FOXA1-dependent PUS1 regulates EIF3b stability in a non-enzymatic pathway mediating prostate cancer bone metastasis.

Bone metastasis is a significant contributor to the poor prognosis in prostate cancer. Recent evidence highlights the pivotal role of pseudouridine synthases in solid tumor progression, yet the specific enzyme driving prostate cancer metastasis remains unidentified. This study uncovers a novel regulatory mechanism of the FOXA1/PUS1/EIF3b signaling axis in prostate cancer bone metastasis. We identified elevated PUS1 expression in prostate cancer tissues, correlating with higher clinical grade and worse prognosis. Knockdown of PUS1 inhibited metastasis independently of its enzymatic activity, with EIF3b acting as a downstream effector, protected from ubiquitin-mediated degradation by PUS1. Overexpression of EIF3b countered the metastasis suppression due to PUS1 knockdown. Additionally, FOXA1 was shown to enhance PUS1 expression by binding to its promoter. Mogroside IV-E, a specific PUS1 inhibitor, demonstrated potent anti-metastatic effects by reducing PUS1 expression. Our findings highlight the FOXA1/PUS1/EIF3b axis as a critical mediator of prostate cancer bone metastasis and suggest that targeting this pathway could be a promising therapeutic strategy.

SERPINH1 modulates apoptosis by inhibiting P62 ubiquitination degradation to promote bone metastasis of prostate cancer.

Prostate cancer (PCa) is one of the most prevalent urogenital malignancies. Bone metastasis from PCa reduces patient survival rates significantly. There currently exists no effective treatment for bone metastatic PCa, and the underlying mechanisms remain unclear. This study performed transcriptomic screening on PCa bone metastasis specimens and intersection analysis in public databases and identified SERPINH1 as a potential target for treatment. SERPINH1 was found to be upregulated in PCa bone metastases and with poor prognosis, high Gleason score, and advanced metastatic status. SERPINH1 induced PCa cells' bone metastasis in vivo, promoted their proliferation, and mitigated apoptosis. Mechanistically, SERPINH1 bound to P62, reducing TRIM21-mediated K63-linked ubiquitination degradation of P62 and promoting proliferation and resistance to apoptosis of PCa. This study suggests the regulation of ubiquitination degradation of P62 by SERPINH1 that promotes PCa bone metastasis and can be considered as a potential target for treatment of bone metastatic PCa.

SALL4 correlates with proliferation, metastasis, and poor prognosis in prostate cancer by affecting MAPK pathway.

BACKGROUND: The mechanism involved in prostate cancer (PCa) metastasis is still poorly understood, and several oncogenes are known to regulate this process. However, the role of spalt-like transcription factor 4 (SALL4) in PCa metastasis remains unclear. METHODS: We performed RNA-sequencing to compare the mRNA expression profiles of seven localized PCa tissues and six metastatic PCa tissues. SALL4 was then identified and compared in the localized PCa and metastatic PCa. Immunohistochemical studies, qRT-PCR, and Western blot were performed to analyze the expression of SALL4 in PCa patients and cell lines. SALL4 expression and its relevance to clinical traits and prognosis were further explored in the TCGA database and in our 68 clinical samples. Subsequently, we knocked down SALL4 in DU145 and PC3 cells and performed a series of functional assays to explore the effect of SALL4 on PCa progression. Finally, protein levels of SALL4 and core components of the MAPK pathway were measured by Western blot, and cells were treated with PD0325901 to observe proliferation and metastasis. RESULTS: Significantly higher expression of SALL4 was found in metastatic PCa than in localized PCa. In addition, high SALL4 expression was significantly associated with high pathological T stage, N stage, Gleason score, and poor disease-free survival in TCGA database and in our clinical samples. Functional studies indicated that knockdown of SALL4 in DU145 and PC3 inhibited proliferation, migration, and angiogenesis. Furthermore, the ERK and P38 protein phosphorylation significantly reduced after knockdown of SALL4 in DU145 and PC3, indicating the inactivation of the MAPK signaling pathway. Finally, the proliferation and migration ability of DU145 and PC3 cells were significantly decreased after PD0325901 treatment. CONCLUSIONS: SALL4 predicts unfavorable outcome and is closely associated with PCa progression, suggesting that SALL4 may be a promising prognostic marker and potential therapeutic target for PCa.

