Clinical application of serum tumor abnormal protein in prostate cancer patients.

PURPOSE: To explore the clinical value of tumor abnormal protein (TAP) in the diagnosis and prognosis evaluation of prostate cancer. METHODS: This study enrolled a total of 265 patients who underwent prostate biopsy procedures from December 2017. TAP levels were assayed in their blood samples using a validated TAP testing kit. Comprehensive pathological assessments, including Gleason scores, TNM staging, and AJCC prognosis stages, were conducted on prostate cancer patients. Further analysis was carried out to examine the correlation between TAP expression levels and various clinical characteristics. RESULTS: A significantly elevated TAP concentration was discerned in prostate cancer patients relative to those with benign prostate hyperplasia. Moreover, a significantly elevated TAP expression was detected in prostate cancer patients with high Gleason score (≥ 8) and advanced stages (III and IV), as compared to those with Gleason scores of 6 and 7 and lower stages (I and II). When diagnosing prostate cancer in gray area of PSA, TAP demonstrated superior diagnostic capabilities over PSA alone, with higher diagnostic sensitivity, specificity and accuracy than fPSA/tPSA ratio. Additionally, post-surgical or hormonal treatment, there was a marked reduction in TAP expression level among prostate cancer patients. CONCLUSION: The assessment of TAP presents itself as a promising tool for early diagnosis and holds potential for sensitivity in monitoring treatment reponse in prostate cancer patients.

A noninvasive method for predicting clinically significant prostate cancer using magnetic resonance imaging combined with PRKY promoter methylation level: a machine learning study.

BACKGROUND: Traditional process for clinically significant prostate cancer (csPCA) diagnosis relies on invasive biopsy and may bring pain and complications. Radiomic features of magnetic resonance imaging MRI and methylation of the PRKY promoter were found to be associated with prostate cancer. METHODS: Fifty-four Patients who underwent prostate biopsy or photoselective vaporization of the prostate (PVP) from 2022 to 2023 were selected for this study, and their clinical data, blood samples and MRI images were obtained before the operation. Methylation level of two PRKY promoter sites, cg05618150 and cg05163709, were tested through bisulfite sequencing PCR (BSP). The PI-RADS score of each patient was estimated and the region of interest (ROI) was delineated by 2 experienced radiologists. After being extracted by a plug-in of 3D-slicer, radiomic features were selected through LASSCO regression and t-test. Selected radiomic features, methylation levels and clinical data were used for model construction through the random forest (RF) algorithm, and the predictive efficiency was analyzed by the area under the receiver operation characteristic (ROC) curve (AUC). RESULTS: Methylation level of the site, cg05618150, was observed to be associated with prostate cancer, for which the AUC was 0.74. The AUC of T2WI in csPCA prediction was 0.84, which was higher than that of the apparent diffusion coefficient ADC (AUC = 0.81). The model combined with T2WI and clinical data reached an AUC of 0.94. The AUC of the T2WI-clinic-methylation-combined model was 0.97, which was greater than that of the model combined with the PI-RADS score, clinical data and PRKY promoter methylation levels (AUC = 0.86). CONCLUSIONS: The model combining with radiomic features, clinical data and PRKY promoter methylation levels based on machine learning had high predictive efficiency in csPCA diagnosis.

CDC20 promotes radioresistance of prostate cancer by activating Twist1 expression.

Currently, radiotherapy is one of the most attractive treatments for prostate cancer (PCa) patients. However, radioresistance remains a challenging issue and the underlying mechanism is unknown. Growing evidence has demonstrated that CDC20 (Cell division cycle protein 20) plays a pivotal role in a variety of tumors, including PCa. Here, GEPIA database mining and western blot analysis showed that higher expression of CDC20 was observed in PCa tissues and cells. We demonstrated that the expression of CDC20 was increased in PCa cells by irradiation, and knockdown of CDC20 resulted in inhibition of cell proliferation, migration, tumor formation, induced cell apoptosis and increased radiosensitivity in PCa in vitro and in vivo. Furthermore, we observed that CDC20 regulated Twist1 pathway, influencing cell proliferation and migration. These results suggest that targeting CDC20 and Twist1 may be an effective way to improve the radiosensitivity of PCa.

