Identification of prognostic stemness-related genes in kidney renal papillary cell carcinoma.

BACKGROUND: Kidney renal papillary cell carcinoma (KIRP) is the second most prevalent malignant cancer originating from the renal epithelium. Nowadays, cancer stem cells and stemness-related genes (SRGs) are revealed to play important roles in the carcinogenesis and metastasis of various tumors. Consequently, we aim to investigate the underlying mechanisms of SRGs in KIRP. METHODS: RNA-seq profiles of 141 KIRP samples were downloaded from the TCGA database, based on which we calculated the mRNA expression-based stemness index (mRNAsi). Next, we selected the differentially expressed genes (DEGs) between low- and high-mRNAsi groups. Then, we utilized weighted gene correlation network analysis (WGCNA) and univariate Cox analysis to identify prognostic SRGs. Afterwards, SRGs were included in the multivariate Cox regression analysis to establish a prognostic model. In addition, a regulatory network was constructed by Pearson correlation analysis, incorporating key genes, upstream transcription factors (TFs), and downstream signaling pathways. Finally, we used Connectivity map analysis to identify the potential inhibitors. RESULTS: In total, 1124 genes were characterized as DEGs between low- and high-RNAsi groups. Based on six prognostic SRGs (CCKBR, GPR50, GDNF, SPOCK3, KC877982.1, and MYO15A), a prediction model was established with an area under curve of 0.861. Furthermore, among the TFs, genes, and signaling pathways that had significant correlations, the CBX2-ASPH-Notch signaling pathway was the most significantly correlated. Finally, resveratrol might be a potential inhibitor for KIRP. CONCLUSIONS: We suggested that CBX2 could regulate ASPH through activation of the Notch signaling pathway, which might be correlated with the carcinogenesis, development, and unfavorable prognosis of KIRP.

Exploration of the influence of GOLGA8B on prostate cancer progression and the resistance of castration-resistant prostate cancer to cabazitaxel.

Castration-resistant prostate cancer (CRPC) represents the final stage of prostate cancer (PCa). Cabazitaxel, a taxane chemotherapy drug, is used in treating CRPC. However, patients with CRPC eventually develop resistance to cabazitaxel, and the underlying mechanism remains unclear. Here, we aimed to investigate potential genetic alterations that may play a role in CRPC resistance to cabazitaxel. Using microarray data from the GSE158494 dataset, we identified ten critical genes (CXCL8, ITGB8, CLIP4, MAP1B, WIPI1, MMP13, CXCL1, C1S, GOLGA8B, and CXCL6) associated with CRPC cell resistance to cabazitaxel. The potential function of these key genes in PCa progression was analyzed using different databases, including Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA). Our findings revealed altered expression of these genes in the development of PCa. Furthermore, CXCL1 and GOLGA8B were found to influence the disease-free survival (DFS) status of patients with PCa, with GOLGA8B affecting the overall prognosis in patients with PCa. Additionally, GOLGA8B expression was associated with the infiltration of various immune cells in PCa, and it was upregulated in clinical PCa and CRPC samples. Through CCK-8 assays, we established that GOLGA8B could influence the sensitivity of CRPC cells to cabazitaxel and docetaxel. In conclusion, we identified GOLGA8B as a crucial gene that influences PCa progression and contributes to CRPC resistance to cabazitaxel.

PRL-mediated STAT5B/ARRB2 pathway promotes the progression of prostate cancer through the activation of MAPK signaling.

