysis showed LMRGs risk was more resistant to Scr kinase inhibitors. We further proved that one of the lactate metabolism related genes, TIMM50 could promote EC cell proliferation, migration and lactate metabolism. CONCLUSION: In conclusion, we have established an effective prognostic signature based on LMRG expression patterns, which may greatly facilitate the assessment of prognosis, molecular features and treatment modalities in EC patients and may be useful in the future translation to clinical applications. TIMM50 was identified as a novel molecule that mediates lactate metabolism in vitro and in vivo, maybe a promising target for EC prognosis.

KIF4A promotes genomic stability and progression of endometrial cancer through regulation of TPX2 protein degradation.

Kinesin family member 4A (KIF4A) belongs to the kinesin superfamily proteins, which are closely associated with mitophagy. Nonetheless, the role of KIF4A in endometrial cancer (EC) remains poorly characterized. The present study showed that KIF4A not only was upregulated but also predicted poor prognosis in patients with EC. KIF4A knockdown in EC cells resulted in attenuated proliferative capacity in vitro and in vivo. Transcriptome sequencing and gene function analysis revealed that KIF4A contributed to the maintenance of EC cells' genomic stability and that KIF4A knockdown induced the DNA damage response, cell cycle arrest, and apoptosis. Mechanistically, KIF4A interacted with TPX2 (a protein involved in DNA damage repair to cope with the replication pressure) to enhance its stability via inhibition of TPX2 ubiquitination and eventually ensured the genomic stability of EC cells during mitosis. Taken together, our results indicated that KIF4A functions as a tumor oncogene that facilitates EC progression via the maintenance of genomic stability. Therefore, targeting the KIF4A/TPX2 axis may provide new concepts and strategies for the treatment of patients with EC.

GPX4 suppresses ferroptosis to promote malignant progression of endometrial carcinoma via transcriptional activation by ELK1.

BACKGROUND: Glutathione Peroxidase 4 (GPX4) is a key protein that inhibits ferroptosis. However, its biological regulation and mechanism in endometrial cancer (EC) have not been reported in detail. METHODS: The expression of GPX4 in EC tissues was determined by TCGA databases, qRT-PCR, Western blot, and immunohistochemistry (IHC). The effects of GPX4 on EC cell proliferation, migration, apoptosis, and tumorigenesis were studied in vivo and in vitro. In addition, ETS Transcription Factor ELK1 (ELK1) was identified by bioinformatics methods, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP). Pearson correlation analysis was used to evaluate the association between ELK1 and GPX4 expression. RESULTS: The expression of GPX4 was significantly up-regulated in EC tissues and cell lines. Silencing GPX4 significantly inhibited the proliferation, migration ability, induced apoptosis, and arrested the cell cycle of Ishikawa and KLE cells. Knockdown of GPX4 accumulated intracellular ferrous iron and ROS, disrupted MMP, and increased MDA levels. The xenograft tumor model also showed that GPX4 knockdown markedly reduced tumor growth in mice. Mechanically, ELK1 could bind to the promoter of GPX4 to promote its transcription. In addition, the expression of ELK1 in EC was positively correlated with GPX4. Rescue experiments confirmed that GPX4 knockdown could reverse the strengthens of cell proliferation and migration ability and the lower level of Fe2+ and MDA caused by upregulating ELK1. CONCLUSION: The results of the present study suggest that ELK1 / GPX4 axis plays an important role in the progress of EC by promoting the malignant biological behavior and inducing ferroptosis of EC cells, which provides evidence for investigating the potential therapeutic strategies of endometrial cancer.