ABSTRACT
The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.
Subject(s)
Biomarkers, Tumor , Endometrial Neoplasms , Gene Expression Regulation, Neoplastic , Neoplasm Staging , Proteomics , Humans , Female , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/mortality , Prognosis , Biomarkers, Tumor/genetics , Proteomics/methods , Tumor Microenvironment/genetics , Gene Expression Profiling , Middle Aged , Transcriptome , Multiomics , HSP90 Heat-Shock ProteinsABSTRACT
A major challenge in combining cancer immunotherapy is the efficient delivery of multiple types of immunological stimulators to elicit a robust anti-tumor immune response and reprogram the immunosuppressive tumor microenvironment (TME). Here, we developed a DNA nanodevice that was generated by precisely assembling three types of immunological stimulators. The doxorubicin (Dox) component induced immunogenic cell death (ICD) in tumor cells and enhanced phagocytosis of antigen-presenting cells (APCs). Exogenous double-stranded DNA (dsDNA) could act as a molecular adjuvant to activate the stimulator of interferon genes (STING) signaling in APCs by engulfing dying tumor cells. Interleukin (IL)-12 and small hairpin programmed cell death-ligand 1 (shPD-L1) transcription templates were designed to regulate TME. Additionally, for targeted drug delivery, multiple cyclo[Arg-Gly-Asp-(d-Phe)-Cys] (cRGD) peptide units on DNA origami were employed. The incorporation of disulfide bonds allowed the release of multiple modules in response to intracellular glutathione (GSH) in tumors. The nanodevice promoted the infiltration of CD8+ and CD4+ cells into the tumor and generated a highly inflamed TME, thereby enhancing the effectiveness of cancer immunotherapy. Our research results indicate that the nanodevice we constructed can effectively inhibit tumor growth and prevent lung metastasis without obvious systemic toxicity, providing a promising strategy for cancer combination treatment.
Subject(s)
DNA , Doxorubicin , Immunotherapy , DNA/chemistry , Doxorubicin/pharmacology , Doxorubicin/chemistry , Doxorubicin/administration & dosage , Mice , Animals , Tumor Microenvironment/drug effects , Humans , Drug Delivery Systems , Mice, Inbred C57BL , Mice, Inbred BALB C , Cell Line, Tumor , Antigen-Presenting Cells/immunology , Nanoparticles/chemistry , Neoplasms/therapy , Neoplasms/drug therapy , Neoplasms/immunology , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/administration & dosage , Particle SizeABSTRACT
Intrauterine adhesion (IUA) is one of the principal causes of secondary infertility in women of reproductive age, which seriously affects female reproductive function and quality of life. In recent years, the incidence of IUA has been increasing year by year, but its pathological mechanism has not yet been clarified. This study intended to reveal the pathogenesis of IUA and find new therapeutic targets by analyzing the proteomic differences between intrauterine adhesion tissues and normal human endometrial tissues. In the label-free quantitative proteomics, we identified 789 up-regulated differentially expressed proteins (DEPs) and 539 down-regulated DEPs. These DEPs were further analyzed by Gene Ontology (GO) annotation and enrichment analysis, Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis to preliminarily clarify the biomarkers involved in the pathogenesis of the IUA. The DEPs were further verified by parallel reaction monitoring (PRM) to confirm the results of proteomics. Finally, 7 target proteins may be candidates for treatment and elucidating the pathophysiology of IUA. SIGNIFICANCE: IUA is a fertility complication, which has increasing incidence recently. Until now, only a little research paid attention to the proteomic changes of IUA. This is the first study focused on the comparative analysis of endometrial tissue between IUA patients and normal women. We found 7 key proteins that may become the potential biomarkers of IUA.