Bibliometric analysis of the global research development of bone metastases in prostate cancer: A 22-year study.

Background: Prostate cancer (PCa) is the second most diagnosed cancer in men. Most PCa-related deaths result from metastatic disease. Metastases occur most often in the bones (90%). However, the current treatments for bone metastases in PCa are not very effective. Here we present an overview of the current research situation of bone metastases in PCa, focusing on hotspots and trends. Methods: We searched the Web of Science Core Collection database for publications related to bone metastases in PCa published between 1999 and 2021. We used VOSviewer, CiteSpace, and a bibliometric online platform to perform a bibliometric analysis of countries, institutions, authors, journals, references, and keywords. Results: A total of 4,832 related articles were included in the present study. The USA published the most articles in the field, followed by China and England. The University of Texas MD Anderson Cancer Center is the leading institution in the research field of bone metastases in PCa. Saad F, from Canada, has made great achievements in this area by publishing 91 related articles. Prostate is the journal which published most related articles, and Mundy GR, 2002, Nat Rev Cancer, is the most cited article in this field. Furthermore, the analysis of author keywords can be divided into five clusters: (1) diagnosis of PCa, (2) mechanism of bone metastasis, (3) drug treatments of bone metastases, (4) radiotherapy of bone metastases, and (5) treatments and prognosis of PCa. Conclusions: mCRPC has been the hottest topic in PCa in recent years. CT is the most common diagnostic method for bone metastases. Enzalutamide and radium-223, as important treatments for bone metastases in PCa, bring about widespread attention. Furthermore, the researchers focus on the tumor microenvironment and biomarkers to explore the mechanism and the therapeutic targets of bone metastases in PCa.

Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer.

Background: Although TP53 and SPOP are frequently mutated in metastatic prostate cancer (PCa), their prognostic value is ambiguous, and large sample studies are lacking, especially when they co-occur with other genetic alterations. Methods: Genomic data and patients' clinical characteristics in PCa were downloaded from the cBioPortal database. We extensively analyzed other gene alterations in different mutation status of TP53 and SPOP. We further subdivided TP53 and SPOP mutation into subgroups based on different mutation status, and then evaluated the prognostic value. Two classification systems for TP53 survival analysis were used. Results: A total of 2,172 patients with PCa were analyzed in our study, of which 1,799 were metastatic PCa patients. The mutual exclusivity analysis showed that TP53 and SPOP mutation has a strong mutual exclusion (p<0.001). In multivariable analysis, truncating TP53 mutations (HR=1.773, 95%CI:1.403-2.239, p<0.001) and other TP53 mutations(HR=1.555, 95%CI:1.267-1.908, p<0.001) were independent negative prognostic markers in metastatic PCa, whereas SPOP mutations(HR=0.592, 95%CI:0.427-0.819, p<0.001) were an independent prognostic factor for better prognosis. Mutations in TP53 were significantly associated with wild-type status for SPOP and CDK12, structural variants/fusions for TMPRSS2 and ERG, AR amplification and PTEN deletion (p<0.001). And truncating TP53 mutations have higher AR amplification rates than other TP53 mutations (p=0.022). Consistently, truncating TP53 mutations had a worse prognosis than other TP53 mutations (p<0.05). Then Kaplan-Meier survival curve showed that Co-occurring TP53 mutations in AR amplification or PTEN deletion tumors significantly reduced survival (p<0.05). Furthermore, those with SPOP-mutant tumors with co-occurring TP53 truncating mutations had shorter overall survival than those with SPOP-mutant tumors with wild-type or other TP53 mutations. Conclusions: This study found that TP53 and SPOP mutations were mutually exclusive and both were independent prognostic markers for metastatic PCa. Genomic alteration and survival analysis revealed that TP53 and SPOP mutations represented distinct molecular subtypes. Our data suggest that molecular stratification on the basis of TP53 and SPOP mutation status should be implemented for metastatic PCa to optimize and modify clinical decision-making.

UBE2S as a novel ubiquitinated regulator of p16 and ß-catenin to promote bone metastasis of prostate cancer.

