The functional implication of ATF6α in castration-resistant prostate cancer cells.

Stress in the endoplasmic reticulum (ER) may perturb proteostasis and activates the unfolded protein response (UPR). UPR activation is frequently observed in cancer cells and is believed to fuel cancer progression. Here, we report that one of the three UPR sensors, ATF6α, was associated with prostate cancer (PCa) development, while both genetic and pharmacological inhibition of ATF6α impaired the survival of castration-resistance PCa (CRPC) cells. Transcriptomic analyses identified the molecular pathways deregulated upon ATF6α depletion, and also discovered considerable disparity in global gene expression between ATF6α knockdown and Ceapin-A7 treatment. In addition, combined analyses of human CRPC bulk RNA-seq and single-cell RNA-seq (scRNA-seq) public datasets confirmed that CRPC tumors with higher ATF6α activity displayed higher androgen receptor (AR) activity, proliferative and neuroendocrine (NE) like phenotypes, as well as immunosuppressive features. Lastly, we identified a 14-gene set as ATF6α NE gene signature with encouraging prognostic power. In conclusion, our results indicate that ATF6α is correlated with PCa progression and is functionally relevant to CRPC cell survival. Both specificity and efficacy of ATF6α inhibitors require further refinement and evaluation.

The SDF-1/CXCR4 axis is involved in adipose-derived stem cell migration.

BACKGROUND: Intravenous injection of adipose-derived stem cells (ADSCs) can improve the urinary function of stress urinary incontinence (SUI) model rats and C-X-C chemokine receptor type 4 (CXCR4)-positive ADSCs are found in urethral tissues. The CXCR4 ligand stromal cell-derived factor-1 (SDF-1) is highly expressed in urinary incontinence model rats. In this study, we investigated the involvement of the SDF-1/CXCR4 axis in the homing of ADSCs. METHODS: ADSCs were isolated from rats and purified. The levels of CXCR4 and CXCR7 were determined by western blot analysis and immunofluorescence assays following stimulation with SDF-1. Hypoxia conditioning was performed to treat the cells in vitro, following which the messenger RNA (mRNA) and protein level of SDF-1, CXCR4, and CXCR7 were estimated. RESULTS: We found that CXCR4 and CXCR7 were expressed in ADSCs at passage zero (P0), P1, and P3, and the expression of both increased after SDF-1 stimulation. The level of expression of the mRNAs and proteins of SDF-1, CXCR4, and CXCR7 in ADSCs was higher after hypoxic conditioning. We then knocked down CXCR4 or CXCR7 using small interfering RNAs and found that the mRNA levels of CXCR4 and CXCR7 were considerably downregulated in the si-CXCR4/7-transfected cells. We also found that the SDF-1/CXCR4 axis was required for the migration of ADSCs. The phosphorylation levels of Janus kinase (JAK), protein kinase B (AKT), and extracellular regulated protein kinase significantly increased in SDF-1-stimulated ADSCs. However, the migration of ADSCs was suppressed when the corresponding specific inhibitors were used to block JAK and AKT signaling or silence CXCR4, whereas no significant change was observed in the migratory ability of ADSCs when the ERK pathway was blocked or CXCR7 was silenced. CONCLUSIONS: The SDF-1/CXCR4 axis is involved in the migration of ADSCs and may play a role in the migrate of ADSCs in SUI.

A new histone deacetylase inhibitor remodels the tumor microenvironment by deletion of polymorphonuclear myeloid-derived suppressor cells and sensitizes prostate cancer to immunotherapy.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy diagnosed in men. Immune checkpoint blockade (ICB) alone showed disappointing results in PCa. It is partly due to the formation of immunosuppressive tumor microenvironment (TME) could not be reversed effectively by ICB alone. METHODS: We used PCa cell lines to evaluate the combined effects of CN133 and anti-PD-1 in the subcutaneous and osseous PCa mice models, as well as the underlying mechanisms. RESULTS: We found that CN133 could reduce the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and CN133 combination with anti-PD-1 could augment antitumor effects in the subcutaneous PCa of allograft models. However, anti-PD-1 combination with CN133 failed to elicit an anti-tumor response to the bone metastatic PCa mice. Mechanistically, CN133 could inhibit the infiltration of PMN-MDSCs in the TME of soft tissues by downregulation gene expression of PMN-MDSC recruitment but not change the gene expression involved in PMN-MDSC activation in the CN133 and anti-PD-1 co-treatment group relative to the anti-PD-1 alone in the bone metastatic mice model. CONCLUSIONS: Taken together, our work firstly demonstrated that combination of CN133 with anti-PD-1 therapy may increase the therapeutic efficacy to PCa by reactivation of the positive immune microenvironment in the TME of soft tissue PCa.

Integrated analysis of single-cell and bulk transcriptomics develops a robust neuroendocrine cell-intrinsic signature to predict prostate cancer progression.

Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined. Methods: Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model. Results: Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets. Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers. Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores. By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression. Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. Conclusion: The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.

Pro-oncogene FBI-1 inhibits the ferroptosis of prostate carcinoma PC-3 cells via the microRNA-324-3p/GPX4 axis.

Ferroptosis has been characterized as non-apoptotic programmed cell death and is considered a novel strategy for antitumor treatment. The factor that binds to inducer of short transcripts-1 (FBI-1) is an important proto-oncogene playing multiple roles in human malignancies and the development of resistance to therapy. However, the roles of FBI-1 in ferroptosis of endocrine independent prostate carcinoma are still unknown. The results of this study showed that FBI-1 inhibited the ferroptosis of prostate carcinoma PC-3 cells (a typical endocrine-independent prostate carcinoma cell line) via the miR-324-3p/glutathione peroxidase 4 (miR-324-3p/GPX4) axis. Overexpression of FBI-1 enhanced the expression levels of GPX4. In contrast, knockdown of FBI-1 decreased the expression of GPX4 and induced the ferroptosis of PC-3 cells. The miR-324-3p decreased the expression of GPX4 by targeting the 3'-untranslated region of GPX4 to induce ferroptosis. Notably, FBI-1 increased the expression of GPX4 by repressing the levels of miR-324-3p. The transcription of miR-324-3p was mediated by specificity protein 1 (SP1), and FBI-1 repressed the expression of miR-324-3p by repressing the activation of SP1. In clinical specimens, the endogenous levels of FBI-1 were positively associated with Glutathione Peroxidase 4 (GPX4) and negatively related with the expression of miR-324-3p. Therefore, the results indicated that the miR-324-3p/GPX4 axis participates in the FBI-1-mediated ferroptosis of prostate carcinoma cells.

Integrated single-cell transcriptomic analyses identify a novel lineage plasticity-related cancer cell type involved in prostate cancer progression.

BACKGROUND: Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging. METHODS: Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples = 3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples = 93, cells = 222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, in vitro and in vivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings. FINDINGS: We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype. INTERPRETATION: Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa. FUNDING: This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).

IDO promotes the proliferation and invasion of prostate cancer cells through KYNU.

BACKGROUND: Prostate cancer (PCa) is one of the most common malignant tumors in male. OBJECTIVE: To explore the effect of indoleamine-2, 3-dioxygenase (IDO) on the proliferation and invasion of PCa cells and the potential mechanism. METHODS: PCa tissues and normal adjacent tissues were collected from 43 PCa patients. The expression of IDO in PCa tissues and cell lines were detected. The String website was used to search for IDO-related proteins. The GEPIA website was used to analyze the relationship between KYNU and the prognosis of PCa. Cells models of IDO overexpression and/or KYNU silencing were constructed to verify the role of KYNU in regulating PCa. The cell proliferation, apoptosis and invasion ability of PCa cells were detected by CCK-8 assay, Flow cytometry and Transwell assay. RESULTS: The IDO levels in PCa tissues and cells were higher than those in normal tissues and cells, which promoted the proliferation and invasion of LNCaP cells, and inhibited apoptosis. Silencing IDO inhibited the cells proliferation and invasion activities, and promoted the cell apoptosis. The high expression of KYNU was related to the poor disease free survival of PCa patients. Inhibiting KYUN significantly inhibited the promotion of PCa induced by IDO. CONCLUSION: IDO is overexpressed in PCa, which promotes the proliferation and invasion of PCa cells, and the cancer-promoting mechanism may be related to KYNU.

Calcium antagonists for acute ischemic stroke.

BACKGROUND: The sudden loss of blood supply in ischemic stroke is associated with the increase of calcium ions within neurons. Inhibiting this increase could protect neurons and hence might reduce neurological impairment, disability and handicap after stroke. OBJECTIVES: To determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke. To investigate the influence of different drugs, dosages, routes of administration, time intervals after stroke and trial design on the risk of a primary outcome. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (January 2012), MEDLINE (1950 to December 2011), EMBASE (1980 to December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011 issue 4) and four Chinese databases (December 2011): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure (CNKI), Chinese scientific periodical database of VIP information and Wanfang Data. We also contacted trialists and researchers. SELECTION CRITERIA: All truly randomized trials comparing a calcium antagonist with control in patients with acute ischemic stroke. DATA COLLECTION AND ANALYSIS: Two authors assessed all trials and extracted the data. We used death or dependency at the end of long-term follow-up (at least three months) in activities of daily living as the primary outcome. Analyses were, if possible, intention-to-treat. MAIN RESULTS: We included 34 trials including 7731 patients. There was no effect of calcium antagonists on the primary outcome (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.98 to 1.13), or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17). Comparisons of different doses of nimodipine suggested that the highest doses were associated with poorer outcome. AUTHORS' CONCLUSIONS: No evidence is available using calcium antagonists in patients with acute ischemic stroke is effective.

