RELATIONSHIP BETWEEN THE INCIDENCE RATES OF TESTICULAR AND PROSTATIC CANCERS AND FOOD CONSUMPTIONS

Objective: To determine the relationships between the incidence rates of testicular and prostatic cancers and food consumptions in order to study the etiologic cause and the mechanism of the development of male genital organ cancer. Methods: The incidence rates of testicular and prostatic cancers in 42 countries (region) were correlated with the dietary practices in these countries. These data came from the cancer rate database (1988–1992) and the food supply database (1961–1990) provided by the Department of Environmental Health, Medical University of Yamanashi, Japan. Results: The incidence rates of testicular and prostatic cancers varied greatly from country to country but in China the rates of the both malignancies were lower than that of USA and Japan. This may be due to the difference in lifestyle, especially in dietary practices. Among the food items we examined, cheese was most closely correlated with the incidence of testicular cancer at ages 20–39, followed by animal fats and milk. The correlation coefficient (r) was the highest (r=0.804) when calculated for cheese consumed during the period of 1961–1965 (maternal or prepubertal consumption). Stepwise-multiple-regression analysis revealed that cheese (1961–1965) made a significant contribution to the incidence of testicular cancer. Multiple coefficient (r) is 0.920. As far as prostatic cancer was concerned, milk was most closely correlated (r=0.711) with its incidence, followed by meat and coffee. Stepwise-multiple-regression analysis identified milk, meat, butter and coffee as significant factors contributing to the incidence of prostatic cancer (R=0.993). The results of our study suggest a role of milk and dairy practices in the development of testicular and prostatic cancers.

Correlation of MR Perfusion-weighted Imaging of Prostatic Cancer with Tumor Angiogenesis

Objective： MR perfusion-weighted imaging（PWI） has been widely applied in the research of cerebral tumor, benign and malignant musculoskeletal neoplasms and so on. The aim of this study is to explore the application of MR perfusion-weighted imaging in prostatic cancer （Pca）, and evaluate the correlation of PWI features with vascular endothelial growth factor （VEGF） and microvessel density （MVD）. Methods： Twenty-eight consecutive patients who were diagnosed clinically as prostatic cancer and thirty healthy volunteers were examined by PWI. MVD and VEGF were stained with immunohistochemical methods. Some parameters of PWI, including the steepest slope of signal intensity-time curve （SSmax） and the change in relaxation rate （ΔR2^＊peak） at lesions, were analyzed. Correlation analysis was used to determine the relationship between the results of PWI and that of immunohistochemistry. Results： （1） In the healthy volunteers, the steepest slope of signal intensity-time curve （SSmax） and ΔR2^＊peak of perfusion curve were： 0.430±0.011, 2.01±0.7 respectively; however, in the prostatic cancer, they were 57.8±5.0, 3.0±0.6 respectively; with significant difference （t=-4.11, 3.28, P〈0.01）. （2）The VEGF and MVD expression of twenty-eight Pca patients were significantly higher. Conclusion： On MR perfusion- weighted imaging, SSmax and ΔR2^＊peak can reflect MVD and VEGF expression levels in prostatic cancer, suggesting information on tumor angiogenesis. Thus they are beneficial to the diagnosis and treatment of prostatic cancer.

Evaluation of the tumor angiogenesis in benign prostate hyperplasia and prostatic cancer with MR perfusion-weighted imaging

Objective： To explore the application of MR perfusion-weighted imaging （PWI） in the benign and malignant prostate diseases, and evaluate the correlations of PWl features with vascular endothelial growth factor （VEGF） and microvessel density （MVD）. Methods： Seventy-four consecutive patients who were diagnosed clinically for the prostate diseases, including forty-four cases with benign prostate hyperplasia and thirty cases with prostatic cancer proved pathologically, were examined by PWI. MVD and VEGF were stained with immunohistochemical methods. Some parameters of PWl, including the steepest slope of signal intensity-time curve （SSmax） and the change in relaxation rate （ΔR2^＊ peak） at lesions, were analyzed. Correlation analysis was used to determine the relationship between the results of PWl and immunohistochemistry. Results： （1） In the benign prostate hyperplasia （BPH）, SSmax and ΔR2^＊ peak of perfusion curve were 34.2 ± 2.9 and 1.49 ± 0.11, respectively; however, in the prostatic cancer （Pca）, they were 58.6± 4.8 and 3.18 ±0.49 respectively; there were statistical differences （t = 2.16 and 2.31, P 〈 0.05）. （2） The VEGF and MVD expressions of thirty Pca patients were significantly higher than those of forty-four BPH patients （x2 = 28.64, P 〈 0.01; t = 21.2, P 〈 0.01）. MVD expressions of Pca and BPH groups showed positive associations with VEGF expressions （P 〈 0.01）. On MR perfusion-weighted imaging, SSmax and ΔR2^＊ peak showed associations with MVD and VEGF expressions （P 〈 0.01）. Conclusion： On MR perfusion-weighted imaging, SSmax and ΔR2^＊ peak can reflect MVD and VEGF expression levels in the benign and malignant prostate diseases and might be implied the tumor angiogenesis so as to distinguish benign from malignant and provide the important information for the surgeon to diagnose and treat the prostatic diseases.