Previous study showed that higher expression of prolactin (PRL) was found in CRPC samples compared with hormone-naive prostate cancer (HNPC) and benign prostatic hyperplasia (BPH) samples. We further investigate the function of PRL in prostate cancer (PCa) and explored its downstream effects. We found heterogeneous expression of the PRLR in clinical prostate samples. The VCaP and 22Rv1 cells exhibited PRLR expression. Among the downstream proteins, STAT5B was the dominant subtype in clinical samples and cell lines. Human recombinant PRL stimulation of PCa cells with PRLR expression resulted in increased phosphorylation of STAT5B(pSTAT5B) and progression of PCa in vitro and in vivo, and STAT5B knockdown can suppress the malignant behavior of PCa. To understand the mechanism further, we performed Bioinformatic analysis, ChIP qPCR, and luciferase reporter gene assay. The results revealed that ARRB2 was the transcription target gene of STAT5B, and higher expression of ARRB2 was related to higher aggression and poorer prognosis of PCa. Additionally, Gene set enrichment analysis indicated that higher expression of ARRB2 was significantly enriched in the MAPK signaling pathway. Immunohistochemistry (IHC) demonstrated elevated pSTAT5B, ARRB2, and pERK1/2 expression levels in CRPC tissues compared to HNPC and BPH. Mechanically, ARRB2 enhanced the activation of the MAPK pathway by binding to ERK1/2, thereby promoting the phosphorylation of ERK1/2 (pERK1/2). In conclusion, our study demonstrated that PRL stimulation can promote the progression of PCa through STAT5B/ARRB2 pathway and activation of MAPK signaling, which can be suppressed by intervention targeting STAT5B. Blockade of the STAT5B can be a potential therapeutic target for PCa.

Nucleophosmin 1 cooperates with BRD4 to facilitate c-Myc transcription to promote prostate cancer progression.

Nucleophosmin 1 (NPM1) is a multifunctional protein that promotes tumor progression in various cancers and is associated with a poor prognosis of prostate cancer (PCa). However, the mechanism by which NPM1 exerts its malignant potential in PCa remains elusive. Here, we showed that NPM1 is overexpressed in PCa cell lines and tissues and that the dysregulation of NPM1 promotes PCa proliferation. We also demonstrated that NPM1 transcriptionally upregulates c-Myc expression in PCa cells that is diminished by blockade of bromodomain-containing protein 4 (BRD4). Furthermore, we detected a correlation between NPM1 and c-Myc in patient PCa specimens. Mechanistically, NPM1 influences and cooperates with BRD4 to facilitate c-Myc transcription to promote PCa progression. In addition, JQ1, a bromodomain and extra-terminal domain (BET) inhibitor, in combination with NPM1 inhibition suppresses PCa progression in vitro and in vivo. These results indicate that NPM1 promotes PCa progression through a c-Myc -mediated pathway via BRD4, and blockade of the NPM1-c-Myc oncogenic pathway may be a therapeutic strategy for PCa.

CYP19A1 is downregulated by BRD4 and suppresses castration-resistant prostate cancer cell invasion and proliferation by decreasing AR expression.

Castration-resistant prostate cancer (CRPC) is the final stage of prostate cancer (PCa). As the main androgen in males, testosterone, and its androgen receptor (AR) play an important role in CRPC. The enzyme that catalyzes testosterone, aromatase, can be influenced by CYP19A1 activity - thus possibly affecting both AR expression and CRPC. However, the function of CYP19A1 in CRPC remains unclear. Using data derived from public databases and clinical samples, we analyzed the expression of CYP19A1 in PCa and CRPC specimens. The effect of CYP19A1 on cell invasion and proliferation was investigated in vitro and in vivo; while its function in metabolizing testosterone was detected in vitro. The effect of BRD4 on CYP19A1 and AR was investigated by qRT-PCR and western blot; whereas the effect of JQ1 on cells was assessed based on the IC50 value. We found that CYP19A1 was downregulated in CRPC samples and cells which correlated with a decrease in CRPC cell invasion and proliferation, and an increase in AR expression. Inversely, CYP19A1 affected CRPC cell invasion and proliferation by suppressing the expression of AR which may be attributed to the metabolism of testosterone by CYP19A1. Moreover, the BRD4 inhibitor JQ1 induced the CYP19A1 expression and suppressed the AR expression. Following BRD4 knockdown, CYP19A1 showed higher expression while AR expression was decreased. Our findings demonstrated that CYP19A1 could reduce CRPC cell invasion and proliferation by targeting AR, and this process could be regulated by BRD4. CYP19A1 may be a potential therapeutic target and enhance BRD4 inhibition in treating CRPC.

