CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling.

BACKGROUND: Circular RNAs (circRNAs) mediate the infiltration of tumor-associated macrophages (TAMs) to facilitate carcinogenesis and development of various types of cancers. However, the role of circRNAs in regulating macrophages in prostate cancer (PCa) remains uncertain. METHODS: Differentially expressed circRNAs in PCa were identified by RNA sequencing. The expression of circSMARCC1 was recognized and evaluated using fluorescence in situ hybridization and quantitative real-time PCR. The oncogenic role of circSMARCC1 in PCa tumor proliferation and metastasis was investigated through a series of in vitro and in vivo assays. Finally, Western blot, biotin-labeled RNA pulldown, luciferase assay, rescue experiments, and co-culture experiments with TAMs were conducted to reveal the mechanistic role of circSMARCC1. RESULTS: CircSMARCC1 was dramatically up-regulated in PCa cells, plasma and tissues. Overexpression of circSMARCC1 promotes tumor proliferation and metastasis both in vitro and in vivo, whereas knockdown of circSMARCC1 exerts the opposite effects. Mechanistically, circSMARCC1 regulates the expression of CC-chemokine ligand 20 (CCL20) via sponging miR-1322 and activate PI3K-Akt signaling pathway involved in the proliferation and epithelial mesenchymal transformation. More importantly, high expression of circSMARCC1 was positively associated with colonization of CD68+/CD163+/CD206+ TAMs in tumor microenvironment. In addition, overexpression of circSMARCC1 facilitates the expression of CD163 in macrophages through the CCL20-CCR6 axis, induces TAMs infiltration and M2 polarization, thereby leading to PCa progression. CONCLUSIONS: CircSMARCC1 up-regulates the chemokine CCL20 secretion by sponging miR-1322, which is involved in the crosstalk between tumor cells and TAMs by targeting CCL20/CCR6 signaling to promote progression of PCa.

Hsa_circ_0003258 promotes prostate cancer metastasis by complexing with IGF2BP3 and sponging miR-653-5p.

BACKGROUND: More and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown. METHODS: Differentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. RESULTS: Increased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa. CONCLUSIONS: Upregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.

A novel immune-related gene-based prognostic signature to predict biochemical recurrence in patients with prostate cancer after radical prostatectomy.

Accumulating evidences indicates that the immune landscape signature dramatically correlates with tumorigenesis and prognosis of prostate cancer (PCa). Here, we identified a novel immune-related gene-based prognostic signature (IRGPS) to predict biochemical recurrence (BCR) after radical prostatectomy. We also explored the correlation between IRGPS and tumor microenvironment. We identified an IRGPS consisting of seven immune-related genes (PPARGC1A, AKR1C2, COMP, EEF1A2, IRF5, NTM, and TPX2) that were related to the BCR-free survival of PCa patients. The high-risk patients exhibited a higher fraction of regulatory T cells and M2 macrophages than the low-risk BCR patients (P < 0.05) as well as a lower fraction of resting memory CD4 T cells and resting mast cells. These high-risk patients also had higher expression levels of CTLA4, TIGIT, PDCD1, LAG3, and TIM3. Finally, a strong correlation was detected between IRGPS and specific clinicopathological features, including Gleason scores and tumor stage. In conclusion, our study reveals the clinical significance and potential functions of the IRGPS, provides more data for predicting outcomes, and suggests more effective immunotherapeutic target strategies for PCa.

UBE2W down-regulation promotes cell apoptosis and correlates with hypospermatogenesis.

Ubiquitin conjugating enzyme (E2) is crucial for mediating N-terminal ubiquitination. Recent study reports that UBE2W is involved in male infertility. However, the correlation between UBE2W expression and hypospermatogenesis is unclear. The present study is to explore the biological role of UBE2W and its association with hypospermatogenesis. Results showed that the sexpression levels of UBE2W in mouse testes were gradually elevated from 2 to 10 weeks, while were significantly deceased in the testes with hypospermatogenesis. When UBE2W expression was successfully down-regulated in spermatogenic cells, the rate of apoptosis was significantly increased and the P53/Bcl-2/caspase 6/caspase 9 signal pathways were activated. Thus, these data indicate that UBE2W down-regulation promotes cell apoptosis and correlates with hypospermatogenesis, which may be helpful for the diagnosis of male infertility.

