Prostate cancer (PCa) is a common malignancy in elderly men. We have applied Traditional Chinese Medicine CFF-1 in clinical treatments for PCa for several years. Here, we aimed to identify the underlying mechanism of CFF-1 on PCa using network pharmacology and experimental validation. Active ingredients, potential targets of CFF-1 were acquired from the public databases. Subsequently, protein-protein interaction (PPI) and the herbs-active ingredients-target network was constructed. A prognostic model for PCa was also constructed based on key targets. In vitro experiments using PCa cell lines CWR22Rv1 and PC-3 were carried out to validate the potential mechanism of CFF-1 on PCa. A total of 112 bioactive compounds and 359 key targets were screened from public databases. PPI and herbs-active ingredients-target network analysis determined 12 genes as the main targets of CFF-1 on PCa. Molecular docking studies indicated that the primary active ingredients of CFF-1 possess strong binding affinity to the top five hub targets. DNMT3B, RXRB and HPRT1 were found to be involved in immune regulation of PCa. In vitro, CFF-1 was found to inhibit PCa cell proliferation, migration, invasion and induce apoptosis via PI3K-Akt, HIF-1, TNF, EGFR-TKI resistance and PD-1 checkpoint signaling pathways. This study comprehensively elucidates the underlying molecular mechanism of CFF-1 against PCa, offering a strong rationale for clinical application of CFF-1 in PCa treatment.
Idiopathic pulmonary fibrosis is a chronic, progressive, and fatal fibrotic lung disease with a poor prognosis, but no effective treatment is available. G protein-coupled receptor 56 (GPR56) plays a role in cell adhesion and tumor progression, but its function in fibrogenesis has not been explored. In this in vitro study, we found that GPR56 in IPF fibroblasts was lower than in normal fibroblasts. GPR56 regulated the production of fibronectin and type I collagen, and also changed the migratory and invasive capacity of lung fibroblasts. However, it was not sufficient to activate some classic markers of fibroblast and myofibroblast, such as α-smooth muscle actin and fibroblast specific protein 1. These findings demonstrate that reduced expression of GPR56 in lung fibroblasts may be an important link with pulmonary fibrosis, playing a role in regulating some important fibroblast functions.
We developed a predictive model associated with ferroptosis to provide a more comprehensive view of esophageal squamous cell carcinoma (ESCC) immunotherapy. Gene expression data and corresponding clinical outcomes were obtained from the GEO and The Cancer Genome Atlas (TCGA) databases, and a ferroptosis-related gene set was obtained from the FerrDb database. We identified 45 ferroptosis-related genes that were differentially expressed, including enrichment in genes involved in the immune system process. We established a ferroptosis-related gene-based prognostic model based on the results of univariate Cox regression and multivariate Cox regression analyses, with an area under the curve (AUC) of 0.76 (3 years). We found that the patients with low-risk scores showed a higher proportion of CD8+ T cells, CD4+ memory activated T cells, etc. Finally, a predictive ferroptosis-related prognostic nomogram, which included the predictive values of age, gender, grade, TNM stage, and risk score, was established to predict overall survival. In sum, we developed a ferroptosis-related gene-based prognostic model that provides novel insights into the prediction of ESCC prognosis and identifies the relevance of the immune microenvironment for patient outcomes. We developed a predictive model associated with ferroptosis to provide a more comprehensive view of esophageal squamous cell carcinoma (ESCC) immunotherapy. Gene expression data and corresponding clinical outcomes were obtained from the GEO and The Cancer Genome Atlas (TCGA) databases, and a ferroptosis-related gene set was obtained from the FerrDb database. We identified 45 ferroptosis-related genes that were differentially expressed, including enrichment in genes involved in the immune system process. We established a ferroptosis-related gene-based prognostic model based on the results of univariate Cox regression and multivariate Cox regression analyses, with an area under the curve (AUC) of 0.76 (3 years). We found that the patients with low-risk scores showed a higher proportion of CD8+ T cells, CD4+ memory activated T cells, etc. Finally, a predictive ferroptosis-related prognostic nomogram, which included the predictive values of age, gender, grade, TNM stage, and risk score, was established to predict overall survival. In sum, we developed a ferroptosis-related gene-based prognostic model that provides novel insights into the prediction of ESCC prognosis and identifies the relevance of the immune microenvironment for patient outcomes.
