MT1G, an emerging ferroptosis-related gene: A novel prognostic biomarker and indicator of immunotherapy sensitivity in prostate cancer.

BACKGROUND: Prostate cancer is a leading cause of cancer-related deaths in men worldwide. Despite advances in treatment strategies, there is still a need for novel therapeutic targets and approaches. Ferroptosis has emerged as a critical process in the development and progression of several cancers, including prostate cancer (PCA). In this study, we investigate the role of MT1G, a gene implicated in immune responses and ferroptosis, in the pathogenesis of PCA. Our objective is to elucidate its prognostic significance and its impact on the tumor microenvironment, while exploring its potential in enhancing the sensitivity to immune checkpoint inhibitor (ICI) therapy. METHODS: We utilized a combination of in silico analysis and experimental techniques to investigate the role of MT1G in PCA. First, we analyzed large-scale genomic datasets to assess the expression pattern and prognostic significance of MT1G in PCA patients. Subsequently, we performed functional assays to explore the impact of MT1G in PCA and its potential involvement in modulating immune responses. In addition, we conducted in vivo experiments to evaluate the effect of MT1G on tumor growth and response to ICI therapy. RESULTS: Our analysis revealed that MT1G expression is significantly downregulated in PCA tissues compared to normal prostate tissues and is associated with poor prognosis. Furthermore, MT1G overexpression inhibited the growth of PCA cells in vitro and in vivo. Importantly, we found that MT1G regulates the tumor microenvironment by modulating immune cell infiltration and inhibiting immunosuppressive factors. Furthermore, our study reveals a significant correlation between MT1G expression levels and the response to immune checkpoint inhibitor (ICI) therapy in prostate cancer (PCA) patients, as MT1G upregulation leads to an increase in PDL-1 expression. These findings underscore the potential of MT1G as a promising predictive biomarker for ICI therapy response in PCA patients. CONCLUSION: Our study elucidates the pivotal role played by MT1G in the pathogenesis of prostate cancer (PCA) and its profound implications for prognosis. Moreover, it raises the intriguing possibility that MT1G could pave the way for novel therapeutic approaches in PCA treatment. This potential arises from its ability to orchestrate immune infiltration within the tumor microenvironment, consequently enhancing sensitivity to immune checkpoint inhibitor (ICI) therapy. Therefore, our findings hold substantial promise for advancing our comprehension of PCA and exploring innovative therapeutic strategies.

The efficacy of cytoreductive surgery for oligometastatic prostate cancer: a meta-analysis.

BACKGROUNDS: At present, the application of tumor reduction surgery in oligometastatic prostate cancer has aroused extensive discussion among urologists, but clinicians have not reached a consensus on this issue. The purpose of this study was to evaluate the effect of cytoreductive surgery for patients with oligometastatic prostate cancer by meta-analysis. METHODS: All relevant studies were systematically searched through The Cochrane Library, PubMed, Web of Science, EMBASE, and China Biomedical Literature Database (CBM) up to December 2019. All the previous clinical studies on the comparison of long-term efficacy between the cytoreductive surgery group and the endocrine therapy group were included in the search. The included studies were analyzed using Stata ver.14.0. The research has been registered on PROSPERO website with the registration number of crd42021224316. The relevant registration information can be obtained from the website: https://www.crd.york.ac.uk/prospero . RESULTS: The case presentation is as follows: ten studies were identified that met the conclusion criteria. The total number of samples was 804; 449 patients underwent cytoreductive surgery, and 355 patients underwent endocrine therapy, and we conducted a meta-analysis of studies to compare the prognosis of endocrine therapy and cytoreductive surgery for treating prostate cancer. After all the studies were analyzed, we found that between cytoreductive surgery and endocrine therapy, a significant difference existed in overall survival (HR = 0.635, 95% CI 0.443-0.908, P = 0.013), cancer-specific survival (HR = 0.407, 95% CI 0.243-0.681, P = 0.001), and progression-free survival (HR = 0.489, 95% CI 0.315-0.758, P = 0.001), while there were no significant difference in progresses to castration-resistant prostate cancer (HR = 0.859, 95% CI 0.475-1.554, P = 0.616). CONCLUSION: The cytoreductive surgery held advantages in overall survival, cancer-specific survival, and progression-free survival. Therefore, compared with endocrine therapy, cytoreductive surgery could be a more suitable approach in treating oligometastatic prostate cancer.

