The implications of single-cell RNA-seq analysis in prostate cancer: unraveling tumor heterogeneity, therapeutic implications and pathways towards personalized therapy.

In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments in the current era, particularly the emerging integration of single-cell and spatiotemporal transcriptomics, have enabled a detailed molecular comprehension of the complex regulation of cell fate. The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine. Currently, single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors. Starting from the perspective of RNA sequencing technology, this review outlined the significance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, encompassing preclinical medicine and clinical applications. We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies, as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis, treatment, and drug resistance characteristics of prostate cancer. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer. Furthermore, we explore the potential clinical applications stemming from other single-cell technologies in this review, paving the way for future research in precision medicine.

Chronobiology of the Tumor Microenvironment: Implications for Therapeutic Strategies and Circadian-Based Interventions.

Numerous research works have emphasized the critical role that circadian rhythm plays in the tumor microenvironment (TME). The goal of clarifying chrono-pharmacological strategies for improving cancer treatment in clinical settings is a continuous endeavor. Consequently, to enhance the use of time-based pharmaceutical therapies in oncology, combining existing knowledge on circadian rhythms' roles within the TME is essential. This perspective elucidates the functions of circadian rhythms in the TME across various stages of cancer development, progression, and metastasis. Specifically, aging, angiogenesis, and inflammation are implicated in modulating circadian rhythm within the TME. Furthermore, circadian rhythm exerts a profound influence on current cancer treatments and thereby generates chronotheray to manage tumors. From a TME perspective, circadian rhythm offers promising opportunities for cancer prevention and treatment; nevertheless, further study is needed to address unanswered scientific problems.

Identification of senescence-related lncRNA prognostic index correlating with prognosis and radiosensitivity in prostate cancer patients.

BACKGROUND: An increasing number of studies are shown how crucial a role cellular senescence plays in tumor development. In this study, we developed a senescence-related lncRNA prognostic index (SRLPI) to forecast radiosensitivity and the probability of biochemical recurrence (BCR) in patients with prostate cancer (PCa). METHODS: PCa cohorts in TCGA and GEO databases were downloaded. Senescence-and prognosis-related lncRNA with differential expression in tumor and normal samples were identified and used to establish the SRLPI score. Mutation landscape, function pathway, tumor stemness and heterogeneity and tumor immune microenvironment were also analyzed. We performed the analysis using R 3.6.3 and the appropriate tools. RESULTS: A SRLPI score was constructed based on SNHG1 and MIAT in the TCGA cohort. Our classification of PCa patients into high- and low-risk groups was based on the median SRLPI score. When compared to the low-SRLPI group, the high-SRLPI group was more vulnerable to BCR (HR: 3.33). In terms of BCR-free survival and metastasis-free survival, the GSE116918 showed similar findings. Surprisingly, the SRLPI score demonstrated a high level of radiosensitivity for diagnosis (AUC: 0.98). Age, Gleason score, T stage, N stage, positive lymph nodes, and residual tumor were all significantly greater in patients with high SRLPI scores. Furthermore, this score was significantly related to markers of senescence. Protein secretion and androgen response were found to be substantially enriched in the low-SRLPI group, whereas E2F targets were found to be strongly enriched in the high-SRLPI group for pathway analysis. For the tumor microenvironment assessment, B cells, CD8+ T cells, immune score and TIDE score were positively related to SRLPI score while endothelial level was negatively associated with SRLPI score with statistical significance. CONCLUSIONS: We developed a SRLPI score that was related to prognosis and radiosensitivity and might be helpful in clinical practice.

Prolyl 4-hydroxylase subunit beta (P4HB) could serve as a prognostic and radiosensitivity biomarker for prostate cancer patients.