Identification of cuproptosis-related genes for predicting the development of prostate cancer.

Copper can be toxic at very high intracellular concentrations and can inhibit prostate cancer (PCa) progression. Recently, a study reported the mechanism of cuproptosis and the potentially associated genes. However, the function of these cuproptosis-related genes in PCa remains unknown. Based on the RNA sequence and clinical data from public databases, we analyzed the clinical value of cuproptosis-related genes in PCa. DLD, DLAT, PDHA1, and CDKN2A were expressed differently between normal and PCa tissues. The FDX1, LIAS, DLAT, GLS, and CDKN2A genes can affect PCa progression, while PDHA1 and CDKN2A influence the patients' disease-free survival (DFS) status. The expression of LIAS, LIPT1, DLAT, and PDHB did not alter upon the incidence of PCa in Chinese patients. A constructed regression model showed that FDX1, PDHA1, MTF1, and CDKN2A can be risk factors leading to PCa in both Western and Chinese patients with PCa. The lasso regression model reflected that these genes can affect the patients' DFS status. Additionally, the cuproptosis-related genes were associated with immune cell infiltration. We also verified the high expression of PDHA1 and CDKN2A, in clinical samples. In conclusion, we identified a novel cuproptosis-related gene signature for predicting the development of PCa.

Identification and validation of MSMB as a critical gene for prostate cancer development in obese people.

Prostate cancer (PCA) is one of the most common types of cancer and can seriously endanger the health of older men. Obesity is prevalent all around the world and triggered by lots of factors such as diet, environment and fat metabolism disorder can cause many neoplasms, including PCA. Evidence suggests that genetic changes increase the risk of PCA and obesity. However, the specific obesity-related genes leading to PCA are unknown. Obesity-related genes associated with PCA were identified and analyzed though three public electronic databases: Gene Expression Omnibus, The Cancer Genome Atlas, and Chinese Prostate Cancer Genome and Epigenome Atlas. The effect of obesity-related genes in PCA were analyzed using clinical data from different databases, while associations with immune cells were determined by TIMER web tool. The expression and function of obesity-related genes were verified using clinical samples from obese patients with PCA and PCA cells. We found that four genes, MSMB, BMP5, THBS4, and POPDC3, may lead to PCA occurrence in patients with obesity. In Gene Expression Omnibus database, MSMB and BMP5 were downregulated, while THBS4 and POPDC3 were upregulated. This trend was mainly preserved in the other electronic databases. We also discovered MSMB and THBS4 can affect PCA progression, and all these genes were risk factors for castration-resistant prostate cancer. Moreover, MSMB can impact disease-free survival status of patients with PCA. These obesity-related genes were also correlated with immune cells and immune cell infiltration in PCA. We further uncovered that MSMB was downregulated in clinical PCA and castration-resistant prostate cancer samples from patients with obesity and MSMB decreased PCA cells proliferation. These results indicate that MSMB is essential for PCA development in people with obesity and can be a biomarker for predicting PCA occurrence and progression in obese people.

Study on clinical outcomes between non-transecting urethroplasty and lingual mucosal urethroplasty for iatrogenic bulbar urethral stricture treatment.