Abstract Background Cuproptosis is a newly discovered form of cell death. It's regulated by a string of genes. The genes are identified to influence the tumor progression, but in glioma, the cuproptosis-related genes are little studied. Method The Cancer Genome Atlas and The Genotype-Tissue Expression were used to screen for SLC31A1 gene expression in glioma and healthy tissue samples. The results were validated using the Gene Expression Omnibus and real-time quantitative PCR. The Human Protein Atlas and The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium were used to validate our results at the protein level. Multivariable analysis and Kaplan-Meier survival curves were used to examine the relationship between SLC31A1 gene expression, clinical parameters, and survival rates. The online Search Tool for the Retrieval of Interacting Genes/Proteins was used to find the genes and proteins that correlate to SLC31A1. The immune infiltration analysis was performed using the Tumor Immune Estimation Resource databases. Results The glioma patients have higher SLC31A1 expression levels, which increase as the WHO grade escalates. The survival analysis illustrates that the SLC31A1 gene expression negatively correlates with OS, PFS, and DSS. The immune infiltration analysis shows the SLC31A1 gene positively correlates with Th2 cells, Macrophages, and M2 type macrophages and negatively correlates with pDC cells, NK CD56bright cells, and CD8 T cells. Conclusion The SLC31A1 gene expression can shorten the survival time of glioma patients. It also can promote the formation of a tumor-suppressive microenvironment.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with an estimated 1.8 million new cases worldwide and associated with high mortality rates of 881 000 CRC-related deaths in 2018. Screening programs and new therapies have only marginally improved the survival of CRC patients. Immune-related genes (IRGs) have attracted attention in recent years as therapeutic targets. The aim of this study was to identify an immune-related prognostic signature for CRC. To this end, we combined gene expression and clinical data from the CRC data sets of The Cancer Genome Atlas (TCGA) into an integrated immune landscape profile. We identified a total of 476 IRGs that were differentially expressed in CRC vs normal tissues, of which 18 were survival related according to univariate Cox analysis. Stepwise multivariate Cox proportional hazards analysis established an immune-related prognostic signature consisting of SLC10A2, FGF2, CCL28, NDRG1, ESM1, UCN, UTS2 and TRDC. The predictive ability of this signature for 3- and 5-year overall survival was determined using receiver operating characteristics (ROC), and the respective areas under the curve (AUC) were 79.2% and 76.6%. The signature showed moderate predictive accuracy in the validation and GSE38832 data sets as well. Furthermore, the 8-IRG signature correlated significantly with tumour stage, invasion, lymph node metastasis and distant metastasis by univariate Cox analysis, and was established an independent prognostic factor by multivariate Cox regression analysis for CRC. Gene set enrichment analysis (GSEA) revealed a relationship between the IRG prognostic signature and various biological pathways. Focal adhesions and ECM-receptor interactions were positively correlated with the risk scores, while cytosolic DNA sensing and metabolism-related pathways were negatively correlated. Finally, the bioinformatics results were validated by real-time RT-qPCR. In conclusion, we identified and validated a novel, immune-related prognostic signature for patients with CRC, and this signature reflects the dysregulated tumour immune microenvironment and has a potential for better CRC patient management.
TPS277 Background: Neoadjuvant hormonal therapy (NHT) serves as the primary treatment approach for metastatic hormone-sensitive prostate cancer (mHSPC) by either inhibiting androgen synthesis or blocking androgen receptor binding, thereby suppressing tumor growth. Despite its effectiveness, patients with mHSPC inevitably develop resistance to NHT over time, advancing to metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis. Androgen synthesis and secretion exhibit a prominent circadian rhythm, with accelerated synthesis in the early morning, peaking around 8:00 AM, followed by a decline to nadir by approximately 8:00 PM. Administrating NHT agents during nighttime may enhance therapeutic efficacy by preemptively inhibiting androgen synthesis and receptor binding before the peak secretion period. Consequently, we have designed a prospective study to evaluate and compare the efficacy and safety of daytime versus nighttime administration of NHT agents in patients with mHSPC. Methods: This prospective, open-label, phase II study will enroll 70 patients with mHSPC. Key eligibility criteria include histologically or pathologically confirmed prostate cancer, classified as mHSPC, without prior NHT or chemotherapy. Patients currently receiving other systemic antitumor therapies, those who have undergone organ transplantation within the past 3 months, or been diagnosed with autoimmune disease will be excluded. Eligible patients will be randomized in a 1:1 ratio to receive NHT agents either between 7:00 and 9:00 AM or between 10:00 and 12:00 PM. Treatment is continued until disease progression. The primary objective is to evaluate the effect of nighttime administration of NHT agents by assessing PSA response rate (PSA-RR), defined as the proportion of patients achieving > 90% reduction in PSA from baseline after 3 months of NHT. Secondary endpoints include circulating tumor cell (CTC) clearance rate, clinical benefit rate, objective response rate (ORR), duration of response (DoR), time to objective response, radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Differences in response rates between the 2 groups will be analyzed using the Chi-square test. Survival endpoints will be estimated using the Kaplan-Meier method, with between-group comparisons conducted by the log-rank test. Currently, 14 of a planned total of 70 participants have been enrolled. Clinical trial information: NCT06505278 .