BACKGROUND: Prolyl 4-hydroxylase subunit beta (P4HB) has been reported as a suppressor in ferroptosis. However, no known empirical research has focused on exploring relationships between P4HB and prostate cancer (PCa). In this research, we initially examine the function of P4HB in PCa by thorough analysis of numerous databases and proliferation experiment. METHODS: We analyzed the correlations of P4HB expression with prognosis, clinical features, mutation genes, tumor heterogeneity, stemness, tumor immune microenvironment and PCa cells using multiple databases and in vitro experiment with R 3.6.3 software and its suitable packages. RESULTS: P4HB was significantly upregulated in tumor tissues compared to normal tissues and was closely related to biochemical recurrence-free survival. In terms of clinical correlations, we found that higher P4HB expression was significantly related to older age, higher Gleason score, advanced T stage and residual tumor. Surprisingly, P4HB had highly diagnostic accuracy of radiotherapy resistance (AUC 0.938). TGF beta signaling pathway and dorso ventral axis formation were upregulated in the group of low-expression P4HB. For tumor stemness, P4HB expression was positively related to EREG.EXPss and RNAss, but was negatively associated with ENHss and DNAss with statistical significance. For tumor heterogeneity, P4HB expression was positively related to MATH, but was negatively associated with tumor ploidy and microsatellite instability. For the overall assessment of TME, we observed that P4HB expression was negatively associated with all parameters, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, stromal score, immune score and ESTIMATE score. Spearman analysis showed that P4HB expression was negatively related to TIDE score with statistical significance. In vitro experiment, RT-qPCR and western blot showed that three siRNAs of P4HB were effective on the knockdown of P4HB expression. Furthermore, we observed that the downregulation of P4HB had significant influence on the cell proliferation of six PCa cell lines, including LNCap, C4-2, C4-2B, PC3, DU145 and 22RV1 cells. CONCLUSIONS: In this study, we found that P4HB might serve as a prognostic biomarker and predict radiotherapy resistance for PCa patients. Downregulation of P4HB expression could inhibit the cell proliferation of PCa cells.

M7G-related molecular subtypes can predict the prognosis and correlate with immunotherapy and chemotherapy responses in bladder cancer patients.

BACKGROUND: N7-methylguanosine (m7G) is closely associated with tumor prognosis and immune response in many cancer types. The correlation between m7G and bladder cancer (BC) needs further study. We aimed to orchestrate molecular subtypes and identify key genes for BC from the perspective of m7G. METHODS: RNA-seq and clinical data of BC patients were extracted from TCGA and GSE13507 datasets. The patients were subtyped by "ConsensusClusterPlus" and "limma." The clusters were validated by the Kaplan‒Meier curves, univariable and multivariate Cox regression models, the concordance index, and calibration curves. The immunotherapy response was evaluated by immune checkpoints, immune infiltration, TIDE score, and IMvigor210 cohort. Genomics of Drug Sensitivity in Cancer was utilized to predict the chemotherapy response between the clusters. RESULTS: The m7G-related cluster was ultimately established by EIF4G1, NUDT11, NUDT10, and CCNB1. The independent prognostic value of the m7G-related cluster was validated by the TCGA and GSE13507 datasets. The cluster was involved in immune-associated pathways, such as neutrophil degranulation, antigen processing cross-presentation, and signaling by interleukins pathways. Meanwhile, cluster 2 was positively correlated with many immune checkpoints, such as CD274, CTLA4, HAVCR2, LAG3, PDCD1, and PDCD1LG2. The cluster 2 was significantly correlated with a higher TIDE score than the cluster 1. Furthermore, in the IMvigor210 cohort, patients in the cluster 1 had a higher response rate than those in the cluster 2. Patients in the cluster 2 were sensitive to many chemotherapies. CONCLUSIONS: We successfully determined molecular subtypes and identified key genes for BC from the perspective of m7G, thereby providing a roadmap for the evolution of immunotherapy and precision medicine.

Immune-related gene index predicts metastasis for prostate cancer patients undergoing radical radiotherapy.

