Objective： To investigate the relationship between the lipid metabolism-related gene sterol carrier protein 2(SCP2) and prostate cancer (PCa) from a multi-omics perspective using single-cell transcriptomes combined with Mendelian randomization. Methods： Single-cell transcriptome data of benign and malignant prostate tissues were obtained from GSE120716, GSE157703 and GSE141445 datasets, respectively. Integration, quality control and annotation were performed on the data to categorize the epithelial cells into high and low SCP2 expression groups, followed by further differential and trajectory analyses. Single nucleotide polymorphism (SNP) data for SCP2 expression quantitative trait loci (eQTL) were subsequently downloaded from Genotype-Tissue Expression (GTEx) and investigated from the PCa Society Cancer-Related Genomic Alteration Panel for the Investigation of Cancer-Related Alterations (PRACTICAL) to obtain PCa outcome data for Mendelian randomization analysis to validate the causal relationship between SCP2 and PCa. Results： High SCP2-expressing epithelial cells had higher energy metabolism and proliferation capacity with low immunotherapy response and metastatic tendency. Trajectory analysis showed that epithelial cells with high SCP2 expression may have a higher degree of malignancy, and SCP2 may be a key marker gene for differentiation of malignant epithelial cells in the prostate. Further Mendelian randomization results showed a significant causal relationship between SCP2 and PCa development (OR=1.045, 95% CI: 1.010 －1.083, P=0.011). Conclusion： By combining single-cell transcriptome and Mendelian randomization, the role of the lipid metabolism-related gene SCP2 in PCa development has been confirmed, and new targets and therapeutic directions for PCa treatment have been provided.
Humans ; Prostatic Neoplasms/genetics* ; Male ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Single-Cell Analysis ; Sequence Analysis, RNA ; Carrier Proteins/genetics* ; Transcriptome ; Lipid Metabolism

BACKGROUND: At present, biopsy is essential for the diagnosis of prostate cancer (PCa) before radical prostatectomy (RP). However, with the development of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) and multiparametric magnetic resonance imaging (mpMRI), it might be feasible to avoid biopsy before RP. Herein, we aimed to explore the feasibility of avoiding biopsy before RP in patients highly suspected of having PCa after assessment of PSMA PET/CT and mpMRI. METHODS: Between December 2017 and April 2022, 56 patients with maximum standardized uptake value (SUVmax) of ≥4 and Prostate Imaging Reporting and Data System (PI-RADS) ≥4 lesions who received RP without preoperative biopsy were enrolled from two tertiary hospitals. The consistency between clinical and pathological diagnoses was evaluated. Preoperative characteristics were compared among patients with different pathological types, T stages, International Society of Urological Pathology (ISUP) grades, and European Association of Urology (EAU) risk groups. RESULTS: Fifty-five (98%) patients were confirmed with PCa by pathology, including 49 (89%) with clinically significant prostate cancer (csPCa, defined as ISUP grade ≥2 malignancy). One patient was diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN). CsPCa patients, compared with clinically insignificant prostate cancer (cisPCa) and HGPIN patients, were associated with a higher level of prostate-specific antigen (22.9 ng/mL vs . 10.0 ng/mL, P = 0.032), a lower median prostate volume (32.2 mL vs . 65.0 mL, P = 0.001), and a higher median SUVmax (13.3 vs . 5.6, P <0.001). CONCLUSIONS It might be feasible to avoid biopsy before RP for patients with a high probability of PCa based on PSMA PET/CT and mpMRI. However, the diagnostic efficacy of csPCa with PI-RADS ≥4 and SUVmax of ≥4 is inadequate for performing a procedure such as RP. Further prospective multicenter studies with larger sample sizes are necessary to confirm our perspectives and establish predictive models with PSMA PET/CT and mpMRI.
Humans ; Male ; Prostatectomy/methods* ; Prostatic Neoplasms/diagnosis* ; Middle Aged ; Aged ; Positron Emission Tomography Computed Tomography/methods* ; Biopsy ; Multiparametric Magnetic Resonance Imaging ; Prostate-Specific Antigen/metabolism*