Assessment of treatment outcomes: cytoreductive surgery compared to radiotherapy in oligometastatic prostate cancer - an in-depth quantitative evaluation and retrospective cohort analysis.

BACKGROUND: The management of oligometastatic prostate cancer, defined by its few metastatic sites, poses distinct clinical dilemmas. Debates persist regarding the most effective treatment approach, with both cytoreductive surgery and radiotherapy being key contenders. The purpose of this research is to thoroughly evaluate and compare the effectiveness of these two treatments in managing patients with oligometastatic prostate cancer. METHODS: A comprehensive search of the literature was carried out to find pertinent publications that compared the results of radiation and cytoreductive surgery for oligometastatic prostate cancer. A meta-analysis was conducted in order to evaluate both short-term and long-term survival. Furthermore, utilizing institutional patient data, a retrospective cohort research was conducted to offer practical insights into the relative performances of the two treatment regimens. RESULTS: Five relevant studies' worth of data were included for this meta-analysis, which included 1425 patients with oligometastatic prostate cancer. The outcomes showed that, in comparison to radiation, cytoreductive surgery was linked to a substantially better cancer-specific survival (CSS) [hazard ratio (HR): 0.70, 95% (CI): 0.59-0.81, P <0.001] and overall survival (OS) [HR, 0.80; 95% (CI), 0.77-0.82; P <0.01]. The two therapy groups' Progression-Free Survival (PFS) and Castration-Resistant Prostate Cancer-Free Survival (CRPCFS), however, did not differ significantly (HR: 0.56, 95% CI: 0.17-1.06; HR: 0.67, 95% CI: 0.26-1.02, respectively). Out of the 102 patients who were recruited in the retrospective cohort research, 36 had cytoreductive surgery (CRP), 36 had radiation therapy (primary lesion), and 30 had radiation therapy (metastatic lesion). The follow-up time was 46.3 months (18.6-60.0) on average. The enhanced OS in the CRP group [OS interquartile range (IQR): 45-60 months] in comparison to the radiation group (OS IQR: 39.0-59.0 months and 25.8-55.0 months, respectively) was further supported by the cohort research. Furthermore, CRP had a better OS than both radiation (primary region) and radiotherapy (metastatic region), with the latter two therapeutic methods having similar OS. CONCLUSION: This meta-analysis and retrospective research provide valuable insights into the comparative efficacy of cytoreductive surgery and radiotherapy for oligometastatic prostate cancer. While short-term survival (PFS, CRPCFS) was similar between the two groups, cytoreductive surgery exhibited superior CSS and OS. Adverse event rates were manageable in both modalities. These findings contribute to informed treatment decision-making for clinicians managing oligometastatic prostate cancer patients. Further prospective studies and randomized controlled trials are essential to corroborate these results and guide personalized therapeutic approaches for this distinct subset of patients.

Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway.

BACKGROUND: Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. METHODS: Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. RESULTS: Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. CONCLUSION: Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.

A protein-encoding CCDC7 circular RNA inhibits the progression of prostate cancer by up-regulating FLRT3.