A Crosstalk Between Castration-Resistant Prostate Cancer Cells, M2 Macrophages, and NK Cells: Role of the ATM-PI3K/AKT-PD-L1 Pathway.

Castration-resistant prostate cancer (CRPC) in males is associated with a poor prognosis and a higher risk of treatment-related adverse effects, with high mortality among cancers globally. It is thus imperative to explore novel potential molecules with dual therapeutic and biomarker functions. Based on the recent research findings, the expression levels of ataxia telangiectasia mutant kinase (ATM) in prostate cancer (PC) tissues collected from CRPC patients were higher than hormone-dependent PC patients. Using CRPC cell lines (C4-2 and CWR22Rv1), the transwell chamber experiments revealed ATM promoted macrophage recruitment in CRPC cells in vitro via C-X-C motif chemokine ligand 12 (CXCL12). Further in vitro investigations demonstrated that polarized macrophages prevented NK cell recruitment and reduced the immunocidal activity of NK cells against CRPC cell lines. Moreover, ATM boosted programmed death receptor ligand 1 (PD-L1) expression while inhibiting NK group 2D (NKG2D) ligand expression in selected cell lines via PI3K/AKT signaling pathway. The in vivo investigations revealed ATM induced proliferation of CRPC and macrophage recruitment, while the NK cell recruitment was found to suppress ATM expression and CRPC proliferation. In conclusion, it could be demonstrated that inhibiting ATM increased the susceptibility of CRPC to NK cell inhibitors by dampening the CXCL12 and PI3K/AKT-PD-L1 pathways, thereby offering a novel and individualized treatment protocol for treating CRPC.

A case report of acute testicular pain secondary to segmental testicular infarction.

BACKGROUND: Segmental testicular infarction is a rare condition that often occurs in the upper pole of the left testicle and usually presents with acute onset of scrotal pain. Contrast-enhanced ultrasound and MR are essential for diagnosing and differentiating segmental testicular infarction in clinical practice, and conservative treatment can only be adopted after a definitive diagnosis. In the present case, after conservative treatment, the infarct volume was reduced, the blood flow around the infarct was increased, and blood flow signals appeared in the infarct. We performed a correlation analysis to investigate the causes of these changes. CASE PRESENTATION: A 33-year-old male, without any specific disease history, was admitted to the hospital with a 5-day history of left testicular pain, and the imaging showed focal necrosis of the left testicle with hemorrhage. He was diagnosed with segmental testicular infarction after differentiating and excluding it from malignant tumors. Conservative medical treatment was given, and the symptoms of testicular pain were relieved after treatment. After discharge, regular reexamination at follow-ups showed that the infarct's size was reduced, the blood flow around the infarct was increased, and blood flow signals appeared in the infarct. CONCLUSION: Conservative treatment has become the standard treatment currently adopted after confirming the diagnosis of segmental testicular infarction through contrast-enhanced ultrasound and MR. The blood flow changes in and around the focus of testicular infarction can be related to various factors. At present, relevant conclusions of the underlying mechanisms were mainly deduced from infarction studies of other related organs such as the heart and brain; thus, the specific pathological mechanism needs further experimental verification.

The clinical outcomes of flexible ureteroscopy and laser lithotripsy (FURSL) for treatment of the upper urinary tract calculi.