Atypical Presentation of Prostatic Cancer with Left Axillary and Supraclavicular Lymphadenopathy

Introduction: The burden of prostatic cancer is rising in Sudan. Usually, they present late in their disease with urinary tract obstruction, hematuria, bony pain, or cachexia because there is no screening program. Here we present a patient with prostatic cancer who presented with left axillary mass as his main concern. Case Description: 82-year-old Sudanese male presented with a left axillary and left supraclavicular lymphadenopathy of a few months’ duration. He underwent a decisional biopsy which showed metastatic adenocarcinoma. Upper and lower GI endoscopy were performed but the latter was complicated by a sigmoid perforation with peritonitis. During laparatomy, multiple enlarged pelvic lymphnodes were encountered and a biopsy result suggested a metastatic prostatic neoplasm. Later, prostatic biopsy confirmed the diagnosis. The patient was treated with bilateral orchidectomy. Clinical discussion: Lymphatic metastasis to axillary lymph nodes is a very rare manifestation of prostate cancer and only a few cases have been reported in the literature. It can cause diagnostic difficulty since prostate cancer typically metastasis to the pelvic lymph node and very rarely involves he supradiaphragmatic lymph node. Conclusion: Metastatic prostatic carcinoma should be considered among the causes of supra-diaphragmatic lymph adenopathy. Careful physical and imaging examinations combined with PSA and pathological analysis are essential in the diagnosis of advanced prostate cancer with unusual presentation.

Prostatic Cancer: Diagnosis and Differentiation by Dynamic Contrast-Enhanced MRI

To assess the role of dynamic contrast-enhanced MRI (DCE-MRI) in thediagnosis and differentiation of prostatic cancer (PC). Methods: Five volunteers, 36 patients withbenign prostatic hyperplasia (BPH) and 13 patients with biopsy-proven prostate cancer underwentconventional MRI, DCE-MRI and delayed enhancement MRI. The value of the signal intensity in DCE-MRIwas measured and calculated to draw the time-signal intensity curve of the normal peripheral zone(PZ), the prostate cancer and the benign prostatic hyperplasia. Results: In DCE-MRI, the normalperipheral zone was enhanced mildly and slowly and the peak value was located in late phase. Theenhancement of the lesions in 36 patients with the benign prostatic hyperplasia was obvious in earlyphase and strengthened gradually, and then turned to decrease in late phase after peak value. Thelesions in 9 of 13 cases with prostate cancer were enhanced obviously in early phase and washed outrapidly, and the peak value was located in early phase, but the peak value was in mediate and latephase in the other 4 cases with diffuse lesion in the prostate on T_2WI. Conclusion: In DCE-MRI, theenhancement patterns of the normal peripheral zone, the prostate cancer and the benign prostatichyperplasia were significantly different. DCE-MRI was very useful in the diagnosis anddifferentiation of prostate cancer.

The Significance of PSA Modified Parameters (F/T)/PSAD for Diagnosing Prostatic Cancer in the Grey Zone of 4～10 ng/ml

