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Background: The global dissemination of carbapenem-resistant Acinetobacter baumannii clonal complex (CC) 92 has become an urgent public health concern. Methods: A. baumannii isolates were collected in 5 tertiary hospitals in south China during 2012-2015, and their clinical data were obtained. The clinical characterization was studied by statistical analysis. Whole-genome sequencing and a Galleria mellonella infection model were used to investigate the genetic characterization and pathogenicity of isolates, respectively. Results: Sequence type (ST)457, following ST195, become the second-most prevalent clone in our collection. Patients infected by ST457 had significantly higher 7-day mortality rates (44.4% vs 14.3%; P = .01) and proportions of 7-day deaths (70.6% vs 26.7%; P = .01) than those infected by the other STs of CC92, except for ST195 and ST208. Consistently, the day of death after culture was significantly sooner in patients infected with ST457 than those with the non-ST195/208 members of CC92 (8.71 ± 15.27 vs 25.20 ± 6.51; P = .02). This is accordant with results that ST457 had enhanced virulence with a high mortality rate through use of the G. mellonella larvae infection model. Genomic analysis suggests that ST457 evolved distinctly from the other CC92 members mainly via recombinations. This clone exclusively shared a few virulence factors with the hypervirulence strain LAC-4, including a capsule biosynthesis locus (KL49) that is supposed to be important for the hypervirulence in LAC-4. Conclusions: The rising trends in prevalence and enhanced virulence of ST457 highlight the urgent need for tailored surveillance to control the further dissemination of this clone.
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Infecções por Acinetobacter/mortalidade , Acinetobacter baumannii/genética , Acinetobacter baumannii/patogenicidade , Doenças Endêmicas , Fatores de Virulência/genética , Infecções por Acinetobacter/microbiologia , Idoso , Idoso de 80 Anos ou mais , Animais , Técnicas de Tipagem Bacteriana , Carbapenêmicos/farmacologia , China/epidemiologia , Evolução Molecular , Feminino , Genômica , Pneumonia Associada a Assistência à Saúde/epidemiologia , Pneumonia Associada a Assistência à Saúde/microbiologia , Humanos , Larva , Masculino , Pessoa de Meia-Idade , Mariposas , Tipagem de Sequências Multilocus , Prevalência , Virulência , Sequenciamento Completo do GenomaRESUMO
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.
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Adenocarcinoma , Proteínas de Transporte , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias da Próstata , Ubiquitinas , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Animais , Apoptose , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Análise de Sobrevida , Ubiquitinas/genética , Ubiquitinas/metabolismoRESUMO
BACKGROUND: Nuclear factor κB (NFκB) signaling is strongly associated with tumor progression, and studies have shown that SHANK-associated RH domain interacting protein (SHARPIN) is crucial for NFκB pathway activation. However, the expression and functions of SHARPIN in prostate cancer (PCa) have not yet been defined. METHODS: The expression of SHARPIN in PCa cell lines and tissues was evaluated with western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. After SHARPIN was silenced in the PCa cell lines, western blots were used to confirm that SHARPIN physically associated with components of the NFκB pathway and the downstream targets (survivin and livin). The functions of SHARPIN in cell proliferation, migration, and invasion in vitro were measured with 5-(3-carboxymethoxyphenyl)-2-(4,5-dimenthylthiazoly)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS), Transwell, and invasion assays, respectively. Flow cytometry was employed to evaluate cell apoptosis. Furthermore, tumorigenesis in vivo was examined with tumorigenicity assays. RESULTS: SHARPIN expression was upregulated in PCa cell lines and tissues. The knockdown of SHARPIN or incubation with Bay 11-7082 (an NFκB inhibitor) led to dramatically decreased levels of phosphorylated IκBα and phosphorylated p65 in comparison with the control group. Downregulation of survivin and livin due to SHARPIN inhibition was attributable to transcriptional repression (P < .05). Decreases in cell viability, migration, invasion, and survival with a higher sensitivity to docetaxel in vitro and with repressed tumorigenesis in vivo were observed upon SHARPIN silencing, and this was consistent with the results from inhibition of the NFκB pathway and its downstream targets. CONCLUSION: The current study demonstrates that overexpression of SHARPIN promotes activation of the NFκB pathway and downstream targets survivin and livin, which potentially contributes to PCa development.
