Data-independent acquisition for proteomic applications in early-stage endometrial cancer progression.

AIM: Most endometrial cancer (EC) patients are diagnosed at an early-stage (FIGO stage I or II), with a favorable prognosis. However, some high-grade, early-stage EC patients have unexpected recurrences and undesirable results, the molecular alterations that underlie these tumors are far from being fully understood. Our goal was to use proteome analysis to examine dysregulated pathways in this specific subgroup of EC. METHODS: We used data-independent acquisition (DIA) quantitative proteomics to analyze cancer and matched paracancerous tissues from 20 EC patients (10 high-grade and 10 low-grade). Immunohistochemistry (IHC) analysis was used to validate protein expression of six hub genes. RESULTS: In total, 7107 proteins were quantified, while 225 downregulated and 366 upregulated proteins in high-grade cancer tissues, 130 downregulated and 413 upregulated proteins in high-grade paracancerous tissues. The pathway associated with oxidative phosphorylation (OXPHOS) was upregulated and have similar expression patterns in high-grade EC tissues and matched paracancerous tissues. OXPHOS-related protein, ATP5F1D showed the best classification and diagnostic ability in distinguishing high-grade from low-grade EC. In both cancer and paracancerous tissues, double-label immunofluorescence demonstrated ITGA4 and COL4A1 co-localized at the basal membrane. CONCLUSIONS: Our present works elucidate that metabolism reprogramming is associated with high-grade, early-stage EC, particularly OXPHOS is upregulated. Noticeably, the paracancerous tissues have undergone molecular changes similar to cancer tissues, maybe they have signal exchange via secreted proteins (ITGA4 and COL4A1). The upregulation of OXPHOS-related proteins may be the potential biomarker for EC diagnosis, and targeting OXPHOS metabolism might be an effective treatment for high-grade, early-stage EC.

A nomogram-based overall survival stratification to identify uterine sarcoma patients without distant metastases who may benefit from adjuvant radiotherapy.

OBJECTIVE: Adjuvant radiotherapy has been commonly performed in uterine sarcoma patients, but its role in overall survival (OS) remains controversial. Therefore, our study aimed to build a nomogram-based prognostic stratification to identify uterine sarcoma patients who might benefit from adjuvant radiotherapy. METHODS: Uterine sarcoma patients without distant metastases between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The LASSO Cox regression was performed to identify essential prognostic predictors and a nomogram was built to predict the 1-, 3-, and 5-year OS. Receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA) were used to validate the nomogram. Finally, prognostic stratification was performed by decision tree analysis based on the total points of the nomogram. RESULTS: 2871 patients with uterine sarcoma were included. Preliminary analysis suggested that adjuvant radiotherapy failed to provide an OS benefit for the total population without our nomogram. The built nomogram showed good discrimination and calibration abilities to predict the OS in uterine sarcoma patients and the patients were stratified into three risk groups based on the nomogram. For patients in the high-risk group, adjuvant radiotherapy significantly improved the 5-year OS and median survival time by 26.4% and 17 months, respectively (P < 0.001); while radiotherapy failed to improve the survival outcomes of patients in the low- and intermediate-risk groups. CONCLUSIONS: The nomogram-based prognostic stratification provides preliminary characterization of uterine sarcoma patients who may benefit from radiotherapy. The newly defined high-risk patients may gain significant OS benefit from adjuvant radiotherapy.

Correlation between malignant peritoneal cytology and survival in patients with uterine leiomyosarcoma and endometrial stromal sarcoma.

OBJECTIVE: This study aimed to examine the correlation between malignant peritoneal cytology and overall survival among patients with uterine leiomyosarcoma and endometrial stromal sarcoma. METHODS: Patients with uterine leiomyosarcoma and endometrial stromal sarcoma between January 2010 and December 2016 were identified from the Surveillance, Epidemiology, and End Results database. The multiple imputation method was used to address missing values. Propensity score matching was conducted to balance baseline data between the malignant and negative peritoneal cytology groups. The prognostic significance of malignant peritoneal cytology was evaluated using Cox regression, random survival forest, and subgroup analyses. RESULTS: Among 733 eligible patients, 8% (59/733) had malignant peritoneal cytology, increasing to 20% (42/209) in advanced cases. Before and after propensity score matching, patients with malignant peritoneal cytology had significantly lower 5-year overall survival rates and shorter median survival time than patients with negative peritoneal cytology. Multivariate Cox regression revealed that malignant peritoneal cytology (hazard ratio 2.03, 95% confidence interval 1.29 to 3.20, p=0.002) was an independent prognostic factor for uterine leiomyosarcoma and endometrial stromal sarcoma. Random survival forest further indicated that, among the factors analyzed, peritoneal cytology status was second only to the International Federation of Gynecology and Obstetrics (FIGO) stage in terms of prognostic prediction. Finally, subgroup analyses substantiated the correlation between malignant peritoneal cytology and unfavorable overall survival in most subgroups. CONCLUSIONS: Malignant peritoneal cytology status was an important prognostic factor complementing FIGO stage and was associated with a reduction in overall survival. Peritoneal cytology evaluation during hysterectomy may be recommended for prognosis estimation for uterine leiomyosarcoma and endometrial stromal sarcoma.

SIK2: A critical glucolipid metabolic reprogramming regulator and potential target in ovarian cancer.