OBJECTIVE To investigate the diagnostic value of modified prostate specific antigen(PSA)parameters in the diagnosis of prostate cancer(PCA) when the serum PSAis in a grey zone of 4~10 ng/ml. METHODS The results of serum PSA determinations of the patients receiving a transrectal ultrasound-guided multiphase prostatic biopsy,were retrospectively analyzed.In the 88 patients with a serum PSA value of 4-10 ng/ml,the final diagnosis of PCA was made in 21,and that of benign prostate hyperplasia(BPH)in 67 patients.The percentage of the free-serum PSA([FPSA]/total-serum PSA[TPSA],F/T),PSA density(PSAD)and the sensitivity and specificity of the new PSA modified parameter(F/T)/PSAD in diagnosing PCA,within a set threshold value,was compared. RESULTS In the 88 patients with serum PSA in the grey zone of 4.0-10.0 ng/ml,there was no significant difference in comparing the TPSA between the 21 PCA patients and 67 BPH patients(P>0.05).However, there was a significant difference in the value of modified PSA parameters, such as F/T,PSAD and(F/T)/PSAD,between the PCA and the BPH groups (P<0.001).As the cut off point-value of the F/T,PSAD and(F/T)/PSAD was set at 0.16,0.15 and 0.8,the diagnostic sensitivity for PCA was 66.7%, 76.2%and 85.7%,and the specificity was 41.8%,43.3%and 68.7%,respectively.There was no significant difference in the sensitivity comparing the modified parameters for diagnosing PCA(P>0.05),whereas an overt predominance was present in the specificity of(F/T)/PSAD for PCAdiagnosis (P<0.05). CONCLUSION In the serum PSA grey zone of 4-10 ng/ml,a modified PSA parameter can improve the PCA diagnostic accuracy rate.With a considerably high sensitivity,application of the(F/T)/PSAD may effectively enhance the diagnostic specificity,which is superior to the F/T and PSAD, and can be expected to be one of the new indices derived from the PSA.

Unraveling the biological link between diabetes mellitus and prostate cancer:Insights and implications

This article is a comprehensive study based on research on the connection between diabetes mellitus(DM)and prostate cancer(PCa).It investigates the potential role of DM as an independent risk factor for PCa,delving into the biological links,including insulin resistance and hormonal changes.The paper critically analyzes previous studies that have shown varying results and introduces mendelian randomization as a method for establishing causality.It emphasizes the importance of early DM screening and lifestyle modifications in preventing PCa,and proposes future research directions for further understanding the DM-PCa relationship.

Marker Ki-67 is a potential biomarker for the diagnosis and prognosis of prostate cancer based on two cohorts

BACKGROUND Prostate cancer(PCa)is a widespread malignancy,predominantly affecting elderly males,and current methods for diagnosis and treatment of this disease continue to fall short.The marker Ki-67(MKI67)has been previously demonstrated to correlate with the proliferation and metastasis of various cancer cells,including those of PCa.Hence,verifying the association between MKI67 and the diagnosis and prognosis of PCa,using bioinformatics databases and clinical data analysis,carries significant clinical implications.AIM To explore the diagnostic and prognostic efficacy of antigens identified by MKI67 expression in PCa.METHODS For cohort 1,the efficacy of MKI67 diagnosis was evaluated using data from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)databases.For cohort 2,the diagnostic and prognostic power of MKI67 expression was further validated using data from 271 patients with clinical PCa.RESULTS In cohort 1,MKI67 expression was correlated with prostate-specific antigen(PSA),Gleason Score,T stage,and N stage.The receiver operating characteristic(ROC)curve showed a strong diagnostic ability,and the Kaplan-Meier method demonstrated that MKI67 expression was negatively associated with the progression-free interval(PFI).The time-ROC curve displayed a weak prognostic capability for MKI67 expression in PCa.In cohort 2,MKI67 expression was significantly related to the Gleason Score,T stage,and N stage;however,it was negatively associated with the PFI.The time-ROC curve revealed the stronger prognostic capability of MKI67 in patients with PCa.Multivariate COX regression analysis was performed to select risk factors,including PSA level,N stage,and MKI67 expression.A nomogram was established to predict the 3-year PFI.CONCLUSION MKI67 expression was positively associated with the Gleason Score,T stage,and N stage and showed a strong diagnostic and prognostic ability in PCa.

Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the associations.We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify riskassociated circRNAs by using the MiOncoCirc database.We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10^(-4))in a dominant genetic model,which altered the secondary structure of the corresponding RNA chain.In the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell transcriptomes.Additionally,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting carcinogenesis.In conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

CircTHSD4 promotes the malignancy and docetaxel (DTX) resistance in prostate cancer by regulating miR-203/HMGA2 axis