BACKGROUND: This study aimed to compare the clinical outcomes of non-transecting urethroplasty and lingual mucosal urethroplasty in the treatment of iatrogenic bulbar urethral stricture. RESULTS: A total of 25 patients with iatrogenic bulbar urethral stricture were enrolled, 12 of whom underwent lingual mucosal urethroplasty, 13 patients who underwent non-transecting urethroplasty. All patients were followed-up and evaluated at 3 postoperative months. Evaluations included urethrography, maximum urine flow rate (Qmax), nocturnal erectile function testing, International Index of Erectile Function (IIEF-5) assessment, and Anxiety Related Scale (SAS) assessment. In terms of operation time, there was a significant difference between non-transecting urethroplasty and lingual mucosal urethroplasty. However, there was no significant intergroup difference in intraoperative blood loss. Both techniques were associated with significantly improved Qmax relative to preoperative rates, but there was no significant difference between the groups in this regard over 3 months of postoperative follow-up. Nocturnal penile tumescence and rigidity results showed that there was no significant change in tip hardness after surgery in the non-transecting urethroplasty group. Moreover, IIEF-5 scores indicated that there was no significant intergroup difference in terms of subjective postoperative erectile function. According to the preliminary psychological evaluations during postoperative follow-up, the anxiety scores of patients undergoing non-transecting urethroplasty significantly improved, but there was no significant change in the mean SAS score among patients who underwent lingual mucosal urethroplasty. CONCLUSION: Both surgical methods can achieve the clinical goal of treating iatrogenic bulbar urethral stricture. Non-transecting urethroplasty has the characteristics of short operation time, relative technical simplicity, and retention of the original erectile function of most patients, and the surgical outcomes of non-transecting urethroplasty are not inferior to those of lingual mucosal urethroplasty, and it is a promising technique for widespread use to treat bulbar urethral strictures.

RéSUMé: CONTEXTE: Cette étude visait à comparer les résultats cliniques de l'urétroplastie non transectante et de l'urétroplastie avec greffe de  muqueuse linguale dans le traitement de la sténose urétrale bulbaire iatrogène. Un total de 25 patients présentant une sténose urétrale bulbaire iatrogène a été recruté, dont 12 ont subi une urétroplastie avec greffe de muqueuse buccale et 13 une urétroplastie non-transectante. Tous les patients ont été suivis et évalués à 3 mois postopératoires. Les évaluations comprenaient une uréthrographie, le débit urinaire maximal (Qmax), un test nocturne de la fonction érectile, l'évaluation de l'index international de la fonction érectile (IIEF5) et une évaluation de l'échelle d'anxiété. RéSULTATS: En termes de durée opératoire, il y avait une différence significative entre l'urétroplastie non-transectante et urétroplastie avec greffe de muqueuse buccale. Cependant, il n'y avait pas de différence significative entre les groupes en ce qui concerne la perte de sang peropératoire. Les deux techniques ont été associées à une amélioration significative du Qmax par rapport aux taux préopératoires, mais il n'y avait pas de différence significative entre les groupes à cet égard sur 3 mois de suivi postopératoire. Les résultats de la tumescence et de la rigidité nocturnes du pénis ont montré qu'il n'y avait pas de changement significatif de la dureté de l'extrémité du pénis après l'opération dans le groupe d'urétroplastie sans transsection. De plus, les scores IIEF-5 ont indiqué qu'il n'y avait pas de différence significative entre les groupes en termes de fonction érectile subjective postopératoire. Selon les évaluations psychologiques préliminaires au cours du suivi postopératoire, les scores d'anxiété des patients ayant subi une urétroplastie non-transectante se sont améliorés de manière significative, mais il n'y a pas eu de changement significatif du score moyen de l'échelle d'anxiété chez les patients ayant subi une urétroplastie avec greffe de muqueuse buccale. CONCLUSIONS: Les deux méthodes permettent d'atteindre l'objectif clinique du traitement de la sténose urétrale bulbaire iatrogène. L'urétroplastie sans transsection présente les caractéristiques suivantes: temps d'opération court, simplicité technique relative et maintien de la fonction érectile initiale chez la plupart des patients. Les résultats chirurgicaux de l'urétroplastie sans transsection ne sont pas inférieurs à ceux de l'urétroplastie avec greffe de muqueuse buccale et cette technique est prometteuse pour une utilisation généralisée dans le traitement des rétrécissements urétraux bulbaires.

The clinical efficacy and limitations of dutasteride-regulated abiraterone metabolism in abiraterone-resistant patients: a prospective single-arm clinical trial in Chinese patients.

