AR expression-independent XRCC3 mediates DNA damage-induced p53/Bax signaling pathway activation against prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) resistance is closely associated with altered AR status. Aberrant AR expression is critical for the induction of ADT resistance, necessitating the identification of an anti-PCa target independent of AR expression. METHODS: Transcriptomic data and clinical information of PRAD were obtained from TCGA database. Genes with PCa-related and AR expression-independent were screened by bioinformatics, and characterized by PPI and GO functional enrichment analyses. Candidate genes were locked by co-expression correlation and disease-free survival (DFS) analyses. A prognostic gene set was established using LASSO Cox regression algorithm. Cox proportional risk regression was performed to identify a key prognostic gene. Expression of the target protein in PCa tissues was verified by The Human Protein Atlas database. In vitro validation of cellular function and molecular mechanism by knockdown and overexpression of the target gene. RESULTS: Two AR expression-independent genes (SLC43A1 and XRCC3) were available for the optimal prognostic model. This gene set effectively predicted PRAD patients' DFS at 1-, 3- and 5-year, where XRCC3 and tumor (T) stage were independent risk factors. XRCC3 was higher expressed in PRAD patients with T3-T4 stages and accompanied by poorer DFS. IHC staining also validated its higher expression in high-risk PCa tissues. In vitro experiments demonstrated that silencing XRCC3 significantly inhibited 22Rv1 and DU145 cell proliferation, migration and invasion, while promoted apoptosis. Further, silencing XRCC3 promoted DNA damage-induced p53/Bax signaling pathway activation, which was absent with overexpression. CONCLUSION: Silencing XRCC3 exerts anti-PCa effects by promoting DNA damage-induced p53/Bax signaling pathway activation in an AR expression-independent manner.

Associations of HALP score with serum prostate-specific antigen and mortality in middle-aged and elderly individuals without prostate cancer.

Background: The association between the Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) score and serum prostate-specific antigen (PSA) and all-cause mortality remains underexplored. We aimed to investigate the relationship between HALP score and these outcomes among middle-aged and elderly individuals without prostate cancer (PCa). Methods: This cross-sectional study included participants aged 40 years and older from National Health and Nutrition Examination Survey (NHANES) 2001-2010. HALP score was calculated using the formula: HALP score = (Hemoglobin × Albumin × Lymphocytes)/Platelets. High PSA level was defined as a percentage free PSA (%fPSA) less than or equal to 25% and a total PSA (tPSA) level equal to or higher than 4.0 ng/mL. Mortality data were obtained through December 30, 2019 by linking to the National Death Index. Results: Among 7,334 participants, 6,826 were classified as having low PSA level, while 508 were categorized as having high PSA level. Logistic regression revealed lower odds of high PSA level with higher HALP quartiles (P trend<0.001). Among 508 participants with high PSA level, over a median follow-up period of 10.13 years (IQR: 5.42-13.17 years), a total of 268 all-cause deaths were recorded. Cox regression analysis showed that participants in the highest HALP quartile had the lowest risk of all-cause mortality (HR = 0.527, 95% CI: 0.368-0.754) in participants with high PSA level. Restricted cubic spline analysis indicated a non-linear and negative correlation between HALP score and all-cause mortality, with an inflection point at 43.98 (P for non-linearity = 0.009). Random survival forest analysis ranked HALP score as the most significant predictor for all-cause mortality. Conclusion: Our study highlights that the HALP score the HALP score is associated with high PSA level and all-cause mortality among middle-aged and elderly individuals without PCa. Further research is warranted to validate these findings and elucidate underlying mechanisms.

CTEN-induced TGF-ß1 expression facilitates EMT and enhances paclitaxel resistance in bladder cancer cells.