Synthesis and biological evaluation of arylpiperazine derivatives as potential anti-prostate cancer agents.

A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.

PRPS2 Expression Correlates with Sertoli-Cell Only Syndrome and Inhibits the Apoptosis of TM4 Sertoli Cells.

PURPOSE: Sertoli-cell only syndrome is one of the reasons for male infertility but its pathogenesis remains unclear. PRPS2, a subset of PRS, is reported to be a potential protein associated with Sertoli-cell only syndrome. In this study we further investigated the correlation between PRPS2 and Sertoli-cell only syndrome, and evaluated the effect of PRPS2 expression on apoptosis of TM4 Sertoli cells. MATERIALS AND METHODS: PRPS2 expression was detected in patients with Sertoli-cell only syndrome and normal spermatogenesis, and in Sertoli-cell only syndrome mouse models by immunohistochemistry, quantitative reverse transcription-polymerase chain reaction and Western blot. PRPS2 expression in TM4 Sertoli cells was then down-regulated and up-regulated by lentivirus vectors. The effect of PRPS2 expression on cell apoptosis and cell cycle transition was evaluated by flow cytometry. RESULTS: PRPS2 expression in patients with Sertoli-cell only syndrome was significantly greater than in those with normal spermatogenesis. A significant increase in PRPS2 expression was observed in Sertoli-cell only syndrome mouse models. PRPS2 over expression significantly inhibited cell apoptosis and promoted cell cycle transition in TM4 Sertoli cells. However, PRPS2 down-regulation showed a reverse effect. Moreover, results revealed that PRPS2 over expression inhibited cell apoptosis via the p53/Bcl-2/caspase-9/caspase-3/caspase-6/caspase-7 signaling pathway. CONCLUSIONS: PRPS2 expression correlates with Sertoli-cell only syndrome and inhibits the apoptosis of TM4 Sertoli cells via the p53/Bcl-2/caspases signaling pathway.

NAT10 Promotes Prostate Cancer Growth and Metastasis by Acetylating mRNAs of HMGA1 and KRT8.

N4-acetylcytidine (ac4C) is essential for the development and migration of tumor cells. According to earlier research, N-acetyltransferase 10 (NAT10) can increase messenger RNAs (mRNAs) stability by catalyzing the synthesis of ac4C. However, little is known about NAT10 expression and its role in the acetylation modifications in prostate cancer (PCa). Thus, the biological function of NAT10 in PCa is investigated in this study. Compared to paraneoplastic tissues, the expression of NAT10 is significantly higher in PCa. The NAT10 expression is strongly correlated with the pathological grade, clinical stage, Gleason score, T-stage, and N-stage of PCa. NAT10 has the ability to advance the cell cycle and the epithelial-mesenchymal transition (EMT), both of which raise the malignancy of tumor cells. Mechanistically, NAT10 enhance the stability of high mobility group AT-hook 1 (HMGA1) by acetylating its mRNA, thereby promoting cell cycle progression to improve cell proliferation. In addition, NAT10 improve the stability of Keratin 8 (KRT8) by acetylating its mRNA, which promotes the progression of EMT to improve cell migration. This findings provide a potential prognostic or therapeutic target for PCa.

Exposure to elevated temperature affects the expression of PIWI-interacting RNAs and associated transcripts in mouse testes.

