Progression-free Interval Time Research Articles

Integrated analysis of the potential roles of microRNA-messenger RNA networks in prostate adenocarcinoma

BackgroundProstate adenocarcinoma is a frequent cancer among men with high incidence and mortality rates. Biomarkers are useful for the treatment of cancers, so we need to explore the regulatory network of prostate adenocarcinoma. MethodThe database from University of California Santa Cruz was used to determine expression of messenger RNAs and microRNAs. Weighted correlation network analysis was used for classifying genes. Search Tool for Recurring Instances of Neighboring Genes and Cytoscape were used for the construction of PPI network and selection of hub genes. The microRNAs were predicted in miRactDB. The relations between microRNAs and messenger RNAs were assessed by Statistical Product and Service Solutions. The prognostic value was evaluated through Kaplan-Meier method. Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Gene Set Enrichment Analysis were used for predicting potential function. Results10 hub genes were all overexpressed in tumor tissues compared to normal tissues, but only aurora kinase B and nucleolar and spindle associated protein 1 were both significantly related to disease-free interval and progression-free interval time.Aurora kinase B and nucleolar and spindle associated protein 1 were negatively related to hsa-miR-1-3p, hsa-miR-133a-3p, hsa-miR-133b and hsa-miR-221-3p but positively related to hsa-miR-15b-5p, hsa-miR-21-5p, hsa-miR-106b-5p, hsa-miR-183-5p, hsa-miR-191-5p, hsa-miR-210-3p, hsa-miR-425-5p and hsa-miR-653-5p. All microRNAs except has-miR-653-5p significantly were related to the disease-free interval and progression-free interval time. The functions of microRNAs were enriched in cell cycle. ConclusionWe identified hub messenger RNAs and core microRNAs and established a novel messenger RNA-microRNA network associated with the prognosis of prostate adenocarcinoma.

Identification and validation of Birc5 as a novel activated cell cycle program biomarker associated with infiltration of immunosuppressive myeloid-derived suppressor cells in hepatocellular carcinoma.

Preclinical studies and clinical trials have demonstrated that tumor-intrinsic activation of the cell cycle program impedes anticancer immunotherapy. Identification of cell cycle-related biomarkers may provide novel therapeutic targets to augment the efficacy of immunotherapy in hepatocellular carcinoma (HCC). Based on the genes related to cell cycle program, two clusters (Cluster 1 and Cluster 2) were detected in HCC patients via non-negative matrix factorization algorithm. Multivariable-adjusted Cox regression analysis indicated that the cell cycle gene-based classification was a significant prognostic factor for predicting the clinical outcome of HCC patients. Cluster 1 showed shorter overall survival time and progression-free interval time was associated with activated cell cycle program, higher infiltration of myeloid-derived suppressor cells (MDSCs) and less sensitivity to immunotherapy. A three-gene prognostic model, including BIRC5, C8G, and SPP1, was constructed to characterize the cell cycle-based classification of HCC, which had strong robustness and a stable predictive performance. Notably, Birc5 was positively correlated with CD11b expression (a MDSC marker) in HCC tissue. Concordant high expression of Birc5 and intratumor infiltration level of MDSCs were correlated with worse prognosis of HCC patients. In vitro, hepatocellular Birc5 overexpression promoted immunosuppressive CD11b+ CD33+ HLA-DR- MDSC expansion from human peripheral blood mononuclear cells. Genetically modified animal model of liver cancer revealed that Birc5 depletion upregulated the genes related to lymphocyte-mediated immunity, natural killer cell-mediated immunity, interferon-gamma production, T-cell activation, and T-cell-mediated cytotoxicity. These results suggest an immunosuppressive function of Birc5 in HCC. Birc5 was a potential biomarker and inducer of intratumor infiltration of MDSCs, which led to T cell exclusion or dysfunction in tumor immune microenvironment, consequently resulting in reduced response to ICIs in HCC.

The Overexpression and Clinical Significance of AP1S1 in Breast Cancer.

PurposeTo explore the mechanism of AP1S1 in breast cancer.Methods and ResultsIn different datasets, we found that AP1S1 is more highly expressed in breast tumors, which was furthermore verified in our local cohort.Immune infiltration analysis showed that AP1S1 was related to a variety of immune cells. The higher AP1S1 expression was negatively correlated with a variety of immune infiltrating cells, suggesting that AP1S1 may affect cellular immunity.Clinical analysis showed that patients with higher AP1S1 expression had higher estrogen receptor gene expression and were more prone to distant metastasis and lymph node metastasis.The overall survival rate, disease-specific survival rate, and progression-free interval time were worse in the group with higher AP1S1 expression. AP1S1 may be a potential oncogene of breast cancer, and overexpression is related to the poor prognosis of breast cancer.Therefore, a nomogram was constructed, along with correlated gene analysis and functional analysis to further explore the carcinogenic mechanism, practical clinical issues, and value of AP1S1.ConclusionAP1S1 is a potential oncogene of breast cancer.

Immune subtypes in LUAD identify novel tumor microenvironment profiles with prognostic and therapeutic implications.

e20512 Background: The incidence of lung adenocarcinoma (LUAD) is increasing year by year worldwide. Thorsson et al. identified six immune subtypes (ISs) (C1 - C6) in 33 diverse cancer types, including LUAD. The tumor microenvironment and lung cancer cells of 6 ISs have complex and different interplay, and the consequence of the interplay determines the growth of tumor cells and the prognosis of patients. Methods: Clinical and molecular information of TCGA LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) (N = 457). Kaplan-Meier survival analysis and Cox proportional-hazard analyses were performed in 4 independent GEO LUAD data sets (GSE31210, GSE37745, GSE50081, and GSE68465) and, where five immune subtypes C1-C4, C6 were stratified according to Thorsson et al.’s immune classification method. Results: Only 5 ISs were identified in the TCGA NSCLC cohort; the proportion of the C3 inflammatory IS (39.2%) was the most common IS observed in the TCGA LUAD cohort, whereas C1 was particularly dominant in LUSC (57.1%). The proportion of C3 was also the most common IS observed in GEO LUAD cohorts (GSE37745, GSE50081, GSE68465), except for one stage I-II lung adenocarcinomas cohort (GSE31210). The prognostic relevance of the C3 IS was associated with significantly longer overall survival and progression-free interval time of LUAD in the TCGA cohort. In contrast, the association was not significant in the TCGA LUSC cohort. C3 was also associated with significantly longer overall survival (p < 0.001) and disease-free interval time (p < 0.001) in the 4 GEO LUAD cohorts by multivariate analyses. To further evaluate prediction accuracies of C3, we compared the C3 model with the other 3 reported immune-related signatures. For all comparisons in these 4 GEO cohorts, C3 outperformed the other 3 signatures with superior overall survival and DFS predictive performances according to the time-dependent Concordance index. C3 presented higher levels of CD8 T, follicular helper T, M1 macrophage, CD4 memory resting, myeloid dendritic, neutrophils, and endothelial cells by using CIBERSORT and MCP counter. Low levels of M2 macrophages and cancer-associated fibroblast cells were also found in the C3 subtype. GSEA pathway analysis showed that the C3 subtype had a heightened activation in the antigen process and presenting pathway, interferon-gamma response pathway, T cell receptor signaling pathway, and neural killer cell-mediated cytotoxicity pathway than C1/C2. In contrast, the C1/C2 presented greater activation of pathways related to the cell cycles, MMR repair DNA repair, and p53 signaling pathways than the C3 subtype. Conclusions: The robust prognostic relevance of the C3 IS allows a more precise categorization of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in LUAD patients.