PURPOSE: To evaluate efficacy and safety of flexible ureteroscopy and laser lithotripsy (FURSL) for treatment of the upper urinary tract calculi. METHODS: We retrospectively analyzed 784 patients who underwent FURSL between January 2015 and October 2020 in our unit. All patients were preoperatively evaluated with urine analysis, serum biochemistry, urinary ultrasonography, non-contrast computed tomography and intravenous urography. The procedure was considered as successful in patients with complete stone disappearance or fragments < 4 mm on B ultrasound or computed tomography. The operative parameters, postoperative outcomes and complications were recorded and analyzed respectively. RESULTS: The average operative time and postoperative hospital stay were 46.9±15.8 min and 1.2±1.1 days, respectively, among 784 patients. In addition, 746 patients were followed up and 38 patients were lost. In these patients, 700 (93.8%) cases met the stone removal criteria and 46 cases (6.2%) did not meet the stone removal criteria who need further treatment. The stone free rate (SFR) is 92.5%after 1-3 months and SFR of middle and upper calyceal calculi was higher than that of lower calyceal calculi significantly. The most common complications were fever (58/784, 7.4%), gross hematuria (540/784, 68.9%) and lpsilateral low back pain (47/784, 6.0%). The incidence rate of serious complication was 1.28%(10/784), including 5 cases of septic shock and 5 cases of subcapsular hematoma, which were cured after active treatment. CONCLUSION: FURSL is a reliable treatment for small and medium calculi patients of upper urinary tract. The curative effect of stone removal is clear. The complications are few and the safety is high. However, there are certain limitations to the efficacy in treating larger stone and lower calyceal calculi.

The feasibility and safety of photoselective vaporization for prostate using a 180-W XPS Greenlight laser in day-surgery pattern in China.

To evaluate the feasibility and safety of photoselective vaporization for prostate (PVP) with a 180-W XPS Greenlight laser as day surgery in the Chinese population. We retrospectively collected 114 cases undergoing the day surgery PVP and 198 cases undergoing conventional inpatient surgery PVP from April 2017 to March 2020. All patients' data including baseline characteristics, peri-operative data, post-operative outcomes, and complications were recorded and evaluated. The day-surgery procedures were successful in 110 patients. There were no significant differences in baseline characteristics in both groups. The catheterization time and hospitalization time were much shorter and economic cost was much lower in the day-surgery group than in the conventional inpatient surgery group. As for the post-operative complications, the incidence rate of the urinary retention is higher in the day-surgery group than in conventional inpatient surgery group. During the follow-up periods, the International Prostate Symptom Score (IPSS), quality of life (QoL), maximal urinary flow rate (Qmax), and post-void residual urine (PVR) improved significantly in both groups, and no differences were observed between the two groups. Compared to the conventional inpatient surgery, the day-surgery PVP is feasible and safe, which can reduce the hospitalization time and economic cost.

Application of 180W XPS GreenLight laser vaporization of the prostate for treatment of benign prostatic hyperplasia.

PURPOSE: To evaluate safety, efficacy and clinical outcomes after photovaporization of the prostate with the 180W-XPS Greenlight laser in patients with low urinary tracts symptom secondary to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: All 102 patients with lower urinary tract symptoms who underwent 180W XPS laser vaporization of the prostate from April 2017 to April 2018 were enrolled. The preoperative parameters, postoperative functional, uroflowmetry outcomes and complications were collected. RESULTS: All patients were successfully treated with 180W XPS laser vaporization. Mean preoperative prostate volume was 81±28.7 ml and mean laser time was 28.2±12.5 minutes. No major complications intraoperatively or postoperatively were observed and no blood transfusions were required. Comparing to preoperative characteristics, International Prostate Symptom Score (IPSS), maximum flow rate (Qmax) and post-void residual (PVR) parameters were improved significantly and sustained during the follow-up period. At 3, 6 and 12-month follow-ups, mean urinary peak flow increased from 6.2±2.1 ml per second to 19.8±4.6, 19.4±4.7 and 19.6±4.9 ml per second, respectively. Mean International Prostate Symptom Scores decreased over time, from 28.9±4.5 to 8.2±1.6, 6.2±1.22 and 5.88±1.15 at 3, 6, 12 months, respectively. CONCLUSIONS: 180W XPS Greenlight laser vaporization is a safe and effective treatment option for patients with lower urinary tract symptoms secondary to BPH.