Background: The steroidal metabolism of abiraterone has been proposed to be involved in abiraterone resistance and limited approaches are available for abiraterone-resistant patients. Dutasteride regulates abiraterone metabolism in patients and might enhance the clinical efficacy of abiraterone. However, the function of dutasteride to overcome abiraterone resistance has not been investigated in clinic. Here we investigated the clinical efficacy and limitations of dutasteride in patients with abiraterone-resistant prostate cancer. Methods: Abiraterone-resistant patients with metastatic castration-resistant prostate cancer (mCRPC) were enrolled in this single-arm, open-label study, patients were treated with dutasteride (0.5 mg/day), abiraterone (1,000 mg/day), and prednisone (5 mg twice daily), prostate-specific antigen (PSA) was tested monthly. The primary objective was PSA response, and the secondary objectives were to assess symptom relief and safety. Kaplan-Meier analysis was used to assess the PSA progression free survival (PSA-PFS) of patients. Results: Twenty-two patients (median age: 75 years) were enrolled, and 19 patients completed the treatment. After a median treatment of 4.0 months, 7 (37%) patients showed a slight PSA reduction (-2% to -32%), and the median PSA-PFS was 2.0 months (1-7 months). No significant improvement was observed in Eastern Cooperative Oncology Group (ECOG) performance status. Bone pain was relieved in 6 patients after 1 month of treatment, but the improvement was not significant. No grade 3 or grade 4 adverse events were observed. Conclusions: The combination of dutasteride and abiraterone showed a mild effect in patients with abiraterone-resistant. The small sample size was the limitation of this study.

Identification of an immune-related gene signature as a prognostic target and the immune microenvironment for adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Even with complete tumor resection and adjuvant therapies, the prognosis of patients with ACC remains unsatisfactory. In the microtumor environment, the impact of a disordered immune system and abnormal immune responses is enormous. To improve treatment, novel prognostic predictors and treatment targets for ACC need to be identified. Hence, credible prognostic biomarkers of immune-associated genes (IRGs) should be explored and developed. MATERIAL AND METHODS: We downloaded RNA-sequencing data and clinical data from The Cancer Genome Atlas (TCGA) data set, Genotype-Tissue Expression data set, and Gene Expression Omnibus data set. Gene set enrichment analysis (GSEA) was applied to reveal the potential functions of differentially expressed genes. RESULTS: GSEA indicated an association between ACC and immune-related functions. We obtained 332 IRGs and constructed a prognostic signature on the strength of 3 IRGs (INHBA, HELLS, and HDAC4) in the training cohort. The high-risk group had significantly poorer overall survival than the low-risk group (p < .001). Multivariate Cox regression was performed with the signature as an independent prognostic indicator for ACC. The testing cohort and the entire TCGA ACC cohort were utilized to validate these findings. Moreover, external validation was conducted in the GSE10927 and GSE19750 cohorts. The tumor-infiltrating immune cells analysis indicated that the quantity of T cells, natural killer cells, macrophage cells, myeloid dendritic cells, and mast cells in the immune microenvironment differed between the low-risk and high-risk groups. CONCLUSION: Our three-IRG prognostic signature and the three IRGs can be used as prognostic indicators and potential immunotherapeutic targets for ACC. Inhibitors of the three novel IRGs might activate immune cells and play a synergistic role in combination therapy with immunotherapy for ACC in the future.

CASC1 Expression in Bladder Cancer Is Regulated by Exosomal miRNA-150: A Comprehensive Pan-Cancer and Bioinformatics Study.

This study explored the role of cancer susceptibility 1 (CASC1) in tumorigenesis and development as well as the key pathways affecting bladder cancer progression. CASC1 was examined in various normal tissues in humans using the HPA database to quantify its expression level and subcellular localization. CASC1 is abundantly expressed in tumor tissues, primarily in cytoplasmic vesicles and stroma. TIMER2 was used to analyze the correlation between CASC1 expression levels and the types of infiltrates associated with immune cells and immunosuppressive cells. MDSC, Treg, M2, and CAF were significantly correlated with CASC1 expression in various tumors. Comparing patients with and without CASC1 mutation, those with CASC1 mutation had worse overall survival, progression-free survival, and disease-free survival. The correlation between has-miR-150 and CASC1 (for the case of bladder cancer) was then analyzed, and the related ceRNA network was mapped. A negative relationship between CASC1 expression and has-miR-150 expression was found in cases of bladder cancer. And the presence of miR-150-targeted CASC1 may be associated with bladder cancer progression. CASC1 is expressed at elevated levels in various tumor tissues, and it is associated with tumorigenesis and development. Exosomes containing miR-150-targeted CASC1 may affect the progression of bladder cancer.