Circular RNAs (circRNAs) are a family of endogenous RNAs that have become a focus of biological research in recent years. Emerging evidence has revealed that circRNAs exert biological functions by acting as transcriptional regulators, microRNA sponges, and binding partners with RNA-binding proteins. However, few studies have identified coding circRNAs, which may lead to a hidden repertoire of proteins. In this study, we unexpectedly discovered a protein-encoding circular RNA circCCDC7(15,16,17,18,19) while we were searching for prostate cancer related chimeric RNAs. circCCDC7(15,16,17,18,19) is derived from exon 19 back spliced to exon 15 of the CCDC7 gene. It is significantly downregulated in patients with high Gleason score. Prostate cancer patients with decreased circCCDC7(15,16,17,18,19) expression have a worse prognosis, while linear CCDC7 had no such association. Overexpressed circCCDC7(15,16,17,18,19) inhibited prostate cancer cell migration, invasion, and viability, supporting classification of circCCDC7(15,16,17,18,19) as a bona fide tumor suppressor gene. We provide evidence that its tumor suppressive activity is driven by the protein it encodes, and that circCCDC7(15,16,17,18,19) encodes a secretory protein. Consistently, conditioned media from circCCDC7(15,16,17,18,19) overexpressing cells has the same tumor suppressive activity. We further demonstrate that the tumor suppressive activity of circCCDC7(15,16,17,18,19) is at least partially mediated by FLRT3, whose expression also negatively correlates with Gleason score and clinical prognosis. In conclusion, circCCDC7(15,16,17,18,19) functions as a tumor suppressor in prostate cancer cells through the circCCDC7-180aa secretory protein it encodes, and is a promising therapeutic peptide for prostate cancer.

Cuproptosis illustrates tumor micro-environment features and predicts prostate cancer therapeutic sensitivity and prognosis.

BACKGROUND: Prostate cancer (PCA) is a common malignant genitourinary tumor that significantly impacts patient survival. Cuproptosis, a copper-dependent programmed cell death mechanism, plays a vital role in tumor development, therapy resistance, and immune microenvironment regulation in PCA. However, research on cuproptosis in prostate cancer is still in its early stages. METHODS: Using the publicly available datasets TCGA and GEO, we first acquired the transcriptome and clinical information of PCA patients. The expression of cuprotosis-related genes (CRG) was identified and a prediction model was established based on LASSO-COX method. The predictive performance of this model was evaluated based on Kaplan-Meier method. Using GEO datasets, we further confirmed the critical genes level in the model. Tumor responses to immune checkpoint (ICP) inhibitors were predicted based on Tumor Immune Dysfunction and Exclusion (TIDE) score. The Genomics of Drug Sensitivity in Cancer (GDSC) was utilized to forecast drug sensitivity in cancer cells, whereas the GSVA was employed to analyze enriched pathways related to the cuproptosis signature. Subsequently, the function of PDHA1 gene in PCA was verified. RESULTS: A predictive risk model on basis of five cuproptosis-related genes (ATP7B, DBT, LIPT1, GCSH, PDHA1) were established. The progression free survival of low-risk group was obviously longer than the high-risk group, and exhibit better response to ICB therapy.Furthermore,PDHA1 is very important in the pathological process of PCA according to regressions analysis result, and the validation of external data sets were conducted. High PDHA1 expression patients with PCA not only had a shorter PFS and were less likely to benefit from ICB treatment, but they were also less responsive to multiple targeted therapeutic drugs. In preliminary research, PDHA1 knockdown significantly decreased the proliferation and invasion of PCA cells. CONCLUSION: This study established a novel cuproptosis-related gene-based prostate cancer prediction model that accurately predicts the prognosis of PCA patients. The model benefits individualized therapy and can assist clinicians in making clinical decisions for PCA patients. Furthermore, our data show that PDHA1 promotes PCA cell proliferation and invasion while modulating the susceptibility to immunotherapy and other targeted therapies. PDHA1 can be regarded as an important target for PCA therapy.

The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment.