In this study, we established a novel immunologic gene prognostic index (IGPI) to predict metastasis and provided new insights into tumor immune microenvironment (TIME) for PCa patients receiving radical radiotherapy. GBP2 and IGF1 were independent factors associated with metastasis-free survival. IGPI score was calculated based on GBP2 and IGF1 and this score was an independent risk factor for PCa patients undergoing radical radiotherapy. Patients with higher IGPI score were at higher risk of metastasis and biochemical recurrence, which were externally validated in the TCGA database and other GEO datasets. IGPI score had demonstrated moderate diagnostic ability of radiation resistance (AUC: 0.889). This score increased with the augment of Gleason score and T stage, as well as biochemical recurrence. Using EPIC, ESTIMATE and immunophenoscore (IPS) algorithms, cancer associated fibroblasts (CAFs), macrophages, stromal score, and estimate score were significantly higher in patients with metastasis group compared to their counterpart. Besides, for CAFs, macrophages, stromal score, and estimate score, patients with higher scores were at higher risk of metastasis, and the HRs were 3.65, 4.01, 4.27, and 3.78, respectively. IGPI score was highly positively associated with stromal score (coefficient: 0.39), immune score (coefficient: 0.43), estimate score (coefficient: 0.45), CAFs (coefficient: 0.42) and macrophages (coefficient: 0.42), while showing the opposite relationship with tumor purity (coefficient: - 0.45). In conclusion, we found that IGPI based on GBP2 and IGF1 might serve as a biomarker predicting metastasis for PCa patients. Besides, the current data further highlight the importance of CAFs in the metastatic process of PCa.

Pyroptosis in urinary malignancies: a literature review.

Urinary neoplasms refer to malignant tumours occurring in any part of the urinary system, including the kidney, renal pelvis, ureter, bladder, prostate, etc. The worldwide incidence of urinary system tumours has been increasing yearly. Available methods include surgical treatment, radiotherapy, chemotherapy, endocrine therapy, molecular targeted therapy, and immune therapy. In recent years, emerging evidence has demonstrated that cell pyroptosis plays an important role in the occurrence and progression of malignant urinary tumours. Pyroptosis is a new type of cell death that involves inflammatory processes regulated by gasdermins (GSDMs) and is characterized by membrane perforation, cell swelling and cell rupture. Recent studies have shown that pyroptosis can inhibit and promote the development of tumours. This manuscript reviews the role of pyroptosis in the development and progression of prostate cancer, kidney cancer and bladder cancer and introduces the latest research results in these fields to discuss the therapeutic potential of the pyroptosis pathway in urinary malignancies.

An autophagy-related gene prognostic index predicting biochemical recurrence, metastasis, and drug resistance for prostate cancer.

Given the dual role of autophagy presenting in tumorigenesis and inhibition, we established an autophagy-related gene prognostic index (ARGPI) with validation to well predict the biochemical recurrence (BCR), metastasis, as well as chemoresistance for patients with prostate cancer (PCa) who underwent radical radiotherapy or prostatectomy. Then, Lasso and COX regression was used to develop the ARGPI. We performed the whole analyses through R packages (version 3.6.3). Secreted phosphoprotein 1 (SPP1), single-minded 2 (SIM2), serine protease inhibitor b5 (SERPINB5), aldehyde dehydrogenase 2 (ALDH2), and acyl-CoA synthetase long-chain 3 (ACSL3) were eventually used to establish the ARGPI score. Patients were divided into two different-risk groups based on the median ARGPI score, high-risk patients with a higher risk of BCR than low-risk patients (hazard ratio [HR]: 5.46, 95% confidence interval [CI]: 3.23-9.24). The risk of metastasis of high-risk patients was higher than low-risk patients (HR: 11.31, 95% CI: 4.89-26.12). In The Cancer Genome Atlas (TCGA) dataset, we observed similar prognostic value of ARGPI in terms of BCR-free survival (HR: 1.79, 95% CI: 1.07-2.99) and metastasis-free survival (HR: 1.80, 95% CI: 1.16-2.78). ARGPI score showed a diagnostic accuracy of 0.703 for drug resistance. Analysis of gene set enrichment analysis (GSEA) indicated that patients in the high-risk group were significantly positively related to interleukin (IL)-18 signaling pathway. Moreover, ARGPI score was significantly related to cancer-related fibroblasts (CAFs; r = 0.36), macrophages (r = 0.28), stromal score (r = 0.38), immune score (r = 0.35), estimate score (r = 0.39), as well as tumor purity (r = -0.39; all P < 0.05). Drug analysis showed that PI-103 was the common sensitive drug and cell line analysis indicated that PC3 was the common cell line of PI-103 and the definitive gene. In conclusion, we found that ARGPI could predict BCR, metastasis, and chemoresistance in PCa patients who underwent radical radiotherapy or prostatectomy.