CDK6 is upregulated and may be a potential therapeutic target in enzalutamide-resistant castration-resistant prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) is still the first-line treatment of prostate cancer (PCa). However, after a certain period of therapy, primary PCa inevitably progresses into castration-resistant PCa (CRPC). Enzalutamide (Enz) is an androgen receptor (AR) signal inhibitor which can delay the progression of CRPC and increase survival of patients with metastatic CRPC. However, the mechanisms involved in enzalutamide-resistant (EnzR) CRPC are still controversial. In the study, we used bioinformatic methods to find potential genes that correlated with the occurrence of EnzR CRPC. METHODS: We collected RNA sequencing data of the EnzR CRPC cell line LNCaP (EnzR LNCaP) from GSE44905, GSE78201, and GSE150807. We found the hub genes from the three datasets. Then we tested the expression of the hub genes in different databases and the potential drugs that can affect the hub genes. Finally, we verified the hub gene expression and drug function. RESULTS: From GSE44905, GSE78201 and GSE150807, we found 45 differentially expressed genes (DEGs) between LNCaP and EnzR LNCaP. Ten hub genes were found in the protein-protein interaction (PPI) network. The expression of hub gene and survival analysis were analyzed by different databases. We found that cyclin-dependent kinase 6 (CDK6) was highly expressed in both the EnzR LNCaP cell and PCa patients. Ten potential small molecules could suppress CDK6 expression as per "CLUE COMMAND" findings. Finally, we found the expression of CDK6 increased in both PCa patients' samples, CRPC and EnzR PCa cell lines. Three potential CDK6 inhibitors, namely apigenin, chrysin and fisetin, can decrease cell proliferation. CONCLUSIONS: The study proved that the abnormal overexpression of CDK6 may be a reason behind EnzR CRPC occurrence and suppression CDK6 expression may help treat EnzR CRPC.

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. METHODS: This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI). RESULTS: The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037). CONCLUSIONS: Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

Identification of hub genes predicting the development of prostate cancer from benign prostate hyperplasia and analyzing their clinical value in prostate cancer by bioinformatic analysis.

Prostate cancer (PCa) and benign prostate hyperplasia (BPH) are commonly encountered diseases in males. Studies showed that genetic factors are responsible for the occurrences of both diseases. However, the genetic association between them is still unclear. Gene Expression Omnibus (GEO) database can help determine the differentially expressed genes (DEGs) between BPH and PCa. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were utilized to find pathways DEGs enriched. The STRING database can provide a protein-protein interaction (PPI) network, and find hub genes in PPI network. R software was used to analyze the clinical value of hub genes in PCa. Finally, the function of these hub genes was tested in different databases, clinical samples, and PCa cells. Fifteen up-regulated and forty-five down-regulated genes were found from GEO database. Seven hub genes were found in PPI network. The expression and clinical value of hub genes were analyzed by The Cancer Genome Atlas (TCGA) data. Except CXCR4, all hub genes expressed differently between tumor and normal samples. Exclude CXCR4, other hub genes have diagnostic value in predicting PCa and their mutations can cause PCa. The expression of CSRP1, MYL9 and SNAI2 changed in different tumor stage. CSRP1 and MYH11 could affect disease-free survival (DFS). Same results reflected in different databases. The expression and function of MYC, MYL9, and SNAI2, were validated in clinical samples and PCa cells. In conclusion, seven hub genes among sixty DEGs may be achievable targets for predicting which BPH patients may later develop PCa and they can influence the progression of PCa.