Objective:Circular ribose nudeic acids(circRNAs)are implicated in tumor progression and drug resistance of prostate cancer(PCa).The current work explored the function of circ_0005203(aircTHSD4)in the malignancy and docetaxel(DTX)resistance of PCa.Methods:circTHSD4 expression within PCa as well as matched non-carcinoma samples was measured through real time reverse transcription quantitative polymerase chain reaction(RT-qPCR).In addition,a subcellular fraction assay was conducted to determine circTHSD4 subcellular localization within PCa cells.In addition,we performed a Western blot(WB)assay to detect high mobility.group A2 protein(HMGA2)levels.Besides,functional associations of two molecules were investigated through dual luciferase reporter assay.Cell Counting Kit(CCK)-8,colony formation together with Transwell assay was conducted to assess malignant phenotypes of PCa cells,whereas flow cytometry was performed to determine cell apoptosis.Furthermore,a xenograft mouse model was constructed to verify the effect of circTHSD4 on the carcinogenesis of PCa cells.Results:According to RT-qPCR results,circTHSD4 was up-regulated within PCa tissues and cells,which predicted the dismal prognostic outcome of PCa cases.circTHSD4 silencing within PCa cells markedly suppressed cell growth,migration,and colony fomation.circTHSD4 silencing remarkably elevated PCa cell apoptosis and carcinogenesis within the xenograft model.Further,circTHSD4 silencing enhanced docetaxel(DTX)sensitivity in PCa cells.Furthermore,we demonstrated that circTHSD4 modulated the malignancy of PCa cells by regulating HMGA2 expression through sponging miR 203.Conclusion:Together,our findings suggest that cirCTHSD4 overexpression could promote the malignant phenotype and DTX resistance in PCa through the regulation of the miR 203/HMGA2 axis.

Analysis of risk factors leading to anxiety and depression in patients with prostate cancer after castration and the construction of a risk prediction model

BACKGROUND Cancer patients often suffer from severe stress reactions psychologically,such as anxiety and depression.Prostate cancer(PC)is one of the common cancer types,with most patients diagnosed at advanced stages that cannot be treated by radical surgery and which are accompanied by complications such as bodily pain and bone metastasis.Therefore,attention should be given to the mental health status of PC patients as well as physical adverse events in the course of clinical treatment.AIM To analyze the risk factors leading to anxiety and depression in PC patients after castration and build a risk prediction model.METHODS A retrospective analysis was performed on the data of 120 PC cases treated in Xi'an People's Hospital between January 2019 and January 2022.The patient cohort was divided into a training group(n=84)and a validation group(n=36)at a ratio of 7:3.The patients’anxiety symptoms and depression levels were assessed 2 wk after surgery with the Self-Rating Anxiety Scale(SAS)and the Selfrating Depression Scale(SDS),respectively.Logistic regression was used to analyze the risk factors affecting negative mood,and a risk prediction model was constructed.RESULTS In the training group,35 patients and 37 patients had an SAS score and an SDS score greater than or equal to 50,respectively.Based on the scores,we further subclassified patients into two groups:a bad mood group(n=35)and an emotional stability group(n=49).Multivariate logistic regression analysis showed that marital status,castration scheme,and postoperative Visual Analogue Scale(VAS)score were independent risk factors affecting a patient's bad mood(P<0.05).In the training and validation groups,patients with adverse emotions exhibited significantly higher risk scores than emotionally stable patients(P<0.0001).The area under the curve(AUC)of the risk prediction model for predicting bad mood in the training group was 0.743,the specificity was 70.96%,and the sensitivity was 66.03%,while in the validation group,the AUC,specificity,and sensitivity were 0.755,66.67%,and 76.19%,respectively.The Hosmer-Lemeshow test showed aχ^(2) of 4.2856,a P value of 0.830,and a C-index of 0.773(0.692-0.854).The calibration curve revealed that the predicted curve was basically consistent with the actual curve,and the calibration curve showed that the prediction model had good discrimination and accuracy.Decision curve analysis showed that the model had a high net profit.CONCLUSION In PC patients,marital status,castration scheme,and postoperative pain(VAS)score are important factors affecting postoperative anxiety and depression.The logistic regression model can be used to successfully predict the risk of adverse psychological emotions.

Unlocking the potential-vitamin D in prostate cancer prevention

Prostate cancer poses a significant health challenge globally,demanding proactive prevention strategies.This editorial explores the emerging role of vitamin D in prostate cancer prevention.While traditionally associated with bone health,vitamin D is increasingly recognized for its broader impact on immune function,cellular signaling,and cancer prevention.Epidemiological studies suggest an intriguing link between vitamin D deficiency and elevated prostate cancer risk,particularly in regions with limited sunlight exposure.Mechanistically,vitamin D regulates cellular processes,inhibiting unchecked cancer cell growth and bols-tering immune surveillance.Personalized prevention strategies,considering individual factors,are deemed essential for harnessing the full potential of vitamin D.To unlock this potential,the future calls for robust research,public awareness campaigns,dietary improvements,and vigilant medical guidance.Collaborative efforts are poised to pave the way toward a future where vitamin D stands as a sentinel in prostate cancer prevention,ushering in hope and improved health for men worldwide.