Circadian rhythm in prostate cancer: time to take notice of the clock.

The circadian clock is an evolutionary molecular product that is associated with better adaptation to changes in the external environment. Disruption of the circadian rhythm plays a critical role in tumorigenesis of many kinds of cancers, including prostate cancer (PCa). Integrating circadian rhythm into PCa research not only brings a closer understanding of the mechanisms of PCa but also provides new and effective options for the precise treatment of patients with PCa. This review begins with patterns of the circadian clock, highlights the role of the disruption of circadian rhythms in PCa at the epidemiological and molecular levels, and discusses possible new approaches to PCa therapy that target the circadian clock.

Identification of senescence-related molecular subtypes and key genes for prostate cancer.

We identified distinct senescence-related molecular subtypes and critical genes among prostate cancer (PCa) patients undergoing radical prostatectomy (RP) or radical radiotherapy (RT). We conducted all analyses using R software and its suitable packages. Twelve genes, namely, secreted frizzled-related protein 4 (SFRP4), DNA topoisomerase II alpha (TOP2A), pleiotrophin (PTN), family with sequence similarity 107 member A (FAM107A), C-X-C motif chemokine ligand 14 (CXCL14), prostate androgen-regulated mucin-like protein 1 (PARM1), leucine zipper protein 2 (LUZP2), cluster of differentiation 38 (CD38), cartilage oligomeric matrix protein (COMP), vestigial-like family member 3 (VGLL3), apolipoprotein E (APOE), and aldehyde dehydrogenase 2 family member (ALDH2), were eventually used to subtype PCa patients from The Cancer Genome Atlas (TCGA) database and GSE116918, and the molecular subtypes showed good correlations with clinical features. In terms of the tumor immune environment (TME) analysis, compared with cluster 1, cancer-associated fibroblasts (CAFs) scored significantly higher, while endothelial cells scored lower in cluster 2 in TCGA database. There was a statistically significant correlation between both CAFs and endothelial cells with biochemical recurrence (BCR)-free survival for PCa patients undergoing RP. For the GSE116918 database, cluster 2 had significantly lower levels of CAFs and tumor purity and higher levels of stromal, immune, and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) scores than cluster 1; in addition, patients with high levels of CAFs, stromal scores, immune scores, and ESTIMATE scores and low levels of tumor purity tended to suffer from BCR. Based on the median of differentially expressed checkpoints, high expression of CD96, hepatitis A virus cellular receptor 2 (HAVCR2), and neuropilin 1 (NRP1) in GSE116918 and high expression of CD160 and tumor necrosis factor (ligand) superfamily member 18 (TNFSF18) in TCGA database were associated with a significantly higher risk of BCR than their counterparts. In conclusion, we first constructed distinct molecular subtypes and critical genes for PCa patients undergoing RP or RT from the fresh perspective of senescence.

A pan-cancer analysis of the oncogenic role of zinc finger protein 419 in human cancer.