Bone metastasis is the main site of metastasis and causes the most deaths in patients with prostate cancer (PCa). The mechanism of bone metastasis is complex and not fully clarified. By RNA sequencing and analysing key pathways in bone metastases of PCa, we found that one of the most important characteristics during PCa bone metastasis was G1/S transition acceleration caused by low protein levels of p16INK4a (p16). Interestingly, we demonstrated that UBE2S bound and degraded p16 through K11- rather than K48- or K63-linked ubiquitination, which accelerated PCa tumour cell G1/S transition in vivo and in vitro. Moreover, UBE2S also stabilized ß-catenin through K11-linked ubiquitination, leading to enhanced migration and invasion of tumour cells in PCa bone metastasis. Based on our cohorts and public databases, UBE2S was overexpressed in bone metastases and positively correlated with a high Gleason score, advanced nodal metastasis status and poor prognosis in PCa. Finally, targeting UBE2S with cephalomannine inhibited proliferation and invasion in vitro, and bone metastasis of PCa in vivo. This study innovatively discovered that UBE2S plays an oncogenic role in bone metastasis of PCa by degrading p16 and stabilizing ß-catenin via K11-linked ubiquitination, suggesting that it may serve as a multipotent target for metastatic PCa treatment.

Neuroimaging Study Investigating the Supraspinal Control of Lower Urinary Tract Function in Man With Orthotopic Ileal Neobladder.

Introduction: Recent studies employing functional imaging methodology have revealed reference brain regions of urinary tract function, namely, the midbrain periaqueductal gray matter, thalamus, and cingulate and prefrontal cortices. The orthotopic ileal neobladder is a desirable method for urinary diversion after radical cystectomy, but its supraspinal control remains unknown. We aimed to evaluate brain activity while maintaining urinary urgency and voluntary urinary control in male subjects with ileal orthotopic neobladders by performing functional MRI (fMRI) during a block design experiment. Materials and Methods: Patients were recruited at the Sun Yat-sen Memorial Hospital of the Sun Yat-sen University from October 2017 to May 2019. Two tasks were performed during fMRI scanning: (1) repeated infusion and withdrawal of sterile saline solution into and out of the neobladder to simulate urgency; and (2) repeated contraction of the pelvic floor muscle with a full neobladder to induce inhibition of micturition since the subjects were asked not to urinate. The obtained data were visualized and statistically analyzed. Results: Sixteen subjects were recruited in the study, and data were obtained from 10 subjects: mean age 60.1 years, average postoperative time 20.2 months, and daytime continence rate 100%. The parahippocampus, frontal lobe, vermis, and anterior cingulate cortex were activated with large bladder volumes, and the thalamus and caudate nucleus were deactivated during voluntary urinary control. Conclusion: A complex supraspinal program is involved during ileal orthotopic neobladder control, which is significantly different from that with normal bladders, in which the original intestine visceral volume sensation is preserved.

GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer.

BACKGROUND: Chemoresistance is the major cause of death in advanced prostate cancer (PCa), especially in metastatic PCa (mPCa). However, the molecular mechanisms underlying the chemoresistance of PCa remain unclear. Understanding the reason behind the drug resistance would be helpful in developing new treatment approaches. METHODS: The Cancer Genome Atlas, Gene Expression Omnibus datasets, and clinical samples were used to examine the correlation between growth arrest and DNA damage-inducible 45 beta (GADD45B) with clinical characteristics and prognosis. Lentiviral transfection was used to construct GADD45B overexpression cell lines. Hypoxic incubator, low serum medium, or docetaxel was used to build environmental stress model or chemotherapy cell model. The MTS assay and colony formation assay were used to test cell viability. Apoptosis and cell cycle were detected by flow cytometry. The RNA and protein levels of related biomarkers were tested by Western blotting and quantitative polymerase chain reaction. Bioinformatics analysis after RNA sequencing was performed to identify the possible mechanism of how GADD45B regulates chemotherapy resistance. RESULTS: GADD45B was related to distant metastasis but not to Gleason score, prostate-specific antigen level, T stage, or lymph node metastasis and indicated a good prognosis. The level of GADD45B increased significantly in PCa cells that faced environmental stress. It was found that a high level of GADD45B significantly enhanced the chemosensitivity. Furthermore, high GADD45B promoted cell apoptosis via mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: GADD45B promoted chemosensitivity of prostate cancer through MAPK pathway. GADD45B could serve as a diagnostic biomarker and therapeutic target for mPCa or chemotherapy-resistant patients.