BACKGROUND: Exposure to heat waves could result in adverse effects on human health, especially in male testicles. PIWI-interacting RNA (piRNA) is a novel type of small non-coding RNA, which can notably impact mRNA turnover and preserve germline maintenance in germline cells. However, piRNA's expression status when adapting to testicular heat stress remains largely unclear. OBJECTIVES: To investigate the function and mechanisms of relevant piRNAs during testicular heat stress. MATERIALS AND METHODS: In this study, a mouse testicular heat stress model was constructed, and the testes were removed for piRNA-sequencing. Bioinformatics analysis was used to discover the differential expressed piRNAs, piRNA clusters, and enriched pathways. A cell heat stress model was constructed to validate the top five upregulated piRNAs. Proliferation and apoptosis assays were utilized to validate the function of selected piRNA. Bioinformatics prediction, western blotting, and immunohistochemistry were used to illustrate the downstream mechanisms. RESULTS: Through the bioinformatics analysis, we identified the differential expression profile and enriched pathways of piRNAs and piRNA clusters during testicular hyperthermia. Besides, piR-020492 was proved to be upregulated in heat stress mouse testes and a germ cell model. A series of in vitro assays illustrated that an overexpression of piR-020492 could restrain the proliferation and promote the apoptosis of mouse germ cells. Kyoto Encyclopedia of Genes and Genomes analysis of piRNA-generating genes in the testicular heat stress model and piR-020492 targeting genes showed that the overlap pathways are adenosine monophosphate-activated protein kinase (AMPK) and insulin pathways. Validation experiments demonstrated that the key genes of AMPK and insulin pathway exhibit differential expression after an overexpression of piR-020492 or testicular heat stress. DISCUSSION AND CONCLUSION: In conclusion, our findings revealed the expression profile of piRNAs in testicular heat stress and illustrated the function and mechanisms of piR-020492 in germ cells, which could provide novel insights into the mechanism of hyperthermia-induced testicular injury.

Hsa_circ_0063329 inhibits prostate cancer growth and metastasis by modulating the miR-605-5p/tgif2 axis.

Circular RNAs play crucial regulatory roles in the progression of various cancers. Nevertheless, the underlying mechanisms of circRNAs in prostate cancer (PCa) proliferation and metastasis remain largely uncertain. Here, we performed circRNA microarray analyses to identify differentially expressed circRNAs in a normal prostate epithelial cell line and PCa cell lines. We found that hsa_circ_0063329 was significantly downregulated in PCa. A series of in vitro and in vivo functional assays showed that overexpression of hsa_circ_0063329 inhibits PCa cell progression, while silencing of hsa_circ_0063329 achieved the opposite effects. Mechanistically, bioinformatics analysis, RNA pulldown, RNA-seq and dual-luciferase reporter assays demonstrated that hsa_circ_0063329 exerts its effect by sponging miR-605-5p to derepress TG-interacting factor 2 (TGIF2) and inactivate the TGF-ß pathway. In conclusion, hsa_circ_0063329 inhibits the proliferation and metastasis of PCa via modulation of the miR-605-5p/TGIF2 axis, and targeting hsa_circ_0063329 may provide a promising treatment strategy for aggressive PCa.

Comprehensive analysis of the biological functions of endoplasmic reticulum stress in prostate cancer.

Introduction: Endoplasmic reticulum stress (ERS) has sizeable affect on cancer proliferation, metastasis, immunotherapy and chemoradiotherapy resistance. However, the effect of ERS on the biochemical recurrence (BCR) of prostate cancer patients remains elusive. Here, we generated an ERS-related genes risk signature to evaluate the physiological function of ERS in PCa with BCR. Methods: We collected the ERS-related genes from the GeneCards. The edgeR package was used to screen the differential ERS-related genes in PCa from TCGA datasets. ERS-related gene risk signature was then established using LASSO and multivariate Cox regression models and validated by GEO data sets. Nomogram was developed to assess BCR-free survival possibility. Meanwhile, the correlations between ERS-related signature, gene mutations, drug sensitivity and tumor microenvironment were also investigated. Results: We obtained an ERS risk signature consisting of five genes (AFP, COL10A1, DNAJB1, EGF and PTGS2). Kaplan Meier survival analysis and ROC Curve analysis indicated that the high risk score of ERS-related gene signature was associated with poor BCR-free prognosis in PCa patients. Besides, immune cell infiltration and immune checkpoint expression levels differed between high- and low-risk scoring subgroups. Moreover, drug sensitivity analyzed indicated that high-risk score group may be involved in apoptosis pathway. Discussion: This study comprehensively analyzed the characteristics of ERS related genes in PCa, and created a five-gene signature, which could effectively predict the BCR time of PCa patients. Targeting ERS related genes and pathways may provide potential guidance for the treatment of PCa.