AIM: To explore the role of salt-inducible kinase 2 (SIK2) on glucose and lipid metabolism in ovarian cancer (OC), so as to increase the understanding of potential inhibitors targeting SIK2 and lay a foundation for future precision medicine in OC patients. METHODS: We reviewed and summarized the regulation effect of SIK2 on glycolysis, gluconeogenesis, lipid synthesis, and fatty acids ß-oxidation (FAO) in OC, as well as the potential molecular mechanism and the prospects of potential inhibitors targeting SIK2 in future cancer treatments. RESULTS: Many pieces of evidence show that SIK2 is closed associated with glucose and lipid metabolism of OC. On the one hand, SIK2 enhances the Warburg effect by promoting glycolysis and inhibiting oxidative phosphorylation and gluconeogenesis, on the other hand, SIK2 regulates intracellular lipid metabolism through promoting lipid synthesis and FAO, all of which ultimately induces growth, proliferation, invasion, metastasis, and therapeutic resistance of OC. On this basis, SIK2 targeting may become a new solution for the treatment of a variety of cancer types including OC. The efficacy of some small molecule kinase inhibitors has also been demonstrated in tumor clinical trials. CONCLUSION: SIK2 displays significant effects in OC progression and treatment through regulating cellular metabolism including glucose and lipid metabolism. Therefore, future research needs to further explore the molecular mechanisms of SIK2 in other types of energy metabolism in OC, based on this to develop more unique and effective inhibitors.

Comprehensive analysis of a NAD+ metabolism-derived gene signature to predict the prognosis and immune landscape in endometrial cancer.

As a crucial regulator influencing tumor progression, nicotinamide adenine dinucleotide (NAD+) is widely acknowledged. However, its role in endometrial cancer (EC) is not completely understood. In this study, we aimed to develop an NAD+metabolic-related genes (NMRGs) risk signature that could reflect the prognosis of EC patients and their responsiveness to immunotherapy and chemotherapy. Data from The Cancer Genome Atlas (TCGA) databases and the Molecular Signatures Database (MSigDB) confirmed two distinct NMRG subtypes in EC patients using consensus clustering, and a risk score was constructed utilizing an NAD+-related prognostic signature depending on the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Receiver operating characteristic (ROC) curves were employed to assess the model's precision. Additionally, we used Gene Set Enrichment Analysis (GSEA) to predict the biological signaling pathways that might be involved. We also explored the role of the risk score in immune cell infiltration, tumor mutation burden (TMB), immunotherapy, and chemotherapy. Our study established a prognostic risk signature based on six NMRGs, and we observed that the high-risk group was associated with a poorer prognosis. Furthermore, we identified a strong correlation between the high-risk group and several pathways, including DNA replication, cell cycle, and mismatch repair. Lastly, our findings highlighted the influence of NMRGs on the regulation of immune infiltration in EC. Therefore, this signature holds potential value in predicting the prognosis of EC patients and guiding their management, including decisions regarding immunotherapy and chemotherapy, ultimately improving the accuracy of EC patient care.

Identification of Common and Specific Genes Involved in Mouse Models of Age-Related and Cyclophosphamide-Induced Diminished Ovarian Reserve.

Diminished ovarian reserve (DOR) is an etiologically heterogeneous disorder that usually leads to poor reproductive outcomes. Does a specific or common pathogenesis exist for DOR subtypes with different etiologies? Two frequently used mouse models, age-related DOR (AR-DOR) and cyclophosphamide (CTX)-induced DOR (CTX-DOR), were successfully established, and RNA sequencing was performed on ovarian tissue samples. Differentially expressed genes (DEGs) in each subtype and common DEGs (co-DEGs) in the two subtypes were identified. Subsequently, we performed comprehensive bioinformatics analyses, including an evaluation of immune cell infiltration. Finally, the genes of interest were further validated by performing RT-qPCR and immunohistochemistry. In AR-DOR mice, functional enrichment analyses showed that upregulated DEGs were mainly involved in the inflammatory/immune response, while downregulated DEGs were involved in DNA damage repair. In CTX-DOR mice, the inflammatory/immune response and cell apoptosis played significant roles. Meanwhile, 406 co-DEGs were identified from the two models. The biological functions of these co-DEGs were associated with inflammatory/immune responses. The analysis of immune cell infiltration showed reduced infiltration of Treg cells, as well as increased infiltration of M0 macrophages, NK resting, and T cells CD4 follicular in both DOR subtypes. The results of the validation experiments were consistent with the RNA sequencing data. In conclusion, the inflammatory/immune response might be the common pathogenesis for the two DOR subtypes, while DNA repair and cell apoptosis may have different roles in the two subtypes. These results may provide potential insights for mechanistic research and therapeutic targets of DOR.

New insights into the role of circular RNAs in ovarian cancer.

Ovarian cancer (OC) is one of the most aggressive tumors in women and has a poor prognosis and the highest mortality rate. Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs that have recently attracted interest in cancer research. Increasing evidence has demonstrated that circRNAs play an oncogenic or suppressive role in tumorigenesis and progression, and show tissue- or developmental-stage-specific expression. Due to high stability, conservation, abundance, and specificity, circRNAs are considered promising biomarkers for the diagnosis and prognosis of cancer. Herein, we have summarized the expression profiles of circRNAs in OC tissues, serums, and cell lines. Moreover, we discuss how circRNAs participate in the regulation of multiple biological processes in OC, including cell proliferation, apoptosis, migration, invasion, autophagy, epithelial-to-mesenchymal transition, glucose metabolism, angiogenesis, immune response, and chemotherapy resistance, by sponging microRNAs and interacting with proteins.