BACKGROUND: Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer. METHODS: A total of 142 pairs of tumor and adjacent formalin-fixed paraf-fin-embedded tissue samples from patients with prostate cancer were collected from the Pathology Department at Sun Yat-sen Memorial Hos-pital. LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo . Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes. RESULTS: LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo . LGR5 promoted the phosphorylation of glycogen synthase kinase-3β (GSK-3β) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/β-catenin signaling pathway. The increased β-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide. CONCLUSIONS LGR5 directly binds to HSP90AB1 and mediates GSK-3β phosphorylation, promoting AR expression by regulating the WNT/β-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.
Male ; Humans ; Phenylthiohydantoin/pharmacology* ; Benzamides ; Receptors, G-Protein-Coupled/genetics* ; Nitriles ; Cell Line, Tumor ; HSP90 Heat-Shock Proteins/metabolism* ; Drug Resistance, Neoplasm/genetics* ; Prostatic Neoplasms/drug therapy* ; beta Catenin/metabolism* ; Receptors, Androgen/genetics* ; Animals ; Mice ; Wnt Signaling Pathway/physiology*

Prostate cancer(PCa) is a common malignant tumor among elderly men, with high incidence and mortality rates worldwide, posing a serious threat to human health. Traditional treatments face limitations, highlighting the urgent need for novel therapeutic strategies. Recent studies on the regulatory mechanisms of micro ribonucleic acid(microRNA, miRNA) in tumor development has identified miRNA as new targets for PCa diagnosis and treatment. Traditional Chinese medicine(TCM), with its multi-mechanism, multi-target, and multi-pathway regulatory properties, shows promising potential in miRNA-based PCa therapy. This review summarized recent findings on miRNA' roles in PCa and research progress of TCM intervention and found that a variety of miRNA played important regulatory roles in cell differentiation, proliferation, apoptosis, invasion, metastasis, immune microenvironment, and drug resistance, and their potential as biomarkers for PCa diagnosis, prognosis, and therapy, indicating the potential to be a biomarker for the diagnosis, prognosis evaluation, and treatment of PCa. The review concluded that the active components of TCM(terpenoids, flavonoids, alkaloids, and others) and compounds(Yishen Tonglong Decoction, Shenhu Decoction, Zhoushi Qiling Decoction, Fuzheng Yiliu Decoction, and Qilan Formula) could regulate the expression of their downstream target genes by acting on specific miRNA and affect the above biological behaviors of PCa cells, thus playing a role in the treatment of PCa. This review aims to provide a theoretical basis for miRNA as potential biomarkers and therapeutic targets for PCa and suggest new avenues for further development of targeted therapy strategies against miRNA.
Humans ; MicroRNAs/metabolism* ; Prostatic Neoplasms/metabolism* ; Male ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional ; Animals ; Gene Expression Regulation, Neoplastic/drug effects*

Androgens play an important role in prostate cancer development and progression. Androgen action is mediated through the androgen receptor (AR), a ligand-dependent DNA-binding transcription factor. AR is arguably the most important target for prostate cancer treatment. Current USA Food and Drug Administration (FDA)-approved AR inhibitors target the ligand-binding domain (LBD) and have exhibited efficacy in prostate cancer patients, particularly when used in combination with androgen deprivation therapy. Unfortunately, patients treated with the currently approved AR-targeting agents develop resistance and relapse with castration-resistant prostate cancer (CRPC). The major mechanism leading to CRPC involves reactivation of AR signaling mainly through AR gene amplification, mutation, and/or splice variants. To effectively inhibit the reactivated AR signaling, new approaches to target AR are being actively explored. These new approaches include novel small molecule inhibitors targeting various domains of AR and agents that can degrade AR. The present review provides a summary of the existing FDA-approved AR antagonists and the current development of some of the AR targeting agents.
Humans ; Male ; Androgen Receptor Antagonists/therapeutic use* ; Receptors, Androgen/metabolism* ; Prostatic Neoplasms/drug therapy* ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Signal Transduction/drug effects*

The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms. Testosterone, as one of the most critical sex hormones, is essential for the development of the reproductive system, maintenance of reproductive function, and the overall health of males. The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes. Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis. We also examined the specific effects of these genes on the occurrence, development, and treatment of common male diseases, including late-onset hypogonadism, erectile dysfunction, male infertility, and prostate cancer.
Testosterone/metabolism* ; Humans ; Male ; Circadian Clocks/genetics* ; Circadian Rhythm Signaling Peptides and Proteins/metabolism* ; Circadian Rhythm/physiology* ; Hypogonadism/metabolism* ; Erectile Dysfunction/metabolism* ; Infertility, Male/metabolism* ; Prostatic Neoplasms/metabolism* ; Men's Health