Photoselective vaporization of the prostate with GreenLight 120-W laser versus transurethral resection of the prostate for benign prostatic hyperplasia: a systematic review with meta-analysis of randomized controlled trials.

The aim of this study is to assess the overall efficacy and safety of photoselective vaporization of the prostate (PVP) with GreenLight 120-W laser versus transurethral resection of the prostate (TURP) for treating patients of benign prostate hyperplasia (BPH) with lower urinary tract symptoms (LUTS). We performed a literature search of The Cochrane Library and the electronic databases, including Embase, Medline, and Web of Science. Manual searches were conducted of the conference proceedings, including European Association of Urology and American Urological Association (2007 to 2012). Outcomes reviewed included clinical baseline characteristics, perioperative data, complications, and postoperative functional results, such as postvoid residual (PVR), international prostate symptom score (IPSS), quality of life (QoL), and maximum flow rate (Qmax). Six randomized controlled trials (RCTs) were enrolled. Three hundred and forty-seven patients undergone 120-W PVP, and 350 patients were treated with TURP in the RCTs. There were no significant differences for clinical characteristics in these trials. In perioperative data, catheterization time and length of hospital stay were shorter in the PVP group. However, the operation time was shorter in the TURP group. Capsular perforation, blood transfusion, clot retention, and macroscopic hematuria were markedly less likely in PVP-treated subjects. The other complications between PVP and TURP did not demonstrate a statistic difference. There were no significant differences in QoL, PVR, IPSS, and Qmax in the 1, 3, 6, 12, and 24 months of postoperative follow-up. There was no significant difference at postoperation follow-up of functional outcomes including IPSS, PVR, Qmax, and QoL between the TURP-treated subjects and PVP-treated subjects. Owing to a shorter catheterization time, reduced hospital duration and less complication, PVP could be used as an alternative and a promising minimal invasive surgical procedure for the treatment of BPH.

Ailanthone suppresses cell proliferation of renal cell carcinoma partially via inhibition of EZH2.

BACKGROUND: Ailanthone (Ail) extracted from medicinal plants has played an anticancer role in multiple cancers, while there is no research about Ail in renal cell carcinoma (RCC). METHODS: In the present study, we performed CCK-8 and flow cytometry to assess the effect of Ail on cell viability, apoptosis and cycle. We also performed tandem mass tags (TMT)-labeled quantitative proteomic technology and bioinformatic analysis to identify the functional pathway and proteins of Ail in RCC. RESULTS: The results showed Ail could inhibit cell viability and induce cell apoptosis. Proteomic profiling identified 1732 differentially expressed proteins in cells treated with Ail, compared to the negative control group. Gene ontology function annotation and Gene Set Enrichment Analysis (GSEA) were performed to identified the involved biological processes, molecular function and pathway. Results of GSEA proved the enrichment of Deps in EZH2 targets. The comparison between Deps and EZH2 co-expressed genes revealed 44 overlapped genes and we identified 4 hub genes (CDC20, CEP55, TOP2A, and UBE2C) associated with RCC progression. The molecular docking study revealed a moderate to tight binding potential of Ail and EZH2, and western blotting showed EZH2 was suppressed after cells treated with Ail. CONCLUSION: Altogether, we identified the anticancer role of Ail in RCC, including inhibition of cell proliferation and induction of apoptosis. The results also screened the key proteins mediate the function of Ail, which have laid a theoretical foundation for elucidating the applications of Ail in clinical research.

The application of 120-W high-performance system GreenLight laser vaporization of the prostate in high-risk patients.