Aspartoacylase suppresses prostate cancer progression by blocking LYN activation

Background:Globally,despite prostate cancer(PCa)representing second most prevalent malignancy in male,the precise molecular mechanisms implicated in its pathogenesis remain unclear.Consequently,elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies,ultimately advancing the management of PCa.Methods:A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University.The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa.The expression of aspartoacylase(ASPA)in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques.To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis,a comprehensive set of in vitro and in vivo assays were conducted,including orthotopic and tumor-bearing mouse models(n=8 for each group).A combination of experimental approaches,such as Western blotting,luciferase assays,immunoprecipitation assays,mass spectrometry,glutathione S-transferase pulldown experiments,and rescue studies,were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa.The Student‘s t-test was employed to assess the statistical significance between two distinct groups,while one-way analysis of variance was utilized for comparisons involving more than two groups.A two-sided P<0.05 was deemed to indicate statistical significance.Results:ASPA was identified as a novel inhibitor of PCa progression.The expression of ASPA was found to be significantly down-regulated in PCa tissue samples,and its decreased expression was independently associated with patients’prognosis(HR=0.60,95%CI 0.40–0.92,P=0.018).Our experiments demonstrated that modulation of ASPA activity,either through gain-or loss-of-function,led to the suppression or enhancement of PCa cell proliferation,migration,and invasion,respectively.The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models.Mechanistically,ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets,JNK1/2 and C-Jun,in both PCa cells and mouse models,in an enzyme-independent manner.Importantly,the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models.Moreover,we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples,suggesting a potential regulatory role of ASPA in modulating LYN signaling.Conclusions:Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy.

Icariin plus curcumol enhances autophagy through the mTOR pathway and promotes cathepsin B-mediated pyroptosis of prostate cancer cells

Objective:To examine the effect of icariin plus curcumol on prostate cancer cells PC3 and elucidate the underlying mechanisms.Methods:We employed the Cell Counting Kit 8 assay and colony formation assay to assess cell viability and proliferation.Autophagy expression was analyzed using monodansylcadaverine staining.Immunofluorescence and Western blot analyses were used to evaluate protein expressions related to autophagy,pyroptosis,and the mTOR pathway.Cellular damage was examined using the lactate dehydrogenase assay.Moreover,cathepsin B and NLRP3 were detected by co-immunoprecipitation.Results:Icariin plus curcumol led to a decrease in PC3 cell proliferation and an enhancement of autophagy.The levels of LC3-Ⅱ/LC3-Ⅰand beclin-1 were increased,while the levels of p62 and mTOR were decreased after treatment with icariin plus curcumol.These changes were reversed upon overexpression of mTOR.Furthermore,3-methyladenine resulted in a decrease in inflammatory cytokines,pyroptosis-related protein levels,and lactate dehydrogenase concentration,compared to the icariin plus curcumol group.Inhibiting cathepsin B reversed the regulatory effects of icariin plus curcumol.Conclusions:Icariin plus curcumol demonstrates great potential as a therapeutic agent for castration-resistant prostate cancer by enhancing autophagy via the mTOR pathway and promoting pyroptosis mediated by cathepsin B.These findings provide valuable insights into the molecular mechanisms underlying the therapeutic potential of icariin and curcumol for prostate cancer treatment.

What benefit can be obtained from magnetic resonance imaging diagnosis with artificial intelligence in prostate cancer compared with clinical assessments?

The present study aimed to explore the potential of artificial intelligence(AI)methodology based on magnetic resonance(MR)images to aid in the management of prostate cancer(PCa).To this end,we reviewed and summarized the studies comparing the diagnostic and predictive performance for PCa between AI and common clinical assessment methods based on MR images and/or clinical characteristics,thereby investigating whether AI methods are generally superior to common clinical assessment methods for the diagnosis and prediction fields of PCa.First,we found that,in the included studies of the present study,AI methods were generally equal to or better than the clinical assessment methods for the risk assessment of PCa,such as risk stratification of prostate lesions and the prediction of therapeutic outcomes or PCa progression.In particular,for the diagnosis of clinically significant PCa,the AI methods achieved a higher summary receiver operator characteristic curve(SROC-AUC)than that of the clinical assessment methods(0.87 vs.0.82).For the prediction of adverse pathology,the AI methods also achieved a higher SROC-AUC than that of the clinical assessment methods(0.86 vs.0.75).Second,as revealed by the radiomics quality score(RQS),the studies included in the present study presented a relatively high total average RQS of 15.2(11.0–20.0).Further,the scores of the individual RQS elements implied that the AI models in these studies were constructed with relatively perfect and standard radiomics processes,but the exact generalizability and clinical practicality of the AI models should be further validated using higher levels of evidence,such as prospective studies and open-testing datasets.