OBJECTIVES: To investigate the role of C-terminal tensin-like (CTEN) in mediating chemotherapy resistance via epithelial-mesenchymal transition (EMT) in bladder cancer (BC) cells, through the regulation of transforming growth factor-ß1 (TGF-ß1) expression. METHODS: Lentiviral vectors were used to create CTEN overexpression and knockdown constructs, which were then introduced into paclitaxel-resistant BC cell lines. The effects of CTEN manipulation on cell proliferation and drug sensitivity was assessed using the CCK-8 assay, and apoptosis was evaluated by flow cytometry. The expression levels of CTEN, TGF-ß1, and EMT markers were quantified by RT-qPCR and Western blot analysis. The interaction between CTEN and TGF-ß1 and its effect on TGF-ß1 methylation were studied using bisulfite sequencing PCR and co-immunoprecipitation. RESULTS: Overexpression of CTEN in BC cells was associated with decreased paclitaxel efficacy, reduced apoptosis, and elevated levels of TGF-ß1 and EMT-related proteins. CTEN was found to bind TGF-ß1, inhibiting its methylation and thereby promoting TGF-ß1 upregulation. This increase in TGF-ß1 expression facilitated the EMT process and enhanced drug resistance in BC cells. CONCLUSIONS: The induction of TGF-ß1 expression by CTEN promotes EMT and increases chemotherapy resistance in BC cells. Targeting CTEN or the EMT pathway could improve chemosensitivity in treatment-resistant BC, suggesting a novel therapeutic strategy to enhance chemotherapy effectiveness.

PRPF19 promotes the proliferation, migration, and inhibits autophagy in prostate cancer by suppressing SLC40A1.

Prostate cancer (PCa) is a common cancer and the leading cause of cancer-related death in men. To investigate the role of pre-mRNA processing factor 19 (PRPF19) in proliferation, migration of PCa, and evaluate the potential ability of PRPF19 as a therapeutic target. PRPF19 expression was analyzed from The Cancer Genome Atlas and GEPIA databank. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate the transcription of PRPF9 and solute carrier family 40 member 1 (SLC40A1). Immunohistochemistry (IHC) was used to test PRPF9 expression in PCa tissues. The cell viability and 5-ethynyl-2'-deoxyuridine incorporation analysis were performed to assess cell proliferation. Transwell assay was performed to investigate the migration and invasion of cancer cells. Western blot was used to measure the expression level of PRPF9, E-cadherin, Vimentin and α-smooth muscle actin (α-SMA), SLC40A1, LC3, Beclin-1 and ATG7. Immunofluorescence assay was performed to measure LC3 expression in PCa cells. The bioinformatic analysis revealed PRPF19 was highly expressed in PCa which was certified by qRT-PCR, western blot and IHC detection in PCa tissues. The proliferation of PCa cells could be promoted by PRPF19 overexpression and suppressed by PRPF19 knockdown. Moreover, the migration and invasion of PCa cells could be positively regulated by PRPF19 which promoted the expression of E-cadherin, Vimentin, and α-SMA. Furthermore, the expression of LC3, Beclin-1, and ATG7 was negatively regulated by PRPF19, indicating that PRPF19 inhibited autophagy in PCa cells. In the double knockdown of PRPF19 and SLC40A1, PRPF19 repressed the mRNA and reduced protein level of SLC40A1, and SLC40A1 antagonized effects of PRPF19 on proliferation, migration and autophagy of PCa cells. PRPF19 promoted proliferation and migration, and inhibited autophagy in PCa by attenuating SLC40A1 expression, indicating PRPF19 was a potential therapeutic target for PCa treatment.

[Superiority of modified method in urine drainage for hypospadias repair: a 20 years' experience with 864 cases].

OBJECTIVE: To explore an ideal urine drainage method and new urethral secretions of hypospadias repair. METHODS: The authors retrospectively analyzed 864 cases of hypospadias undergoing hypospadias repair and different post-operative urine drainages. The patients were divided into 5 groups based on the methods of urine drainage. RESULTS: The rates of such complications as cystospasm, infection of incisional wound and urinary fistula were as follows: modified method group: 2.86%, 3.33%, 1.90%; 3-tube method group: 10.77%, 11.54%, 8.46%; He's method group: 20.89%, 15.04%, 9.75%; traditional method group: 36.25%, 41.25%, 37.50%; 1-tube method group: 56.47%, 58.82%, 48.23%. The modified method was significantly better than all the other four methods (P < 0.05). CONCLUSION: As an ideal drainage method of urine and new urethral secretions of hypospadias repair, the modified method boosts the success ratio of hypospadias repair.