Background: As a ferroptosis-related gene, the polymorphism of zinc finger protein 419 (ZNF419) at the splice donor site may generate renal cell carcinoma-associated novel minor histocompatibility antigen ZAPHIR. However, the role of ZNF419 in prognosis and immunology in human tumors remains largely unknown. This study aimed to visualize the prognostic landscape of ZNF419 at pan-cancer level and explore the relationship between ZNF419 expression and the tumor immune microenvironment. Method: Pan-cancer and mutation data were downloaded from TCGA databases and analyzed through R (version 3.6.4) and its suitable packages. Differential ZNF419 expression and prognosis were analyzed. Correlations with ferroptosis-related genes, pathway analysis, tumor stemness, heterogeneity, mutation landscape, and RNA modifications were also explored. The relationships between ZNF419 expression and tumor immunity were investigated through the TIMER and ESTIMATE methods. Result: ZNF419 was differentially expressed between tumor and normal samples and was associated with overall survival, disease-specific survival and progression-free interval for STES, KIRC, LIHC, LUSC, PRAD, and BLCA. We found the interaction between ZNF419 and FANCD2 might involve in ferroptosis in pan-cancer level. In addition, the mutation frequencies of STES, KIRC, LIHC, LUSC, PRAD, and BLCA were 1.5%, 0.3%, 0.3%, 1.9%, 0.2%, and 0.7%, respectively. We detected that the expression of ZNF419 was closely correlated with most immune checkpoint genes and immune regulatory genes. Furthermore, we found that the ZNF419 expression level was negatively related to the immune score in the six cancers mentioned above. The expression of ZNF419 was significantly associated with various infiltrating immune cells, such as CD4+ T cells, CD8+ T cells, and macrophages in patients with KIRC, PRAD, and LUSC but was only significantly related to macrophages in BLCA patients. Conclusion: ZNF419 might serve as a potential prognostic and immunological pan-cancer biomarker, especially for KIRC, LIHC, LUSC, PRAD, and BLCA.

Spindle and kinetochore-associated complex subunit 3 could serve as a prognostic biomarker for prostate cancer.

Spindle and kinetochore-associated complex subunit 3 (SKA3) is a microtubule-binding subcomplex of the outer kinetochore that is required for proper chromosomal segregation and cell division. However, little is known regarding the probable mechanism of SKA3, particularly in terms of prostate cancer (PCA) progression. Multiple databases, including TCGA and GTEx, were utilized to examine the expression of SKA3 in PCA patients and to shed light on the clinical significance and potential mechanism of SKA3 in the onset and progression of PCA. The biological function of SKA3 was evaluated in vitro using RT-qPCR and the CCK8 assay. For statistical analysis, the R 3.6.3 software and its associated packages were utilized. SKA3 was shown to be considerably elevated in PCA patients and was linked to a shorter progress free interval (PFI). Furthermore, we discovered that SKA3 mRNA expression was higher in PCA cells than in normal cells, and inhibition of SKA3 could clearly reduce PCA cell proliferation using the CCK8 assay. Finally, SKA3 could be used as a predictive biomarker in PCA patients.

Leucine zipper protein 2 serves as a prognostic biomarker for prostate cancer correlating with immune infiltration and epigenetic regulation.

Background: We sought to determine whether leucine zipper protein 2 (LUZP2) could benefit men with prostate cancer (PCa) undergoing radical radiotherapy (RT) or prostatectomy (RP). Methods: Analysis was done on differentiating expression, clinical prognosis, co-expressed genes, immune infiltration, and epigenetic changes. All of our analyses were done using the R software (version 3.6.3) and the appropriate packages. Results: In terms of PCa, tumor samples expressed LUZP2 more than normal samples did. In the TCGA database and GSE116918, we found that LUZP2 was the only independent risk factor for PCa. The shared enriched pathways for patients undergoing RP or RT were cell-cell adhesion, regulation of filopodium assembly, and extracellular matrix containing collagen. With the exception of TNFRSF14, we discovered that LUZP2 was negatively correlated with 21 immune checkpoints in PCa patients receiving RT. We found a significant inverse relationship between LUZP2 expression and the tumor immune environment, which included B cells, CD4+ T cells, neutrophils, macrophages, dendritic cells, stromal score, immune score, and estimate score, in patients receiving RP or RT. Additionally, tumor purity was positively correlated with LUZP2. We found that the drug bortezomib may be susceptible to the LUZP2. DNA methylation was significantly associated with the mRNA expression of LUZP2 in PCa patients from the TCGA database, and LUZP2 methylation was positively correlated with immune cells. The proliferative activity of various PCa cells, which correlated to different stages of this disease, was also found to be significantly reduced by LUZP2 reduction, according to the results of our experimental work. Conclusions: We proposed a relatively comprehensive understanding of the roles of LUZP2 on PCa from the fresh perspective of senescence.