Prostate cancer is one of the most common malignant tumors in men and posing a serious threat to men's health. Detection methods such as prostate-specific antigen (PSA), prostate biopsy, and magnetic resonance imaging are widely used for prostate cancer screening, but they have low specificity, high cost, and significant risks. Therefore, there is an urgent need to develop highly specific, low-cost, easily obtained, stable, and reliable biomarkers, and use them as the basis to establish non-invasive screening and diagnostic methods for prostate cancer. This paper reviewed the recent advances in the use of prostate cancer biomarkers and combined detection methods for prostate cancer diagnosis and prognosis assessment and provides an in-depth analysis and comparison of different biomarkers and combined detection methods, as well as points out the directions and challenges for future research. The paper emphasizes the importance of developing efficient, cost-effective and easy-to-implement biomarkers to increase the early diagnosis rate of prostate cancer, improve patient prognosis, and reduce the waste of healthcare resources. This paper provides an important theoretical basis and technical guidance for early diagnosis, precise treatment and prognostic evaluation of prostate cancer, and has important reference value for promoting clinical research and practice of prostate cancer.
Humans ; Male ; Prostatic Neoplasms/diagnosis* ; Biomarkers, Tumor/blood* ; Early Detection of Cancer/methods* ; Prognosis ; Prostate-Specific Antigen/blood* ; Glutamate Carboxypeptidase II/metabolism* ; Antigens, Neoplasm/blood* ; Antigens, Surface ; Serine Endopeptidases

OBJECTIVE: To investigate the relationship of the expression levels of protein arginine methyltransferase 5 (PRMT5) and Dickkopf-related protein 3 (DKK3) in the PCa tissue with biochemical recurrence (BR) of the malignancy after radical surgery. METHODS: This study included 105 cases of PCa diagnosed in our hospital from January 2016 to December 2020 and, according to BR within 3 years after surgery, we divided them into a BR (n = 22) and a non-BR group (n = 83). We detected the expressions of PRMT5 and DKK3 in the prostate tissues of the patients by immunohistochemistry, analyzed the correlation of the expression levels of PRMT5 and DKK3 using the Spearman method, and conducted a multivariate analysis of postoperative BR of the malignancy using the Cox multivariate regression model. RESULTS: The positive expression of PRMT5 was significantly higher while that of DKK3 remarkably lower in the PCa than in the adjacent tissue (P<0.05). Spearman correlation analysis showed a negative correlation between the expression levels of PRMT5 and DKK3 in the PCa tissue (r = －0.532, P<0.05). The expressions of PRMT5 and DKK3 were significantly associated with tumor-node-metastasis (TNM) stages, positive surgical margins, peripheral nerve invasion, capsular invasion, seminal vesicle invasion and vascular invasion (P<0.05). The percentage of TNM stages III－IV, the positive expression of PRMT5 and the negative expression of DKK3 were remarkably higher in the BR than in the non-BR group (P<0.05). PRMT5 was found to be an independent risk factor for while DKK3 a protective factor against postoperative BR of PCa in the patients (P<0.05). CONCLUSION PRMT5 is highly while DKK3 lowly expressed in PCa tissue, and their expressions are both closely related to the biochemical recurrence of PCa after radical surgery.
Humans ; Male ; Protein-Arginine N-Methyltransferases/metabolism* ; Prostatectomy ; Prostatic Neoplasms/pathology* ; Neoplasm Recurrence, Local ; Adaptor Proteins, Signal Transducing ; Intercellular Signaling Peptides and Proteins/metabolism* ; Middle Aged ; Immunohistochemistry