BACKGROUND: Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients with castration-resistant prostate cancer (CRPC), but drug resistance remains a considerable clinical challenge. METHODS: We explored the role of Ribonucleotide reductase subunit M2 (RRM2), a gene associated with senescence, in the sensitivity of prostate cancer to docetaxel. We evaluated the RRM2 expression, docetaxel resistance, and ANXA1 expression in prostate cancer cell lines and tumour xenografts models. In addition, We assessed the impact of RRM2 knockdown, ANXA1 over-expression, and PI3K/AKT pathway inhibition on the sensitivity of prostate cancer cells to docetaxel. Furthermore, we assessed the sensitivity of prostate cancer cells to the combination treatment of COH29 and docetaxel. RESULTS: Our results demonstrated a positive association between RRM2 expression and docetaxel resistance in prostate cancer cell lines and tumor xenograft models. Knockdown of RRM2 increased the sensitivity of prostate cancer cells to docetaxel, suggesting its role in mediating resistance. Furthermore, we observed that RRM2 stabilizes the expression of ANXA1, which in turn activates the PI3K/AKT pathway and contributes to docetaxel resistance. Importantly, we found that the combination treatment of COH29 and docetaxel resulted in a synergistic effect, further augmenting the sensitivity of prostate cancer cells to docetaxel. CONCLUSION: Our findings suggest that RRM2 regulates docetaxel resistance in prostate cancer by stabilizing ANXA1-mediated activation of the PI3K/AKT pathway. Targeting RRM2 or ANXA1 may offer a promising therapeutic strategy to overcome docetaxel resistance in prostate cancer.

Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer.

Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-ß signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC.

Bladder cancer biomarker screening based on non-targeted urine metabolomics.

PURPOSE: Bladder cancer is one of the most common malignancies of the urinary system, and its screening relies heavily on invasive cystoscopy, which increases the risk of urethral injury and infection. This study aims to use non-targeted metabolomics methods to screen for metabolites that are significantly different between the urine of bladder cancer patients and cancer-free controls. METHODS: In this study, liquid chromatography-mass spectrometry was used to analyze the urine of bladder cancer patients (n = 57) and the cancer-free controls (n = 38) by non-targeted metabolomic analysis and metabolite identification. RESULTS: The results showed that there were significant differences in the expression of 27 metabolites between bladder cancer patients and the cancer-free controls. CONCLUSION: In the multivariate statistical analysis of this study, the urinary metabolic profile data of bladder cancer patients were analyzed, and the receiver operating characteristic curve analysis showed that it is possible to perform non-invasive clinical diagnoses of bladder cancer through these candidate biomarkers.

Glutathione-sensitive nanoparticles enhance the combined therapeutic effect of checkpoint kinase 1 inhibitor and cisplatin in prostate cancer.

Prostate cancer (PCa) is the second most common malignant tumor among males. Traditional treatments for PCa, which include surgery and endocrine therapy, have shown limited success, and more effective therapies are needed. Cisplatin (DDP) is an approved chemotherapeutic drug that causes DNA damage in cancer, whereas AZD7762, an inhibitor of CHK1, can significantly inhibit DNA repair. The effective therapeutic combination of cisplatin and the DNA damage response inhibitor AZD7762 has been considered to be a potential solution to the resistance to cisplatin and the adverse reactions that occur in many cancers. However, the co-transmission of cisplatin and AZD7762 and the unsatisfactory tumor-targeting efficacy of this therapy remain problems to be solved. Here, we confirmed the combined therapeutic efficacy of cisplatin and AZD7762 in PCa. Furthermore, we show that the glutathione-targeted Cys8E nanoparticles we synthesized, which have high drug-loading capacity, remarkable stability, and satisfactory release efficiency, enhanced the therapeutic efficacy of this treatment and reduced the required dosages of these drugs both in vitro and in vivo. Overall, we propose combination therapy of cisplatin and AZD7762 for PCa and facilitate it using Cys8E nanoparticles, which allow for better drug loading release, higher release efficiency, and more accurate tumor-targeting efficacy.

ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression.

Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKß activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKß to phosphorylate ARID1A, leading to its degradation via ß-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKß/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.