Exosomal PGAM1 promotes prostate cancer angiogenesis and metastasis by interacting with ACTG1.

Tumor-derived exosomes and their contents promote cancer metastasis. Phosphoglycerate mutase 1 (PGAM1) is involved in various cancer-related processes. Nevertheless, the underlying mechanism of exosomal PGAM1 in prostate cancer (PCa) metastasis remains unclear. In this study, we performed in vitro and in vivo to determine the functions of exosomal PGAM1 in the angiogenesis of patients with metastatic PCa. We performed Glutathione-S-transferase pulldown, co-immunoprecipitation, western blotting and gelatin degradation assays to determine the pathway mediating the effect of exosomal PGAM1 in PCa. Our results revealed a significant increase in exosomal PGAM1 levels in the plasma of patients with metastatic PCa compared to patients with non-metastatic PCa. Furthermore, PGAM1 was a key factor initiating PCa cell metastasis by promoting invadopodia formation and could be conveyed by exosomes from PCa cells to human umbilical vein endothelial cells (HUVECs). In addition, exosomal PGAM1 could bind to γ-actin (ACTG1), which promotes podosome formation and neovascular sprouting in HUVECs. In vivo results revealed exosomal PGAM1 enhanced lung metastasis in nude mice injected with PCa cells via the tail vein. In summary, exosomal PGAM1 promotes angiogenesis and could be used as a liquid biopsy marker for PCa metastasis.

Identification and validation of a novel signature for prediction the prognosis and immunotherapy benefit in bladder cancer.

BACKGROUND: Bladder cancer (BC) is a common urinary tract system tumor with high recurrence rate and different populations show distinct response to immunotherapy. Novel biomarkers that can accurately predict prognosis and therapeutic responses are urgently needed. Here, we aim to identify a novel prognostic and therapeutic responses immune-related gene signature of BC through a comprehensive bioinformatics analysis. METHODS: The robust rank aggregation was conducted to integrate differently expressed genes (DEGs) in datasets of the Cancer Genome Atlas (TCGA) and the gene expression omnibus (GEO). Lasso and Cox regression analyses were performed to formulate a novel mRNA signature that could predict prognosis of BC patients. Subsequently, the prognostic value and predictive value of the signature was validated with two independent cohorts GSE13507 and IMvigor210. Finally, quantitative Real-time PCR (qRT-PCR) analysis was conducted to determine the expression of mRNAs in BC cell lines (UM-UC-3, EJ-1, SW780 and T24). RESULTS: We built a signature comprised the eight mRNAs: CNKSR1, COPZ2, CXorf57, FASN, PCOLCE2, RGS1, SPINT1 and TPST1. Our prognostic signature could be used to stratify BC population into two risk groups with distinct immune profile and responsiveness to immunotherapy. The results of qRT-PCR demonstrated that the eight mRNAs exhibited different expression levels in BC cell lines. CONCLUSION: Our study constructed a convenient and reliable 8-mRNA gene signature, which might provide prognostic prediction and aid treatment decision making of BC patients in clinical practice.

Gut dysbiosis promotes prostate cancer progression and docetaxel resistance via activating NF-κB-IL6-STAT3 axis.