OBJECTIVE: To investigate the clinicopathological features and prognosis of urinary bladder urothelial carcinoma (UBUC) with incidental prostate cancer (IPCa). METHODS: We retrospectively analyzed the clinicopathological features of 65 cases of UBUC and 38 cases of UBUC + IPCa after radical cystoprostatectomy (RCP) from January 2017 to February 2020. We compared their expressions of the immunohistochemical markers androgen receptor (AR) and (human epidermal growth factor receptor 2,HER2) between the two groups of patients, and analyzed their clinicopathological characteristics by chi-square test and their survival rates using the Kaplan-Meier method and log-rank test. RESULTS: The detection rate of UBUC + IPCa was 16.5%, and that of clinically significant IPCa was 39.5%, with preoperative PSA≥4 μg/L in 23.7% of the patients. Compared with the patients with UBUC, most of the UBUC + IPCa cases had no smoking history (73.8% vs 92.1%, P = 0.024), and fewer had histological variants (43.1% vs 10.5%, P = 0.003). The incidence rate of vascular invasion was significantly higher in the UBUC than in the UBUC + IPCa group (49.2% vs 21.1%, P = 0.005), and so was the rate of advanced cases (67.7% vs 31.6%, P<0.001). In comparison with the patients of the UBUC group, those of the UBUC + IPCa group showed remarkably higher expressions of AR (9.2% vs 31.6%, P = 0.004) and HER2 (43.1% vs 71.1%, P = 0.006). The mean overall survival time was longer in the UBUC + IPCa than in the UBUC group (48.8 mo ［95% CI: 2.5－42.6 mo］ vs 39.9 mo ［95% CI: 2.8－34.5 mo］), but with no statistically significant difference between the two groups (P = 0.608). CONCLUSION Standardized sampling of prostate samples after RCP helps to improve the detection rate of IPCa. Preoperative level of PSA is not a good predictor of IPCa. Few patients with UBUC + IPCa have a history of cigarette smoking, and the predominant histological type of the malignancy is high-grade invasive urothelial carcinoma, which is not significantly different from UBUC in prognosis. The expressions of HER2 and AR are significantly higher in UBUC + IPCa than in UBUC, suggesting that UBUC + IPCa may benefit from HER2- and AR-targeted therapy.
Humans ; Male ; Urinary Bladder Neoplasms/metabolism* ; Receptors, Androgen/metabolism* ; Prostatic Neoplasms/metabolism* ; Retrospective Studies ; Receptor, ErbB-2/metabolism* ; Prognosis ; Middle Aged ; Aged ; Survival Rate ; Prostatectomy

Based on the focal adhesion kinase(FAK)/steroid receptor coactivator(Src)/extracellular regulated protein kinase(ERK) pathway, this study explored the effects of Xihuang Pills on angiogenesis, invasion, and metastasis in prostate cancer. Liquid chromatography-tandem mass spectrometry(LC-MS/MS) was used to analyze and identify the active ingredients of Xihuang Pills. Bioinformatics techniques, including R language and Perl programs, were employed to analyze the interactions between prostate cancer-related targets and the potential targets of Xihuang Pills. A subcutaneous transplantation tumor model of prostate cancer was established in nude mice using PC3 cells to verify the efficacy and molecular mechanisms of Xihuang Pills. In vitro cellular experiments, including cell proliferation assays(CCK-8), Transwell assays, scratch assays, real-time quantitative reverse transcription PCR, and Western blot, were used to detect the effects of Xihuang Pills on the proliferation, invasion, and migration of prostate cancer cells, as well as on FAK/Src/ERK pathway-related targets. LC-MS/MS identified 99 active ingredients in Xihuang Pills, including gallic acid, gentisic acid, artemisinin, corilagin, phenylbutazone-glucoside, thujic acid, and arecoic acid B. Network pharmacological analysis of the active ingredients in Xihuang Pills revealed that the FAK/Src/ERK signaling pathway was a key pathway in its anti-prostate cancer effects. In vivo and in vitro experiments confirmed that Xihuang Pills significantly inhibited the proliferation, invasion, and migration of PC3 and LNCaP cells, suppressed the growth of PC3 subcutaneous tumors, and reduced the protein expression levels related to the FAK/Src/ERK signaling pathway. In conclusion, the inhibition of angiogenesis, invasion, and metastasis by regulating the FAK/Src/ERK pathway is one of the mechanisms by which Xihuang Pills exert anti-prostate cancer effects.
Humans ; Male ; Prostatic Neoplasms/enzymology* ; Drugs, Chinese Herbal/chemistry* ; Animals ; Mice ; Cell Proliferation/drug effects* ; Mice, Nude ; Cell Movement/drug effects* ; Cell Line, Tumor ; src-Family Kinases/genetics* ; Neovascularization, Pathologic/metabolism* ; Neoplasm Metastasis ; Neoplasm Invasiveness ; Focal Adhesion Kinase 1/genetics* ; Extracellular Signal-Regulated MAP Kinases/genetics* ; MAP Kinase Signaling System/drug effects* ; Focal Adhesion Protein-Tyrosine Kinases/genetics* ; Signal Transduction/drug effects* ; Angiogenesis