The purpose of this study is to evaluate the safety and efficacy of 120-W potassium titanyl phosphate (KTP) laser vaporization in patients with benign prostatic hyperplasia (BPH) who also had cardiopulmonary diseases who were taking long-term anticoagulants and were at high risk of bleeding complications. The prospective study included 188 patients with severe lower urinary tract symptoms who underwent 120-W KTP laser vaporization of the prostate. All patients were at high cardiopulmonary risk, having presented with an American Society of Anesthesiology score of 3 or greater. Of those, 45 patients were taking oral anticoagulants, and 1 had a severe bleeding disorder. BPH was successfully treated with 120-W KTP laser vaporization in all patients. Mean preoperative prostate volume ± SD was 66 ± 23.1 ml, and mean operative time was 50.8 ± 15.5 min. There were no major complications intraoperatively or postoperatively, and no blood transfusions were required. Postoperatively, only 14 patients (7.4 %) required bladder irrigation. Average catheterization time was 1.9 ± 1.5 days (range, 1-5 days). Three patients required reoperation due to enlarged prostates from residual adenoma. At 3-, 6,- 12-, and 24-month follow-ups, mean urinary peak flow increased from 8.0 ± 3.6 ml/s to 19.1 ± 5.6, 19.2 ± 4.7, 19.1 ± 4.65, and 19.2 ± 4.34 ml/s, respectively. Mean International Prostate Symptom Scores decreased over time, from 25.6 ± 5.1 (3 months) to 9.4 ± 2.8, 7.05 ± 1.46, 6.24 ± 1.36, and 6.20 ± 1.32 (24 months), respectively. 120-W HPS KTP laser vaporization is a safe and effective treatment option in BPH patients at high risk and those on anticoagulation therapy who have severe LUTS secondary to BPH.

GreenLight HPS 120-W laser vaporization versus transurethral resection of the prostate for treatment of benign prostatic hyperplasia: a prospective randomized trial.

The most recent advance in laser treatment of benign prostatic hyperplasia (BPH) is the introduction of a high-performance system (HPS) 120-W laser. The HPS laser beam at a wavelength of 532~nm is highly absorbed by oxyhemoglobin in the tissue and maintains focus with negligible divergence up to 3 mm from the fiber and with limited divergence at 5 mm. This study is designed to evaluate the three-year clinical efficacy and safety of photoselective vaporization of the prostate (PVP, n=100 cases) with GreenLight HPS laser compared with transurethral resection of the prostate (TURP, n=100 cases) for treatment of BPH. The results showed that the mean operating time, catheterization time and admission time were significantly shorter in the PVP group, respectively. There were dramatic improvements in International Prostate Symptom Score (IPSS), quality of life (Qol), maximum flow rate (Qmax) and postvoid residual (PVR) compared with preoperative values and the degree of improvements was comparable in both groups. The intraoperative complications were lower in PVP group. In summary, PVP is an effective technique in patients with BPH, when compared to TURP, producing equivalent improvements in IPSS, Qmax, Qol and PVR with the advantages of markedly reduced catheterization time, admission time and adverse events.

Photoselective vaporization of the prostate with GreenLight HPS 120-W laser for benign prostatic hyperplasia: 36 months' follow-up.

OBJECTIVE: To evaluate the 3-year clinical outcomes and durability of photoselective vaporization of the prostate (PVP) with the GreenLight HPS laser in the treatment of symptomatic and obstructive benign prostatic hyperplasia (BPH). METHODS: A total of 78 patients underwent PVP with the GreenLight HPS laser from October 2007 to November 2008. The baseline and treatment outcomes after surgery were evaluated 3 years later with the International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Q(max)), postvoid residual rate (PVR), and transrectal ultrasound-determined prostate volume. These parameters were assessed at 1, 3, 6, 12, 24, and 36 months. RESULTS: Patients' urinary symptoms and QoL significantly improved after surgery. The functional outcomes showed immediate and stable improvements during the entire follow-up period. At 36 months, the average percentage of improvements compared with baseline was as follows: IPSS, 60.2%; QoL, 80.9%; Q(max), 138.7%, and PVR, 82.6%. The median prostate volume, evaluated by transrectal ultrasonography, showed a 50.4% reduction when compared to preoperative volume. Overall, complications from surgery were low; only 6.7% of the 75 patients required reoperation during the 3-year follow-up. CONCLUSION: PVP using the GreenLight HPS laser showed a safe and effective treatment outcome for the treatment of symptomatic and obstructive BPH.