BACKGROUND: The gut microbiota is reportedly involved in the progression and chemoresistance of various human malignancies. However, the underlying mechanisms behind how it exerts some effect on prostate cancer, as an extra-intestinal tumor, in a contact-independent way remain elusive and deserve exploration. Antibiotic exposure, one of the various factors affecting the gut microbiota community and capable of causing gut dysbiosis, is associated with multiple disorders. This study aims to preliminarily clarify the link between gut dysbiosis and prostate cancer. RESULTS: First, we discovered that perturbing the gut microbiota by consuming broad-spectrum antibiotics in water promoted the growth of subcutaneous and orthotopic tumors in mice. Fecal microbiota transplantation could transmit the effect of antibiotic exposure on tumor growth. Then, 16S rRNA sequencing for mouse feces indicated that the relative abundance of Proteobacteria was significantly higher after antibiotic exposure. Meanwhile, intratumoral lipopolysaccharide (LPS) profoundly increased under the elevation of gut permeability. Both in vivo and in vitro experiments revealed that the NF-κB-IL6-STAT3 axis activated by intratumoral LPS facilitated prostate cancer proliferation and docetaxel chemoresistance. Finally, 16S rRNA sequencing of patients' fecal samples revealed that Proteobacteria was enriched in patients with metastatic prostate cancer and was positively correlated with plasma IL6 level, regional lymph node metastasis status, and distant metastasis status. The receiver operating characteristic (ROC) curves showed that the relative abundance of Proteobacteria had better performance than the prostate-specific antigen (PSA) level in predicting the probability of distant metastasis in prostate cancer (area under the ROC curve, 0.860; p < 0.001). CONCLUSION: Collectively, this research demonstrated that gut dysbiosis, characterized by the enrichment of Proteobacteria due to antibiotic exposure, resulted in the elevation of gut permeability and intratumoral LPS, promoting the development of prostate cancer via the NF-κB-IL6-STAT3 axis in mice. Considering findings from human patients, Proteobacteria might act as an intestinal biomarker for progressive prostate cancer. Video Abstract.

N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability.

The fat mass and obesity-associated protein (FTO) is an N6-Methyladenosine (m6A) demethylase, which has been revealed to play critical roles in tumorigenesis. However, its role in the development and progression of prostate cancer (PCa) remains poorly understood. Here, we aimed to investigate the function and clinical relevance of FTO in PCa. Our results demonstrated that FTO was notably downregulated in PCa tissues compared with the paired normal tissues. In addition, the decreased expression of FTO was correlated with poor prognosis of PCa. Functional experiments showed that depletion of FTO promoted the proliferation and metastasis of PCa both in vitro and in vivo. Conversely, ectopic expression of FTO exhibited the opposite effects. Combined with RNA-sequencing, MeRIP-RT-qPCR, and mRNA stability assays indicated chloride intracellular channel 4(CLIC4) was a functional target of FTO-mediated m6A modification. FTO depletion significantly increased the m6A level of CLIC4 mRNA and then reduced the mRNA stability. In conclusion, our findings suggest that FTO suppresses PCa proliferation and metastasis through reducing the degradation of CLIC4 mRNA in an m6A dependent manner. FTO may be used as a promising novel therapeutic target and prognostic evaluation biomarker for PCa.

Evaluating the Lower Urinary Tract Syndrome with a Telemedicine Application: An Exploration of the Electronic Audiovisual Prostate Symptom Score.