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Proteínas Inibidoras de Apoptose/metabolismo , NF-kappa B/metabolismo , Neoplasias da Próstata/metabolismo , Ubiquitinas/metabolismo , Apoptose/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Progressão da Doença , Humanos , Imuno-Histoquímica , Masculino , Metástase Neoplásica , Neoplasias da Próstata/patologia , Transdução de Sinais , Survivina , TransfecçãoRESUMO
PURPOSE: To describe the surgical technique and to report the midterm outcomes of laparoendoscopic single-site radical prostatectomy (LESS-RP) with a homemade single-port device. METHODS: Between August 2009 and October 2011, 20 LESS-RP procedures were performed in a single center by a high-volume surgeon. The surgical methods are outlined in the paper. Preoperative, perioperative, pathologic, midterm oncological, and functional outcomes data were analyzed. RESULTS: On average, patients were 66.1 years old, had a mean body mass index of 24.4 kg/m(2), and a mean prostate-specific antigen (PSA) value of 12.2 ng/ml. No conversion was required; however, a single additional 5-mm port was required in one case. The mean operative time was 248 min; mean estimated blood loss was 94 ml. The mean visual analog pain score at day 3 was 1.5 out of 10, and the mean hospital stay was 15.4 day. Pathology showed one focal positive margin (5 %) in a T3a patient, and mean Gleason score was 6.7. There were a total of four Clavien grade 2 complications. The median follow-up was 22.8 month (range 12-36 month). No PSA recurrence was detected during follow-up period; the potency rate after bilateral neurovascular bundle preservation was 60 % (3/5). Complete continence recovery (no pad) was observed in 85 % of the patients at 1 year, in 90 % at 2 years, and in all three patients at 3 years. CONCLUSIONS: LESS-RP is technically feasible and safe, with excellent cosmesis, low postoperative pain levels, and acceptable midterm oncological, and functional outcomes. Comparative investigation to conventional LRP is needed.
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Laparoscópios , Laparoscopia/instrumentação , Prostatectomia/instrumentação , Neoplasias da Próstata/cirurgia , Idoso , Desenho de Equipamento , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Satisfação do Paciente , Neoplasias da Próstata/diagnóstico , Estudos Retrospectivos , Fatores de Tempo , UmbigoRESUMO
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.
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BACKGROUND: Regulated activation of p38 is crucial for cell proliferation, survival, and metabolism. Our previous studies had showed that prostate specific membrane antigen (PSMA) can facilitate the proliferation, migration, survival of the LNCaP prostate cancer cell line, but the mechanisms are poorly defined. METHODS: Our LNCaP cells had been stably transfected with lentivirus-mediated shRNA for PSMA silencing in previous study. We first testify the efficacy of PSMA knockdown in our LNCaP cell line. Then using this PSMA (-) LNCaP cell line, we compared the expression of PSMA and P-p38 by Western blotting among groups. Furthermore, we also performed immunofluorescence to confirm the change of P-p38 in cells. Then, cell viability and migration were measured by cell counting kit-8 reagent and Transwell analysis respectively. Flow cytometry was employed to evaluate cell survival. RESULTS: After silencing the expression of PSMA, the level of the phospho-p38 (P-p38) decreased approximate 40% compared with the blank and NC groups (P < 0.05). When the cells were incubated with SB203582 (p38 inhibitor), the P-p38 in three groups was at low level and no difference among groups (P > 0.05). Then the results of immunofluorescence further proved the relationship between PSMA and P-p38. Decrease of cell viability, migration, and survival was observed upon PSMA silencing. SB203580, a specific inhibitor of p38 MAPK pathway, also reduced proliferation, migration, and survival of LNCaP cells. CONCLUSION: These data suggests PSMA may stimulate prostate cancer cells proliferation, migration and survival through p38 MAPK pathway, revealing a novel mechanism for PSMA playing positive role on LNCaP cells.
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Antígenos de Superfície/metabolismo , Movimento Celular/fisiologia , Glutamato Carboxipeptidase II/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Citometria de Fluxo , Humanos , Imidazóis/farmacologia , Masculino , Neoplasias da Próstata/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , RNA Neoplásico/química , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
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.
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Neoplasias da Próstata , Masculino , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias da Próstata/patologia , Prognóstico , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
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.
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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.
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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.