A pan-cancer analysis of the oncogenic role of leucine zipper protein 2 in human cancer.

In this study, we aimed to perform a pan-cancer analysis of leucine zipper protein 2 (LUZP2). A standardized TCGA pan-cancer dataset was downloaded. Differential expression, clinical prognosis, genetic mutations, immune infiltration, epigenetic modifications, tumor stemness and heterogeneity were analyzed. We conducted all analyses through software R 3.6.3 and its suitable packages. Compared to normal samples, we observed that the LUZP2 mRNA expression was significantly upregulated in LGG, PRAD, LUSC and downregulated in KIRC and other eleven cancer species patients. In terms of overall survival, low-expression of LUZP2 was significantly associated with poor prognosis in lower grade glioma (LGG), lung squamous cell carcinoma (LUSC), kidney renal clear cell carcinoma (KIRC) and prostate adenocarcinoma (PRAD). For progression-free survival, we observed that downregulation of LUZP2 was significantly related to LGG, KIRC, LUSC, and PRAD. Our results observed negative correlations of the stemness of LGG and PRAD with the mRNA expression of LUZP2, whose downregulation was closely associated with poor prognosis. The mutation frequencies of LGG, PRAD, KIRC, and LUSC were 0.4%, 0.4%, 0.3%, and 2.1%, respectively. We detected that the LUZP2 level was negatively associated with TILs in most cancers, including LGG, LUSC, PRAD, and KIRC, while the LUZP2 methylation showed the opposite results. In conclusion, the results of our initial pan-cancer investigation provided a somewhat thorough understanding of the functions of LUZP2 on KIRC, LGG, PRAD, and LUSC.

A cellular senescence-related gene prognostic index for biochemical recurrence and drug resistance in patients with prostate cancer.

In this study, we aimed to establish a novel cellular senescence-related gene prognostic index (CSG PI) to predict biochemical recurrence (BCR) and drug resistance in patients with prostate cancer (PCa) undergoing radical radiotherapy or prostatectomy. We performed all analyses using R version 3.6.3 and its suitable packages. Cytoscape 3.8.2 was used to establish a network of transcription factors and competing endogenous RNAs. Three cellular senescence-related genes were used to establish the CSGPI. We observed that CSGPI was an independent risk factor for BCR in PCa patients (HR: 2.62; 95% CI: 1.55-4.44), consistent with the results of external validation (HR: 1.88; 95% CI: 1.12-3.14). The CSGPI had a moderate diagnostic effect on drug resistance (AUC: 0.812, 95% CI: 0.586-1.000). The lncRNA PART1 was significantly associated with BCR (HR: 0.46; 95% CI: 0.27-0.77), and might modulate the mRNA expression of definitive genes through interactions with 57 miRNAs. Gene set enrichment analysis indicated that CSGPI was closely related to ECM receptor interaction, focal adhesion, TGF beta signaling pathway, pathway in cancer, regulation of actin cytoskeleton, and so on. Immune checkpoint analysis showed that PDCD1LG2 and CD96 were significantly higher in the BCR group compared to non-BCR group, and patients with higher expression of CD96 were more prone to BCR than their counterparts (HR: 1.79; 95% CI: 1.06-3.03). In addition, the CSGPI score was significantly associated with the mRNA expression of HAVCR2, CD96, and CD47. Analysis of mismatch repair and methyltransferase genes showed that DNMT3B was more highly expressed in the BCR group and that patients with higher expression of DNMT3B experienced a higher risk of BCR (HR: 2.08; 95% CI: 1.23-3.52). We observed that M1 macrophage, CD8+ T cells, stromal score, immune score, and ESTIMATE score were higher in the BCR group. In contrast, tumor purity was less scored in the BCR group. Spearman analysis revealed a positive relationship between CSGPI and M1 macrophages, CD4+ T cells, dendritic cells, stromal score, immune score, and ESTIMATE score. In conclusion, we found that the CSGPI might serve as a biomarker to predict BCR and drug resistance in PCa patients. Moreover, CD96 and DNMT3B might be potential treatment targets, and immune evasion might contribute to the BCR process of PCa.