Background: The Visual Prostate Symptom Score (VPSS) is used for the assessment of lower urinary tract symptoms (LUTS). It is usually administered by general practitioners (GPs), but in these cases, outcomes do not seem to be reflecting the real conditions of a patient well, with consequent risks of misestimations and misinterpretations. We developed an electronic audiovisual version of VPSS (EPSS), a new symptom scale based on a telemedicine mobile light-based app. The aim of this study is to test and evaluate its reliability. Methods: We enrolled male patients aged between 50 and 80 years across 24 community-based healthcare facilities in Guangzhou, China. Patients were asked to complete the Chinese version of VPSS and EPSS before consultation with the urology specialists. Patients were divided into two groups based on age. First, we analyzed the rate of full understanding of EPSS using a chi-square test. Then, we analyzed the difference between each score of EPSS, VPSS, and outcomes measured by specialists, used as the reference score (RS). Finally, the outcomes were analyzed with the Spearman test and Bartlett test separately. Results: Seventy-nine male patients were included (mean age 70.42 years). Patients were divided into two groups: group 1 (>70 years, n = 40) and group 2 (<70 years, n = 39). The full-understanding rates in groups 1 and 2 were 50% and 64.1%, respectively. No significant differences were noted between groups (p = 0.206). A t-test was presented between each question of VPSS, EPSS, and RS. All questions did not display significant differences (p > 0.05); total scores from the three scales had no significant differences in the evaluation of LUTS. We further explored the variations of choices made by patients in different scales. Spearman's test among VPSS, EPSS, and RS showed positive correlations, and coefficients of the total score were 0.92, 0.91, and 0.93 (p < 0.05). Conclusion: EPSS can be easily used in a significant number of patients and showed correlation with the VPSS and RS. Moreover, certain items resulted in better performance than VPSS. The results showed that EPSS could be a valuable option for both patients and GPs monitoring LUTS and particularly helpful when teleconsultations are considered, especially during the COVID-19 pandemic.

Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer.

Owing to incurable castration-resistant prostate cancer (CRPC) ultimately developing after treating with androgen deprivation therapy (ADT), it is vital to devise new therapeutic strategies to treat CRPC. Treatments that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for human cancers with clinical benefit. However, many patients, especially prostate cancer, fail to respond to anti-PD-1/PD-L1 treatment, so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy. In the present study, analyzing the data from our prostate cancer tissue microarray, we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L (HnRNP L). Hence, we further investigated the potential role of HnRNP L on the PD-L1 expression, the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC. Indeed, HnRNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo, on the contrary, HnRNP L overexpression led to the opposite effect in CRPC cells. In addition, consistent with the previous study, we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death, and HnRNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells. Furthermore, HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with anti-PD-1 therapy in CRPC tumors. This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.

CD8+ T Cell-Based Molecular Classification With Heterogeneous Immunogenomic Landscapes and Clinical Significance of Clear Cell Renal Cell Carcinoma.

The tumor microenvironment (TME) exerts a high impact on tumor biology and immunotherapy. The heterogeneous phenotypes and the clinical significance of CD8+ T cells in TME have not been fully elucidated. Here, a comprehensive immunogenomic analysis based on multi-omics data was performed to investigate the clinical significance and tumor heterogeneity between CD8+ T cell-related molecular clusters. We identified two distinct molecular clusters of ccRCC (C1 and C2) in TCGA and validated in E-MTAB-1980 cohorts. The C1 cluster was characterized by unfavorable prognosis, increased expression levels of CD8+ T cell exhaustion markers, high immune infiltration levels as well as more immune escape mechanisms. The C2 cluster was featured by favorable prognosis, elevated expression levels of CD8+ T cell effector markers, low load of copy number loss and low frequency of 9p21.3 deletion. Moreover, the effect of molecular classifications on Nivolumab therapeutic efficacy in the CheckMate 025 cohort was examined, and the C2 cluster exhibited a better prognosis. Taken together, we determine two CD8+ T cell-related molecular clusters in ccRCC, and provide new insights for evaluating the functions of CD8+ T cells. Our molecular classification is a potential strategy for prognostic prediction and immunotherapeutic guidance for ccRCC patients.

Cause-specific mortality of low and selective intermediate-risk prostate cancer patients with active surveillance or watchful waiting.