Background and purpose Pyroptosis is a form of programmed cell death, which plays an important role in tumorigenesis, progression, and regulation of the tumor microenvironment. It can affect lung adenocarcinoma (LUAD) progression. This study aimed to construct a pyroptosis-related mRNA prognostic index (PRMPI) for LUAD and clarify the tumor microenvironment infiltration characterization of LUAD. Materials and methods We performed a univariate Cox regression analysis for pyroptosis-related mRNAs in the TCGA cohort. Then, we used LASSO Cox regression to establish a PRMPI. The quantitative real time polymerase chain reaction (qRT-PCR) was used to quantify the relative expression of pyroptosis-related mRNAs. The CPTAC cohort was used to confirm the stability and wide applicability of the PRMPI. The single-sample gene set enrichment analysis (ssGSEA) was performed to assess the tumor microenvironment infiltration characterization. Results A total of 36 pyroptosis-related mRNAs were identified. The PRMPI was established based on five pyroptosis-related mRNAs. The expression patterns of these mRNAs were verified in LUAD samples from our medical center by qRT-PCR. High-PRMPI patients had worse overall survival than low-PRMPI patients. The result was validated in the CPTAC cohort. The comprehensive analysis indicated that the high-PRMPI patients exhibited lower immune activity, more aggressive immunophenotype, lower expression of immune checkpoint molecule, higher TP53 mutation rate, and higher tumor stemness than low-PRMPI patients. Low-PRMPI patients may be more sensitive to immunotherapy, while high-PRMPI patients may benefit more from chemotherapy and targeted therapy. Conclusions The PRMPI may be a promising biomarker to predict the prognosis, tumor microenvironment infiltration characterization, and the response to adjuvant therapy in LUAD.
Circular ribonucleic acids (circRNAs) play a key role in the development of different types of cancer. Ferroptosis is a type of programmed cell death that contributes to cancer progression. However, the role of circRNAs in lung adenocarcinoma (LUAD) ferroptosis remains unclear.The gene expression levels of circRNA P4HB (circP4HB), microRNA-1184 (miR-1184) and Solute carrier family 7 member 11 (Slc7a11), also known as Xct were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Ferroptosis of established LUAD cells was induced by erastin. Cell viability was examined via Cell Counting Kit 8 assays. Ferroptosis was evaluated by malondialdehyde (MDA), Prostaglandin-endoperoxide Synthase 2 (Ptgs2), lipid reactive oxygen species (lipid ROS), and JC-1 detection. The mechanism of circP4HB/miR-1184/SLC7A11 was investigated by luciferase reporter assays, RNA immunoprecipitation, RNA pull-down, and western blot assays. A functional for circP4HB in vivo was determined using xenograft nude mice models.CircP4HB expression levels were increased in LUAD. It triggered glutathione (GSH) synthesis and, therefore protected LUAD cells from ferroptosis induced by erastin. CircP4HB may function as a competing endogenous RNA by modulating miR-1184 to regulate SLC7A11. CircP4HB inhibited ferroptosis by regulating miR-1184/ SLC7A11-mediated GSH synthesis. In vivo, overexpression of circP4HB promoted tumor growth and inhibited ferroptosis.The circRNA, circP4HB acts as a novel ferroptosis suppressor in LUAD. Furthermore, circP4HB protects LUAD from ferroptosis via modulation of the miR-1184/SLC7A11 axis. Our findings identified circP4HB as a novel biomarker in LUAD and warrants further investigation in the early diagnosis and treatment of LUAD.
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