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Neoplasias Ósseas , Inibidor p16 de Quinase Dependente de Ciclina , Neoplasias da Próstata , Enzimas de Conjugação de Ubiquitina , beta Catenina , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Enzimas de Conjugação de Ubiquitina/genética , beta Catenina/genéticaRESUMO
Increasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to tumorigenesis. microRNA-125b (miR-125b) was implicated to have close relationship with cell proliferation and differentiation, and downregulation of miR-125b was observed in various types of cancers. However, the biological function of miR-125b in bladder tumorigenesis is still unknown. In our study, we showed that the expression of miR-125b was significantly decreased in bladder cancer tissues and four bladder cancer cell lines. Moreover, miR-125b could suppress bladder cancer cells to form colonies in vitro and to develop tumors in nude mice. E2F3, which was critical for G1/S transition and was overexpressed in most of poor-differentiated bladder cancers, was identified as a target of miR-125b by luciferase assay. The E2F3 mRNA and protein expression levels were detected in bladder cancer tissues and cell lines, and interestingly, inverse correlations between miR-125b and E2F3 protein level were found in bladder cancer tissues and four E2F3 nonamplified cell lines. Introduction of miR-125b could reduce the expression of E2F3 protein but not the E2F3 mRNA. In addition, we observed that transfection of miR-125b could inhibit the expression of Cyclin A2, one of the E2Fs-responsive genes involved in G1/S transition. These results suggest that miR-125b may regulate G1/S transition through the E2F3-Cyclin A2 signaling pathway. Taken together, miR-125b may act as a tumor suppressor in bladder urothelium, and downregulation of miR-125b may contribute to the tumorigenesis of bladder cancer.
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Carcinoma de Células de Transição/prevenção & controle , Fator de Transcrição E2F3/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/fisiologia , Neoplasias da Bexiga Urinária/prevenção & controle , Adulto , Idoso , Animais , Northern Blotting , Western Blotting , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Ciclo Celular , Proliferação de Células , Ciclina A2/metabolismo , Regulação para Baixo , Feminino , Humanos , Técnicas Imunoenzimáticas , Luciferases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Conventional percutaneous nephrolithotomy (PCNL) is usually performed in a prone position, which compresses the thorax and results in difficulty in rescue during operation. When PCNL is performed in a supine position, the flank renal puncture area is limited, so it is difficult to treat disseminated and complex renal calculi. Herein, we introduce a modified semisupine position for performing PCNL, which has numerous benefits as well as safe and effective. Between May 2002 and May 2009, a total of 452 patients with renal calculi were treated with semisupine PCNL. The patient was placed in 45° semisupine position during the procedure, with the affected flank arched as much as possible. In this series, no one converted to open surgery. The average operating time was (115.2 ± 44.5) min. Single tract PCNL was performed for 80.97% of the cases, two tracts 13.94%, three tracts 4.65%, and four tracts 0.44%. The upper, middle, and lower calix tracts accounted for 12.1, 63.0, and 24.9%, of procedures, respectively. Stone-free rate was 85.7% overall, 92.2% for single calculus (83/90), and 72.9% for staghorn calculi (78/107). Major postoperative complications occurred in 3.3% of the cases. This study demonstrated PCNL in a semisupine position is an effective alternative for treating renal calculi, which combines the advantages of PCNL in a prone position, and PCNL in a supine position. The semisupine position allows easier irrigation of stone fragments, is more comfortable for the patient, and facilitates monitoring of anesthesia.
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Cálculos Renais/terapia , Nefrostomia Percutânea/métodos , Postura , Decúbito Dorsal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
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.
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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.
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OBJECTIVE: To study the inhibition and significance of pigment epithelium-derived factor (PEDF) in the development and metastasis of prostate cancer. METHODS: The expression of PEDF was examined in the normal prostate tissue, benign prostatic hyperplasia, prostate cancer tissue and prostate cancer cell lines, PC-3 and Lncap by immunohistochemical SP method and Western blot. In combination with clinical data, statistical analysis was performed to evaluate the relation of the expression level of PEDF in prostate cancer and the relationship between different histological grades of prostate cancer. RESULTS: In normal prostate tissue and benign prostate tissue, the expression of PEDF were elevated and it was far higher than the prostate cancer and prostate cancer cell line. The expression of PEDF and the pathological grade of prostate cancer were related to the differentiated carcinoma of prostate tissue, and the expression level of PEDF in poorly differentiated carcinoma below the highly differentiated carcinoma of prostate cancer. In metastatic prostate cancer, the expression of PEDF was lower than that of prostate cancer without metastasis (12% vs 43.1%). CONCLUSION: The expression of PEDF and the incidence of prostate cancer have a negative correlation. The lower grade of prostate cancer cells, the less the tissue expression of PEDF and the higher tendency of invasion and metastasis.
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Proteínas do Olho/metabolismo , Fatores de Crescimento Neural/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Serpinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase NeoplásicaRESUMO
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.
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Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Transporte/genética , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Neoplasias da Próstata/genética , Transdução de Sinais/genética , Bases de Dados Genéticas , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.
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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.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Bases de Dados de Compostos Químicos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
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.