Construction of the metabolic reprogramming-associated gene signature for clear cell renal cell carcinoma prognosis prediction.

BACKGROUND: Metabolism reprogramming is a hallmark that associates tumor growth, metastasis, progressive, and poor prognosis. However, the metabolism-related molecular patterns and mechanism in clear cell renal cell carcinoma (ccRCC) remain unclear. Herein, the purpose of this study was to identify metabolism-related molecular pattern and to investigate the characteristics and prognostic values of the metabolism-related clustering. METHODS: We comprehensively analyzed the differentially expressed genes (DEGs), and metabolism-related genes (MAGs) in ccRCC based on the TCGA database. Consensus clustering was used to construct a metabolism-related molecular pattern. Then, the biological function, molecular characteristics, Estimate/immune/stomal scores, immune cell infiltration, response to immunotherapy, and chemotherapy were analyzed. We also identified the DEGs between subclusters and constructed a poor signature and risk model based on LASSO regression cox analysis and univariable and multivariable cox regression analyses. Then, a predictive nomogram was constructed and validated by calibration curves. RESULTS: A total of 1942 DEGs (1004 upregulated and 838 downregulated) between ccRCC tumor and normal samples were identified, and 254 MRGs were screened out from those DEGs. Then, 526 ccRCC patients were divided into two subclusters. The 7 metabolism-related pathways enriched in cluster 2. And cluster 2 with high Estimate/immune/stomal scores and poor survival. While, cluster 1 with higher immune cell infiltrating, expression of the immune checkpoint, IFN, HLA, immune activation-related genes, response to anti-CTLA4 treatment, and chemotherapy. Moreover, we identified 295 DEGs between two metabolism-related subclusters and constructed a 15-gene signature and 9 risk factors. Then, a risk score was calculated and the patients into high- and low-risk groups in TCGA-KIRC and E-MTAB-1980 datasets. And the prediction viability of the risk score was validated by ROC curves. Finally, the clinicopathological characteristics (age and stage), risk score, and molecular clustering, were identified as independent prognostic variables, and were used to construct a nomogram for 1-, 3-, 5-year overall survival predicting. The calibration curves were used to verify the performance of the predicted ability of the nomogram. CONCLUSION: Our finding identified two metabolism-related molecular subclusters for ccRCC, which facilitates the estimation of response to immunotherapy and chemotherapy, and prognosis after treatment.

Estrogen receptor ß suppresses inflammation and the progression of prostate cancer.

Previous studies demonstrated that estrogen receptor ß (ERß) signaling alleviates systemic inflammation in animal models, and suggested that ERß­selective agonists may deactivate microglia and suppress T cell activity via downregulation of nuclear factor κ­light­chain­enhancer of activated B cells (NF­κB). In the present study, the role of ERß in lipopolysaccharide (LPS)­induced inflammation and association with NF­κB activity were investigated in PC­3 and DU145 prostate cancer cell lines. Cells were treated with LPS to induce inflammation, and ELISA was performed to determine the expression levels of inflammatory cytokines, including tumor necrosis factor­α (TNF­α), monocyte chemoattractant protein 1 (MCP­1), interleukin (IL)­1ß and IL­6. MTT and Transwell assays, and Annexin V/propidium iodide staining were conducted to measure cell viability, apoptosis and migration, respectively. Protein expression was determined via western blot analysis. LPS­induced inflammation resulted in elevated expression levels of TNF­α, IL­1ß, MCP­1 and IL­6 compared with controls. ERß overexpression significantly inhibited the LPS­induced production of TNF­α, IL­1ß, MCP­1 and IL­6. In addition, the results indicated that ERß suppressed viability and migration, and induced apoptosis in prostate cancer cells, which was further demonstrated by altered expression of proliferating cell nuclear antigen, B­cell lymphoma 2­associated X protein, caspase­3, E­cadherin and matrix metalloproteinase­2. These effects were reversed by treatment with the ERß antagonist PHTPP or ERß­specific short interfering RNA. ERß overexpression reduced the expression levels of p65 and phosphorylated NF­κB inhibitor α (IκBα), but not total IκBα expression in LPS­treated cells. In conclusion, ERß suppressed the viability and migration of the PC­3 and DU145 prostate cancer cell lines and induced apoptosis. Furthermore, it reduced inflammation and suppressed the activation of the NF­κB pathway, suggesting that ERß may serve roles as an anti­inflammatory and anticancer agent in prostate cancer.