Corrigendum: TPX2 enhanced the activation of the HGF/ETS-1 pathway and increased the invasion of endocrine-independent prostate carcinoma cells.

[This corrects the article DOI: 10.3389/fonc.2021.618540.].

Clinical significance of EPHX2 deregulation in prostate cancer.

The arachidonic acid (AA) metabolic pathway participates in various physiological processes as well as in the development of malignancies. We analyzed genomic alterations in AA metabolic enzymes in the Cancer Genome Atlas (TCGA) prostate cancer (PCa) dataset and found that the gene encoding soluble epoxide hydrolase (EPHX2) is frequently deleted in PCa. EPHX2 mRNA and protein expression in PCa was examined in multiple datasets by differential gene expression analysis and in a tissue microarray by immunohistochemistry. The expression data were analyzed in conjunction with clinicopathological variables. Both the mRNA and protein expression levels of EPHX2 were significantly decreased in tumors compared with normal prostate tissues and were inversely correlated with the Gleason grade and disease-free survival time. Furthermore, EPHX2 mRNA expression was significantly decreased in metastatic and recurrent PCa compared with localized and primary PCa, respectively. In addition, EPHX2 protein expression correlated negatively with Ki67 expression. In conclusion, EPHX2 deregulation is significantly correlated with the clinical characteristics of PCa progression and may serve as a prognostic marker for PCa.

Long Non-coding RNA AGAP2-AS1 Silencing Inhibits PDLIM5 Expression Impeding Prostate Cancer Progression via Up-Regulation of MicroRNA-195-5p.

Prostate cancer remains a significant cause of cancer-related deaths in male population. More recently, accumulating evidence continues to implicate long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in various types of cancers, including prostate cancer. The current study aimed to elucidate the role of lncRNA AGAP2-AS1/miR-195-5p/PDZ and LIM domain 5 (PDLIM5) in prostate cancer progression. Initially, microarray expression profiles were applied to screen differentially expressed lncRNAs/miRNAs/genes associated with prostate cancer. Dual-luciferase reporter and RNA pull-down/RIP assays were subsequently performed to explore the interactions among lncRNA AGAP2-AS1, miR-195-5p, and PDLIM5, after which their expression was detected in cancer tissues and cells. Next, gain- and loss-of-function approaches were employed to elucidate the mechanism of lncRNA AGAP2-AS1/miR-195-5p/PDLIM5 in the processes of cell proliferation, migration and invasion as well as tumor growth. LncRNA AGAP2-AS1 was found to be highly expressed in prostate cancer. Silencing of lncRNA AGAP2-AS1 contributed to the suppression of proliferation, migration and invasion of cancer cells in vitro. Besides, lncRNA AGAP2-AS1 could bind to miR-195-5p which targeted PDLIM5 and subsequently downregulated its expression, ultimately impeding the progression of prostate cancer. Additionally, lncRNA AGAP2-AS1 inhibition led to an up-regulated expression of miR-195-5p and down-regulated PDLIM5 expression, resulting in delayed tumor growth in vivo. Taken together, the key findings of our study demonstrated that lncRNA AGAP2-AS1 silencing exerted suppressive effects on the development of prostate cancer via the miR-195-5p-dependent downregulation of PDLIM5. Our findings highlighted the potential of lncRNA AGAP2-AS1 as a promising novel molecular target for prostate cancer therapy.

The TGF-ß/Smad Pathway Inhibitor SB431542 Enhances The Antitumor Effect Of Radiofrequency Ablation On Bladder Cancer Cells.

BACKGROUND: Despite progress achieved in bladder cancer (BC) treatment, the prognosis of patients with advanced BC (ie, metastasized from the bladder to other organs) is poor. Although mortality in cases of low-grade BC is rare, the treatment, such as a radical cystectomy, often has a serious impact on the quality of life. Thus, research is needed to identify more effective treatment strategies and this work is aiming to examine the potential application of combination of radiofrequency ablation (RFA) and SB435142, a inhibitor of transforming growth factor ß (TGFß)/Smad pathway. METHODS: BC cells were transplanted into nude mice (thymusdeficiency Bal B/c) to form subcutaneous tumors. The mice with subcutaneous tumors were then treated with RFA and oral administration of SB431542, an inhibitor of TGFß/Smad signaling pathway. The antitumor effect of RFA was measured by tumor proliferation curves and micro-positron emission computed tomography (micro-PET). The effect of SB431542 on epithelial-mesenchymal transition (EMT) related regulators in subcutaneous tumor tissues formed by BC cells were examined by quantitative real-time polymerase chain reaction (qPCR) experiments. RESULTS: The SB431542 treatment enhanced the antitumor effect of RFA on subcutaneous growth of BCs. SB431542 also decreased EMT-related regulators in subcutaneous tumor tissues formed by BC cells in nude mice. CONCLUSION: SB431542 enhances the effect of RFA on BC.