Management of prostate cancer by targeting 3ßHSD1 after enzalutamide and abiraterone treatment.

Novel strategies for prostate cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3ßHSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3ßHSD1, overcomes drug resistance. 3ßHSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3ßHSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3ßHSD1 and suppresses prostate cancer development alone or together with abiraterone and enzalutamide. Daidzein, a BCA analog of dietary origin, is associated with higher plasma abiraterone concentrations and prevented prostate-specific antigen (PSA) increases in abiraterone-resistant patients. Overall, our results show that 3ßHSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3ßHSD1 inhibitor even after abiraterone and enzalutamide resistance.

Histone methyltransferase KMT2C plays an oncogenic role in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a leading cause of morbidity and mortality in males. Epigenetic modifier abnormalities are becoming a driving event in PCa. The specific role of KMT2C, a histone methyltransferase that is frequently aberrant in various tumors, is poorly understood in PCa. This study aimed to reveal the potential carcinogenic role of KMT2C in PCa. METHODS: We first examined the expression levels of KMT2C in prostate cancer tissues. Then, we assessed the function of KMT2C in prostate cancer cell proliferation, colony formation, and migration. To explore the mechanism of the biological consequences, RNA-seq and CHIP-qPCR were performed. We also analyzed the effects of overexpression of the KMT2C downstream genes CLDN8 and ITGAV to reverse the effects of KMT2C on prostate cancer cells. RESULTS: Herein, we first confirmed KMT2C overexpression in PCa at the transcript and protein levels. Knocking down KMT2C in VCaP and LNCaP cells inhibited cell viability, colony formation, and migration. Consistently, stable KMT2C depletion effectively decreased tumor growth by approximately 70% in vivo. Mechanistically, the results suggested that CLDN8 and ITGAV are two key downstream genes of KMT2C and further regulate the MAPK/ERK and EMT pathways. CONCLUSION: Our study suggests that KMT2C plays an oncogenic role in PCa. One of the mechanisms may be the epigenetic regulation of CLDN8 and ITGAV by KMT2C to modulate tumor-signaling pathways. Therefore, KMT2C may serve as a potential therapeutic target for PCa patients.

Quick identification of prostate cancer by wavelet transform-based photoacoustic power spectrum analysis.

Pathology is currently the gold standard for grading prostate cancer (PCa). However, pathology takes considerable time to provide a final result and is significantly dependent on subjective judgment. In this study, wavelet transform-based photoacoustic power spectrum analysis (WT-PASA) was used for grading PCa with different Gleason scores (GSs). The tumor region was accurately identified via wavelet transform time-frequency analysis. Then, a linear fitting was conducted on the photoacoustic power spectrum curve of the tumor region to obtain the quantified spectral parameter slope. The results showed that high GSs have small glandular cavity structures and higher heterogeneity, and consequently, the slopes at both 1210 nm and 1310 nm were high (p < 0.01). The classification accuracy of the PA time frequency spectrum (PA-TFS) of tumor region using ResNet-18 was 89% at 1210 nm and 92.7% at 1310 nm. Further, the testing time was less than 7 mins. The results demonstrated that identification of PCa can be rapidly and objectively realized using WT-PASA.

CCNB1 and AURKA are critical genes for prostate cancer progression and castration-resistant prostate cancer resistant to vinblastine.