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression

Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and identify a crucial target for PCa treatment.Methods The Cancer Genome Atlas(TCGA)database,online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase(ADPGK)in PCa.The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo.Quantitative proteomics,metabolomics,and extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)tests were performed to evaluate the impact of ADPGK on PCa metabolism.The underlying mechanisms were explored through ADPGK overexpression and knockdown,co-immunoprecipitation(Co-IP),ECAR analysis and cell counting kit-8(CCK-8)assays.Results ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival(OS)in prostate adenocarcinoma(PRAD).Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs.non-PCa tissues.High ADPGK expression indicates worse survival outcomes,and ADPGK serves as an independent factor of biochemical recurrence.In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration,and ADPGK inhibition suppressed malignant phenotypes.Metabolomics,proteomics,and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa.Mechanistically,ADPGK binds aldolase C(ALDOC)to promote glycolysis via AMP-activated protein kinase(AMPK)phosphorylation.ALDOC was positively correlated with ADPGK,and high ALDOC expression was associated with worse survival outcomes in PCa.Conclusions In summary,ADPGK is a driving factor in PCa progression,and its high expression contributes to a poor prognosis in PCa patients.ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling,suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression

Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

Targeted anti-tumor synergistic effects of Myc decoy oligodeoxynucleotides-loaded selenium nanostructure combined with chemoradiotherapy on LNCaP prostate cancer cells

In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells.Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays.ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure.The physicochemical characteristics of nanostructures were determined by FTIR,DLS,UV-vis,TEM,EDX,in vitro release,and hemolysis tests.Subsequently,the cytotoxicity properties of them with and without X-irradiation were investigated by uptake,MTT,cell cycle,apoptosis,and scratch assays on the LNCaP cell line.The results of DLS and TEM showed negative charge(−9 mV)and nanometer size(40 nm)for Se@BSA@Chi-DEC-MTX NPs,respectively.The results of FTIR,UV-vis,and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles.The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL.The ODNs release from the nanostructures showed a pH-dependent manner,and the release rate was 15%higher in acidic pH.The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen(PSMA).The significant synergistic effects of nanostructure(containing MTX drug)treatment along with X-irradiation showed cell growth inhibition,apoptosis induction(~57%),cell cycle arrest(G2/M phase),and migration inhibition(up to 90%)compared to the control.The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells.This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.

MAPK9 as a therapeutic target:unveiling ferroptosis in localized prostate cancer progression

Background:Ferroptosis,a lipid peroxidation-mediated programmed cell death,is closely linked to tumor development,including prostate cancer(PCa).Despite established connections between ferroptosis and PCa,a comprehensive investigation is essential for understanding its impact on patient prognosis.Methods:A risk model incorporating four ferroptosis-related genes was developed and validated.Elevated risk scores correlated with an increased likelihood of biochemical recurrence(BCR),diminished immune infiltration,and adverse clinicopathological characteristics.To corroborate these results,we performed validation analyses utilizing datasets from both the Cancer Genome Atlas Cohort(TCGA)and the Gene Expression Synthesis Cohort(GEO).Moreover,we conducted further investigations into the pivotal gene identified in our model to explore its impact on tumor characteristics through cell proliferation and invasion assays,as well as animal studies conducted in vivo.Additionally,we conducted further experiments involving ferroptosis-related analysis to validate its association with ferroptosis.Results:The risk model demonstrated exceptional predictive capabilities for prognosis and therapeutic outcomes in PCa patients.Mitogen-activated protein kinase 9(MAPK9)emerged as a crucial gene within the model.In vivo and in vitro experiments explored MAPK9’s role in ferroptosis and its influence on tumor migration and proliferation.Conclusion:The findings provide a novel perspective for advancing ferroptosis exploration in PCa,bridging basic research and clinical applications.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.