BACKGROUND: Active surveillance or watchful waiting (AS/WW) is increasingly being used as an alternative strategy to radical prostatectomy or radiation therapy for appropriately selected patients with prostate cancer (PCa). However, the prognosis of low-risk and selective intermediate-risk PCa patients after AS/WW is poorly defined. In this study we reviewed the patients registered in the Surveillance, Epidemiology, and End Results (SEER) Program to establish a competing risk nomogram for the prediction of prostate cancer-specific mortality (PCSM). METHODS: The information of patients undergoing AS/WW in the SEER program from 2004 to 2015 was obtained. All patients were ISUP (International Society of Urological Pathology) grade 1 or 2 PCa and also fulfilled the National Comprehensive Cancer Network's definition of low-risk PCa [prostate specific antigen (PSA) <10 ng/mL and cT2aN0M0 or less)]. A competing risk nomogram was used to analyze the association of tumor characteristics with PCSM and non-PCSM among the PCa patients with AS/WW. All cases were randomly divided into a training cohort and a validation cohort (1:1). A competing risk nomogram was constructed to predict PCSM in PCa patients with AS/WW. The performance of the PCSM nomogram was evaluated using the concordance index (C-index) and calibration curve. RESULTS: A total of 30,538 PCa patients were identified as low risk or selective intermediate risk with AS/WW. The 10-year cumulative incidence of death from prostate cancer and death from other cause were 2.8% (95% CI: 2.4-3.1%) and 19.3% (95% CI: 17.8-20.5%), respectively. Variables associated with PCSM included age, marital status, PSA, and ISUP grade. The PCSM nomogram had a good performance in both the training and validation cohorts, with a C-index of 0.744 (95% CI: 0.700-0.781, P<0.001) and 0.738 (95% CI: 0.700-0.777, P<0.001), respectively. CONCLUSIONS: Overall, the prognosis was favorable for the low- and selective intermediate-risk PCa patients with AS/WW. The competing risk nomogram yielded a good performance in identifying subgroups of patients with a higher risk of PCSM and potential candidates for AS/WW.

Identification and Validation of a Prognostic 5-Protein Signature for Biochemical Recurrence Following Radical Prostatectomy for Prostate Cancer.

Background: Biochemical recurrence (BCR) is an indicator of prostate cancer (PCa)-specific recurrence and mortality. However, there is a lack of an effective prediction model that can be used to predict prognosis and to determine the optimal method of treatment for patients with BCR. Hence, the aim of this study was to construct a protein-based nomogram that could predict BCR in PCa. Methods: Protein expression data of PCa patients was obtained from The Cancer Proteome Atlas (TCPA) database. Clinical data on the patients was downloaded from The Cancer Genome Atlas (TCGA) database. Lasso and Cox regression analyses were conducted to select the most significant prognostic proteins and formulate a protein signature that could predict BCR. Subsequently, Kaplan-Meier survival analysis and Cox regression analyses were conducted to evaluate the performance of the prognostic protein-based signature. Additionally, a nomogram was constructed using multivariate Cox regression analysis. Results: We constructed a 5-protein-based prognostic prediction signature that could be used to identify high-risk and low-risk groups of PCa patients. The survival analysis demonstrated that patients with a higher BCR showed significantly worse survival than those with a lower BCR (p < 0.0001). The time-dependent receiver operating characteristic curve showed that the signature had an excellent prognostic efficiency for 1, 3, and 5-year BCR (area under curve in training set: 0.691, 0.797, 0.808 and 0.74, 0.739, 0.82 in the test set). Univariate and multivariate analyses indicated that this 5-protein signature could be used as independent prognosis marker for PCa patients. Moreover, the concordance index (C-index) confirmed the predictive value of this 5-protein signature in 3, 5, and 10-year BCR overall survival (C-index: 0.764, 95% confidence interval: 0.701-0.827). Finally, we constructed a nomogram to predict BCR of PCa. Conclusions: Our study identified a 5-protein-based signature and constructed a nomogram that could reliably predict BCR. The findings might be of paramount importance for the prediction of PCa prognosis and medical decision-making. Subjects: Bioinformatics, oncology, urology.