Topoisomerase II-binding protein 1 promotes the progression of prostate cancer via ATR-CHK1 signaling pathway.

DNA damage response (DDR) plays an important role in the progression of cancers, including prostate cancer (PCa). Topoisomerase II-binding protein 1 (TopBP1) is an essential promotor of ATR-mediated DDR. Herein, we investigated the association between TopBP1 and PCa and determined its effect on the progression of PCa. The expression and clinical features of TopBP1 were analyzed using large-scale cohort of tissue microarray analyses and The Cancer Genome Atlas database, which indicated that TopBP1 was positively correlated with high Gleason Score, advanced clinical and pathological stages, the metastasis status. Multivariate analysis revealed that the upregulation of TopBP1 was an independent predictor for a worse biochemical recurrence-free survival (BCR-free survival). Furthermore, we discovered that downregulation of TopBP1 significantly suppressed the growth and migration ability of PCa lines by loss-of-function assays in vitro. Further mechanistic investigations clarified that TopBP1 promoted proliferation and migration by activating ATR-Chk1 signaling pathway.

Discovering novel P38α inhibitors for the treatment of prostate cancer through virtual screening methods.

Aim: P38α plays a crucial role in the development of castration-resistant prostate cancer. Discovering novel inhibitors of P38α offers potential for the development of new anticancer drugs. Methods & results: Compounds from the Chemdiv and Enamine virtual libraries were filtered to construct the P38α inhibitor-like library. A total of 58 new P38α inhibitors were discovered via virtual screening; these included three compounds (compound 1, 5, 9) with kinase IC50 of below 10 µM. In vitro, these three compounds have the potential to suppress the viabilities of prostate cancer cell lines, however, only compound 9 can inhibit the proliferation and migration of prostate cancer cells. Conclusion: The potent compounds discovered in this study demonstrate anticancer functions by targeting the P38α mitogen-activated protein kinases signaling pathway and are worthy of further investigation.

Overexpression of malignant brain tumor domain containing protein 1 predicts a poor prognosis of prostate cancer.

Malignant brain tumor domain containing protein 1 (MBTD1) is a member of the polycomb group protein family that is associated with tumorigenesis. The present study investigated the role of MBTD1 within defined clinicopathological parameters and the prognosis of patients with prostate cancer (PCa). A human tissue microarray containing samples from 71 patients with PCa and seven healthy donors was employed for immunohistochemistry (IHC). The clinicopathological characteristics and prognostic value of MBTD1 were investigated using a dataset of 499 patients from The Cancer Genome Atlas (TCGA). IHC illustrated that the levels of MBTD1 protein were enhanced and markedly associated with aggressive clinical stage and advanced tumor invasion, distant metastasis and lymph node metastasis in patients with PCa. In the TCGA data set, the level of MBTD1 was found to positively correlate with the prostate-specific antigen level, Gleason score and distant metastasis. The multivariate analysis of Cox regression revealed that the levels of MBTD1 may act as an independent prognostic factor for low non-biochemical, recurrence-free survival. In conclusion, MBTD1 was overexpressed in PCa tissues and is associated with aggressive clinicopathological characteristics. It may therefore act as a novel prognostic factor and diagnostic marker in PCa.

Polo-like kinase 3 is associated with poor prognosis and regulates proliferation and metastasis in prostate cancer.

BACKGROUND: Biological mechanism of prostate cancer (PCa) recurrence and progress is complex but many of the key elements are not fully understood. Polo-like kinases (Plks) represent a family of highly conserved serine-threonine kinases that play essential roles in cell cycle progression. Plk3 plays contradictory roles in different cancers. However, the roles of Plk3 in PCa remain largely unexplored. METHODS: Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the relationship between Plk3 and prognosis of patients with PCa. Gene set enrichment analysis (GSEA) was conducted to evaluate proliferation and metastasis gene sets using The Cancer Genome Atlas Dataset. MTS assay, clone formation assay, cell migration, and wound healing assay were carried out to investigate biological functions of Plk3. RESULTS: We found that high Plk3 expression was closely correlated with poor prognosis. GSEA revealed that Plk3 was involved in proliferation and metastasis. Loss-of-function assays demonstrated that Plk3 promoted proliferation and metastasis in PCa cells in vitro. CONCLUSION: We discovered that Plk3 plays a critical role in PCa, indicating that it may be a potential prognostic marker and help predict the progression, especially recurrence of PCa.