Background: Prostate cancer (PCa) is a common malignancy occurring in men. As both an endocrine and gonadal organ, prostate is closely correlated with androgen. So, androgen deprivation therapy (ADT) is effective for treating PCa. However, patients will develop castration-resistant prostate cancer (CRPC) stage after ADT. Many other treatments for CRPC exist, including chemotherapy. Vinblastine, a chemotherapeutic drug, is used to treat CRPC. However, patients will develop resistance to vinblastine. Genetic alterations have been speculated to play a critical role in CRPC resistance to vinblastine; however, its mechanism remains unclear. Methods: Various databases, such as Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA), were used to collect the RNA-sequence data of PCa and CRPC patients and vinblastine-resistant PCa cells. Using online tools, Metascape and TIMER, the pathways and immune infiltration associated with vinblastine resistance-related genes in PCa were analyzed. The function of these genes was verified in clinical samples and CRPC cells. Results: Using GSE81277 dataset, we collected the RNA-sequence data of vinblastine sensitive and resistant LNCaP cells and found nine genes (CDC20, LRRFIP1, CCNB1, GPSM2, AURKA, EBLN2, CCDC150, CENPA and TROAP) that correlated with vinblastine resistance. Furthermore, CCNB1, GPSM2 and AURKA were differently expressed between normal prostate and PCa tissues, even influencing PCa progression. The GSE35988 dataset revealed that CCNB1 and AURKA were upregulated in PCa and CRPC samples. Various genes were also found to affect the survival status of PCa patients based on TCGA. These genes were also related to immune cell infiltration. Finally, we verified the function of CCNB1 and AURKA and observed that they were upregulated in PCa and CRPC clinical samples and increased the sensitivity of CRPC cells to vinblastine. Conclusion: CCNB1 and AURKA are central to CRPC resistance to vinblastine and affect PCa progression.

Immune microenvironment infiltration landscape and immune-related subtypes in prostate cancer.

Background: The tumor microenvironment (TME) primarily comprises cancer cells, cancer-infiltrating immune cells, and stromal cells. The tumor cells alter the TME by secreting signaling molecules to induce immune tolerance. The immune cell infiltrating the TME influences the prognosis of patients with cancers. However, immune cell infiltration (ICI) in the TME of patients with prostate cancer (PC) has not yet been studied. Methods: In this study, we used Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and Estimation of Stromal and Immune cells in Malignant Tumors using Expression data (ESTIMATE) algorithms to identify three ICI clusters based on 1,099 genes associated with ICI in the TME. The patients were classified into three distinct ICI gene clusters based on overlapping differentially expressed genes in ICI clusters. Furthermore, the ICI scores were calculated using principal component analysis. Results: The results revealed that patients with high ICI scores had poor prognoses and reduced expression of immune-checkpoint genes and immune-related genes. Furthermore, the transforming growth factor-beta (TGF-ß) and WNT-ß signaling pathways were enriched in the high ICI score subgroup, which suggests that suppression of T cells could contribute to poor prognosis of patients with PC. A positive correlation was observed between the high-ICI-score subgroup and the high tumor mutation burden (TMB) value. Patients with low ICI scores could benefit from immunotherapy, indicating that the ICI score could be used to predict the efficacy of immunotherapeutic response. Conclusions: In summary, we provide a comprehensive overview of the landscape of ICI in PC, which could aid in designing the strategies for immunotherapy for patients with PC.

Efficacy and safety of bipolar androgen therapy in castration-resistant prostate cancer following abiraterone or enzalutamide resistance: A systematic review.

Bipolar androgen therapy (BAT) is a new endocrinologic treatment for castration-resistant prostate cancer (CRPC) that can restore some patients' sensitivity to drugs such as abiraterone (Abi) and enzalutamide (Enz). We performed a meta-analysis using STATA16. Sensitivity analyses were performed by examining the effects of individual studies using different effect models and detecting any publication bias using the Harbord test. In a total of 108 unique records, ten studies were included in the final meta-analysis. Participants who underwent BAT achieved a PSA50 response rate of 27% (95%CI [0.22,0.31], I2=17.98%), ORR of 34% (95%CI [0.24,0.43], I2=0), and incidence of AEs (grade≥3) of 14% (95%CI [0.09,0.19], I2=0). Patients who completed BAT proceeded to AR-targeted therapy (Abi or Enz) and achieved a PSA50 response rate of 57% (95% CI [0.36,0.78], I2=0). Patients with prior Enz resistance had a stronger impact on the PSA50 of AR-target therapy rechallenge. The results of this meta-analysis indicate that BAT is a safe and effective treatment for patients who have progressed after Abi or Enz. BAT can trigger the resensitization of patients with CRPC to subsequent endocrine therapy and improve the overall survival of patients and their quality of life.