Voltage-gated chloride ion channels (CLCs) are transmembrane proteins that maintain chloride ion homeostasis in various cells. Accumulating studies indicated CLCs were related to cell growth, proliferation, and cell cycle. Nevertheless, the role of CLCs in prostate cancer (PCa) has not been systematically profiled. The purpose of this study was to investigate the expression profiles and biofunctions of CLCs genes, and construct a novel risk signature to predict biochemical recurrence (BCR) of PCa patients. We identified five differentially expressed CLCs genes in our cohort and then constructed a signature composed of CLCN2 and CLCN6 through Lasso-Cox regression analysis in the training cohort from the Cancer Genome Atlas (TCGA). The testing and entire cohorts from TCGA and the GSE21034 from the Gene Expression Omnibus (GEO) were used as internal and independent external validation datasets. This signature could divide PCa patients into the high and low risk groups with different prognoses, was apparently correlated with clinical features, and was an independent excellent prognostic indicator. Enrichment analysis indicated our signature was primarily concentrated in cellular process and metabolic process. The expression patterns of CLCN2 and CLCN6 were detected in our own cohort based immunohistochemistry staining, and we found CLCN2 and CLCN6 were highly expressed in PCa tissues compared with benign tissues and positively associated with higher Gleason score and shorter BCR-free time. Functional experiments revealed that CLCN2 and CLCN6 downregulation inhibited cell proliferation, colony formation, invasion, and migration, but prolonged cell cycle and promoted apoptosis. Furthermore, Seahorse assay showed that silencing CLCN2 or CLCN6 exerted potential inhibitory effects on energy metabolism in PCa. Collectively, our signature could provide a novel and robust strategy for the prognostic evaluation and improve treatment decision making for PCa patients.
<abstract> <p>The aim of this study is to construct an inflammatory response-related genes (IRRGs) signature to monitor biochemical recurrence (BCR) and treatment effects in prostate cancer patients (PCa). A gene signature for inflammatory responses was constructed on the basis of the data from the Cancer Genome Atlas (TCGA) database, and validated in external datasets. It was analyzed using receiver operating characteristic curve, BCR-free survival, Cox regression, and nomogram. Distribution analysis and external model comparison were utilized. Then, enrichment analysis, tumor mutation burden, tumor immune microenvironment, and immune cell infiltration signatures were investigated. The role of the signature in immunotherapy was evaluated. The expression patterns of core genes were verified by RNA sequencing. We identified an IRRGs signature in the TCGA-PRAD cohort and verified it well in two other independent external datasets. The signature was a robust and independent prognostic index for predicting the BCR of PCa. The high-risk group of our signature predicted a shortened BCR time and an aggressive disease progression. A nomogram was constructed to predict BCR-free time in clinical practices. Neutrophils and CD8+ T cells were in higher abundance among the low-risk individuals. Immune functions varied significantly between the two groups and immune checkpoint therapy worked better for the low-risk patients. The expression of four IRRGs showed significant differences between PCa and surrounding benign tissues, and were validated in BPH-1 and DU145 cell lines by RNA sequencing. Our signature served as a reliable and promising biomarker for predicting the prognosis and evaluating the efficacy of immunotherapy, facilitating a better outcome for PCa patients.</p> </abstract>
<abstract> <p>Tumor mutation burden (TMB), an emerging molecular determinant, is accompanied by microsatellite instability and immune infiltrates in various malignancies. However, whether TMB is related to the prognosis or immune responsiveness of adrenocortical carcinoma (ACC) remains to be elucidated. This paper aims to investigate the impact of TMB on the prognosis and immune microenvironment infiltration in ACC. The somatic mutation data, gene expression profile, and corresponding clinicopathological information were retrieved from TCGA. The mutation landscape was summarized and visualized with the waterfall diagram. The ACC patients were divided into low and high TMB groups based on the median TMB value and differentially expressed genes (DEGs) between the two groups were identified. Diverse functional analyses were conducted to determine the functionality of the DEGs. The immune cell infiltration signatures were evaluated based on multiple algorithms. Eventually, a TMB Prognostic Signature (TMBPS) was established and its predictive accuracy for ACC was evaluated. Single nucleotide polymorphism and C > T were found to be more common than other missense mutations. In addition, lower TMB levels indicated improved survival outcomes and were correlated with younger age and earlier clinical stage. Functional analysis suggested that DEGs were primarily related to the cell cycle, DNA replication, and cancer progression. Additionally, significant differences in infiltration levels of activated CD4+ T cells, naive B cells, and activated NK cells were observed in two TMB groups. We also found that patients with higher TMBPS showed worse survival outcomes, which was validated in the Gene Expression Omnibus database. Our study systematically analyzed the mutation and identified a TMBPS combined with immune microenvironment infiltration in ACC. It is expected that this paper can promote the development of ACC treatment strategies.</p> </abstract>
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