Decreased expression of serine protease inhibitor family G1 (SERPING1) in prostate cancer can help distinguish high-risk prostate cancer and predicts malignant progression.

PURPOSE: The aim of this study was to investigate the associations of serine proteinase inhibitor family G1 (SERPING1) down-regulation with poor prognosis in patients with prostate cancer (PCa). Furthermore, we aim to find more novel and effective PCa molecular markers to provide an early screening of PCa, distinguish patients with aggressive PCa, predict the prognosis, or reduce the economic burden of PCa. METHODS: SERPING1 protein expression in both human PCa and normal prostate tissues was detected by immunohistochemical staining, which intensity was analyzed in association with clinical pathological parameters such Gleason score, pathological grade, clinical stage, tumor stage, lymph node metastasis, and distant metastasis. Moreover, we used The Cancer Genome Atlas (TCGA) Database, Taylor Database, and Oncomine dataset to validate our immunohistochemical results and investigated the value of SERPING1 in PCa at mRNA level. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the relationship between SERPING1 and prognosis of patients with PCa. RESULTS: The outcome showed that SERPING1 was expressed mainly in cytoplasm of grand cells of prostate tissue and was significantly expressed less in PCa (P<0.001). Furthermore, in the tissue microarray of our samples, decreasing expression of SERPING1 was correlated with the higher Gleason score (P = 0.004), the higher pathological grade (P = 0.01) and the advanced tumor stage (P = 0.005) at protein level. In TCGA dataset and Taylor Dataset, low-expressed SERPING1 was correlated with the younger patient (P = 0.02 in TCGA, P = 0.044 in Taylor) and the higher Gleason score (P = 0.019 in TCGA, P<0.001 in Taylor) at mRNA level. Kaplan-Meier analysis revealed that the lower mRNA of SERPING1 predicted lower overall survivals (P = 0.027 in TCGA), lower disease-free survival (P = 0.029) and lower biochemical recurrence-free survival (P = 0.011 in Taylor). Data from Oncomine database shown that SERPING1 low expression implying higher malignancy of prostate lesions. Using multivariate analysis, we also found that SERPING1 expression was independent prognostic marker of poor disease-free survival and biochemical recurrence-free survival. CONCLUSION: SERPING1 may play an important role in PCa and can be serve as a novel marker in diagnosis and prognostic prediction in PCa. In addition, levels of SERPING1 can help identify low-risk prostate to provide reference for patients with PCa to accept active surveillance and reduce overtreatment.

Bacteremic and non-bacteremic pneumonia caused by Acinetobacter baumannii in ICUs of South China: A Clinical and Microbiological Study.

Acinetobacter baumannii has been a dreadful problem for ICU physicians for a long time. Bacteremic pneumonia (BP) caused by this organism has a higher mortality compared to other organisms. Between 2012 and 2015, 86 BP and 89 non-bacteremic pneumonia (NBP) patients from five ICUs were enrolled into the study. The 7-day and 14-day mortality rates were higher in BP patients than in NBP patients (P < 0.001). Procalcitonin elevation, high APACHEII score and recent surgery, were independently associated with BP episodes. Acute respiratory distress syndrome, coma, high APACHEII score and procalcitonin elevation, were independently associated with mortality in the BP group. Extensively drug-resistant isolates were detected in 34.9% of BP and 25.8% of NBP isolates. PFGE identified 12 and 9 genotypes in the BP and NBP isolates, respectively, with 6 genotypes shared by both groups. ST195 was the most prevalent type (40%), followed by ST457 (18.9%). The pandemic clonal complex 92 was predominant, accounting for 94.3% of the strains. For all studied periods, mortality remained higher in the BP than the NBP group. Disease severity was the main risk factor for high mortality in the BP group, and other factors related to mortality were infection, and not treatment or microbiology-related.

Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals.

BACKGROUND: SHARPIN, SHANK-associated RH domain interacting protein, associates with a linear ubiquitin chain assembly complex (LUBAC) to regulate inflammation and immunity. It has been reported that SHARPIN is highly expressed in several human tumors including ovarian cancer and liver cancer. We found that SHARPIN is also highly expressed in prostate cancer cell lines of DU145, LNCAP, and PC-3. Suppression of SHARPIN caused an inhibition of NF-κB signal and decreases in tumorigenesis of cultured cells in NOD/SCID mouse model. Overexpression of SHARPIN in prostate cancer cells promoted cell growth and reduced apoptosis through NF-kB/ERK/Akt pathway and apoptosis-associated proteins. METHODS: We analyzed the expression of SHARPIN in prostate cancer tissues from 95 patients and its relationship with other clinical characteristics associated with PCA malignancies and patient survivals, and examined the impacts of SHARPIN suppression with siRNA on proliferation, angiogenesis, invasion, and expression levels of MMP-9 of prostate cancer cells and metastasis to lung by these cells in nude mice. RESULTS: High levels of SHARPIN were associated with high malignancies of PCA and predicted shorter survivals of PCA patients. Suppression of SHARPIN impaired cell proliferation, angiogenesis, and invasion and reduced levels of MMP-9 in prostate cancer cells and reduced the size of metastatic lung tumors induced by these cells in mice. CONCLUSIONS: SHARPIN enhances the metastasis of prostate cancer and impair patient survivals. Prostate 77:718-728, 2017. © 2017 Wiley Periodicals, Inc.

Elevated levels of epithelial cell transforming sequence 2 predicts poor prognosis for prostate cancer.

Epithelial cell transforming sequence 2 (Ect2) was originally reported as an oncogene that is involved in several types of human cancers. However, little is known about its expression and function in prostate cancer. Immunohistochemical staining for Ect2 was performed on a human tissue microarray. The staining intensity was analyzed in association with clinical pathological parameters such as Gleason score, pathological grade, clinical stage, tumor invasion, lymph node and distant metastasis. Furthermore, we repeated such analysis and investigated the prognostic value of Ect2 using the TCGA (The Cancer Genome Atlas) Dataset. Our immunohistochemical results showed that the expression levels of Ect2 protein were enhanced in human prostate cancer tissues. There existed positive correlations between the expression levels of Ect2 and several clinicopathological parameters, including advanced clinical stage, enhanced tumor invasion and lymph node metastasis. Similarly, we found that the expression levels of Ect2 were positively related to Gleason score, tumor invasion, lymph node metastasis and high distant metastasis in the TCGA Dataset. Kaplan-Meier analysis revealed that lower levels of Ect2 mRNA predicted higher overall survivals and biochemical recurrence (BCR)-free survivals in all patients or non-metastatic patients. Multivariate analysis by Cox regression showed that the expression of Ect2 could be an independent prognostic marker of poor BCR-free survivals. Therefore, levels of Ect2 may serve as a novel marker for the diagnosis or prognosis of prostate cancer.

SHARPIN overexpression induces tumorigenesis in human prostate cancer LNCaP, DU145 and PC-3 cells via NF-κB/ERK/Akt signaling pathway.

SHARPIN emerges higher expression in prostate cancerous tissues than in benign prostate hyperplasia by means of immunohistochemistry in our previous study. In this work, we performed the gain of function assay and find that overexpression of SHARPIN in LNCaP, DU145 and PC-3 cells promoted cell proliferation, invasiveness and reduced apoptosis. Furthermore, SHARPIN overexpression displayed elevated Bcl-2 and Survivin expression and reduced levels of Bax, cleaved caspase-3. Meanwhile, entropic expression of SHARPIN increased the levels of phosphorylated p65, IkBα, ERK and Akt, were selectively increased in these cells. Collectively, our study unraveled the ability of SHARPIN overexpression to induce tumorigenesis of prostate cancer cells through the NF-kB/ERK/Akt pathway and transformation of apoptosis-associated proteins.