A Cohort Study of Decompressive Craniectomy for Malignant Middle Cerebral Artery Infarction: A Real-World Experience in Clinical Practice.

Decompressive hemicraniectomy with malignant middle cerebral artery (MCA) infarction is effective but remains underutilized. The aim of this study was to observe the utilization of this intervention in mainland China.We included patients with malignant MCA infarction who admitted in West China Hospital between December 2007 to March 2011. The outcomes were death and favorable outcome (mRS < 4) at 1 month and 1 year. The multivariate logistic regression model was used to identify the independent predictors for outcomes.Ten percent (219/2174) of patients with acute ischemic stroke had malignant MCA infarction and 31.1% (68/219) patients meet the criteria that ≤60 years of age and the timing to hospital <48 hours after stroke onset. Of them, 18 patients (26.5%) underwent to decompressive hemicraniectomy. In total, 31 patients (14.2%) underwent the decompressive surgery. The average age was 53 ±â€Š12 years; median NIHSS score was 21. The case fatality rate of patients in surgery group was significantly lower than those of in nonsurgery group at 1 month and 1 year follow-ups (32.3% and 38.7% vs. 51.1% and 61.2%, respectively, P < 0.05). Patients in surgery group had a higher proportion of good outcome at 1 year follow-up (32.2% vs. 13.3%, P = 0.006). After adjusting for confounders including age, sex, NIHSS score, and GCS score on admission, decompressive hemicraniectomy was an independent predictor of good outcome for 1 year (OR = 3.44, 95% CI, 1.27-9.31).This study shows better outcomes in the surgical group, which are consistent with findings in previous prospective randomized trials. However, this beneficial intervention remains underutilized in clinical settings.

Association between asymptomatic carotid stenosis and cognitive function: a systematic review.

BACKGROUND: Asymptomatic carotid stenosis (CS), traditionally considered clinically silent, may be an independent risk factor for a cognitive impairment. METHODS: To determine whether an association exists between asymptomatic CS and cognitive function, we systematically reviewed the literature in the Cochrane Library, MEDLINE, EMBASE and the China National Knowledge Infrastructure databases. RESULTS: A total of 8 cross-sectional studies and 2 community-based cohort studies were included, comprising 763 participants in the CS group and 6308 participants in the non-CS group. All but one study supported the association between asymptomatic CS and cognitive impairment. Pooled analysis identified older age (2 studies) and cerebral hypoperfusion (2 studies) as additional factors in patients with asymptomatic CS that may linked to cognitive decline. CONCLUSIONS: These results suggest that rather than being clinically silent, asymptomatic CS may be associated with cognitive impairment, and this should be further investigated in high-quality studies.

Ozagrel for acute ischemic stroke: a meta-analysis of data from randomized controlled trials.

BACKGROUND: In patients with acute ischemic stroke (AIS), platelets are activated in the acute phase, releasing neurotoxic, and thrombogenic eicosanoids, which may reduce the brain blood flow and cause brain damage. Sodium ozagrel (ozagrel), a thromboxane A2 synthase inhibitor, is one of the most studied drugs which may reduce the risk of neurological impairment and reduce the volume of brain damage. We systematically reviewed all published randomized controlled trials (RCTs) comparing ozagrel with control among patients with AIS. METHODS: We searched seven databases, using the Cochrane Stroke Group search strategy and the terms of ozagrel and stroke. Two independent investigators evaluated trial quality using the Cochrane Collaboration's risk of bias tool and extracted the data from each study. Pooled analyses for the outcomes of combined death or disability and improvement of neurological impairment were calculated. RESULTS: The effect of ozagrel on the reduction of death for AIS at the end of follow-up was relative risk (RR) = 0·67 (95% CI: 0·11 to 4·04, P = 0·67). The effect evaluated by Modified Edinburgh-Scandinavian Stroke Scale (MESSS) at the end of treatment was mean difference (MD) = -4·17 (95% CI, -4·95 to -3·40; P<0·00001). The most severe adverse events of ozagrel were digestive hemorrhage and hemorrhagic stroke; however, there was no significant difference between the two groups. The subgroup analysis of different dose showed that 80 and 160 mg ozagrel per day might both increase the improvement of the neurological impairment. DISCUSSION: During scheduled treatment, ozagrel is effective for the improvement of neurological impairment for AIS patients. However, the evidence of ozagrel to reduce the long-term death or disability is limited and quality of these trials is insufficent hence, large-sample and high quality RCTs are warrented to confirm the efficacy of ozagrel for acute ischemic stroke.