Mitochondrial Aldehyde Dehydrogenase 2 Represents a Potential Biomarker of Biochemical Recurrence in Prostate Cancer Patients.

BACKGROUND: We aimed to explore the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in prostate cancer (PCa) patients and provide insights into the tumor immune microenvironment (TME) for those patients undergoing radical radiotherapy. METHODS: We performed all analyses using R version 3.6.3 and its suitable packages. Cytoscape 3.8.2 was used to establish network of competing endogenous RNAs (ceRNAs). RESULTS: Downregulation of ADLH2 was significantly associated with higher risk of BCR-free survival (HR: 0.40, 95%CI: 0.24-0.68, p = 0.001) and metastasis-free survival (HR: 0.21, 95%CI: 0.09-0.49, p = 0.002). Additionally, ALDH2 repression contributed to significantly shorter BCR-free survival in the TCGA database (HR: 0.55, 95%CI: 0.33-0.93, p = 0.027). For immune checkpoints, patients that expressed a higher level of CD96 had a higher risk of BCR than their counterparts (HR: 1.79, 95%CI: 1.06-3.03, p = 0.032), as well as NRP1 (HR: 2.18, 95%CI: 1.29-3.69, p = 0.005). In terms of the TME parameters, the spearman analysis showed that ALDH was positively associated with B cells (r: 0.13), CD8+ T cells (r: 0.19), neutrophils (r: 0.13), and macrophages (r: 0.17). Patients with higher score of neutrophils (HR: 1.75, 95%CI: 1.03-2.95, p = 0.038), immune score (HR: 1.92, 95%CI: 1.14-3.25, p = 0.017), stromal score (HR: 2.52, 95%CI: 1.49-4.26, p = 0.001), and estimate score (HR: 1.81, 95%CI: 1.07-3.06, p = 0.028) had higher risk of BCR than their counterparts. Our ceRNA network found that PART1 might regulate the expression of ALDH via has-miR-578 and has-miR-6833-3p. Besides, PHA-793887, PI-103, and piperlongumine had better correlations with ALDH2. CONCLUSIONS: We found that ALDH2 might serve as a potential biomarker predicting biochemical recurrence for PCa patients.

The Potential Role of Mitochondrial Acetaldehyde Dehydrogenase 2 in Urological Cancers From the Perspective of Ferroptosis and Cellular Senescence.

Overproduction of reactive oxygen species (ROS) and superlative lipid peroxidation promote tumorigenesis, and mitochondrial aldehyde dehydrogenase 2 (ALDH2) is associated with the detoxification of ROS-mediated lipid peroxidation-generated reactive aldehydes such as 4-hydroxy-2-nonenal (4-HNE), malondialdehyde, and acrolein due to tobacco smoking. ALDH2 has been demonstrated to be highly associated with the prognosis and chemoradiotherapy sensitivity of many types of cancer, including leukemia, lung cancer, head and neck cancer, esophageal cancer, hepatocellular cancer, pancreatic cancer, and ovarian cancer. In this study, we explored the possible relationship between ALDH2 and urological cancers from the aspects of ferroptosis, epigenetic alterations, proteostasis, mitochondrial dysfunction, and cellular senescence.