[Evaluation of 80-W and 120-W GreenLight laser vaporization for benign prostatic hyperplasia in high-risk patients].

OBJECTIVE: To investigate and compare the effectiveness and safety of 80-W GreenLight laser vaporization and GreenLight high-performance system (HPS) 120-W laser vaporization for the treatment of benign prostatic hyperplasia (BPH) in high-risk patients. METHODS: We allocated 290 high-risk patients with BPH to two groups to receive 80-W (n = 220) and HPS 120-W GreenLight laser vaporization (n = 70). We recorded and compared the pre-, intra- and post-operative clinical data of the two groups. RESULTS: The operations were successful in both of the groups. There were statistically significant differences in the prostate volume, IPSS, Qmax and PVR before and after surgery (P < 0.01), but not between the two groups (P > 0.05). The operation time, lasing time and energy consumption were (56.5 +/- 22.6) min, (31.2 +/- 10.3) min and (159.8 +/- 29.0) kJ in the 80-W group, as compared with (45.1 +/- 20.4) min, (24.6 +/- 8.3) min and (134.2 +/- 23.3) kJ in the 120 W group, with significant differences between the two (P < 0.01). CONCLUSION: GreenLight laser vaporization of the prostate is a safe and effective procedure for the treatment of BPH, and the new HPS 120-W laser therapy, with its advantages of easier operation and shorter surgical time, is an even better minimally invasive option for elderly high-risk patients.

miR-137-3p Modulates the Progression of Prostate Cancer by Regulating the JNK3/EZH2 Axis.

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in men worldwide. Early detection of prostate cancer by prostate-specific antigen (PSA) screening still has limitations. The discovery of new candidates is urgent and can provide insights into the mechanism involved in prostate cancer tumorigenesis. METHODS: We conducted a cross-sectional study involving prostate cancer cell lines and clinical samples. qPCR and IHC were used to evaluate the expression of miR-137-3p/JNK3/EZH2. Furthermore, cell growth, migration, invasion, cell cycle and apoptosis were analyzed to describe the function of this axis. Moreover, xenograft models, pathology platforms and TCGA data were generated to confirm the role of the miR-137-3p/JNK3/EZH2 axis. RESULTS: In this study, we determined that miR-137-3p was significantly reduced in prostate cancer, and low expression of miR-137-3p was correlated with tumor stage . The overexpression of miR-137-3p suppressed cell proliferation, migration and invasion in prostate cancer by enhancing cell apoptosis. We also validated JNK3 (MAPK10) as a direct target gene of miR-137-3p. Down-regulation of JNK3 in prostate cancer also inhibited cell proliferation and invasion and promoted apoptosis. Moreover, JNK3 expression was up-regulated and negatively correlated with miR-137-3p in prostate cancer tissues. Furthermore, JNK3 modulated EZH2 expression, which is a key oncogene in prostate cancer. Survival data indicated that patients with high levels of JNK3 and EZH2 had a worse prognosis. CONCLUSION: Collectively, the identification of miR-137-3p and the JNK3/EZH2 pathway might facilitate the development of biomarkers and therapeutic targets for prostate cancer.

ATM­JAK­PD­L1 signaling pathway inhibition decreases EMT and metastasis of androgen­independent prostate cancer.

Castration-resistant prostate cancer (CRPC), also known as androgen-independent prostate cancer, frequently develops local and distant metastases, the underlying mechanisms of which remain undetermined. In the present study, surgical specimens obtained from patients with clinical prostate cancer were investigated, and it was revealed that the expression levels of ataxia telangiectasia mutated kinase (ATM) were significantly enhanced in prostate cancer tissues isolated from patients with CRPC compared with from patients with hormone­dependent prostate cancer. CRPC C4­2 and CWR22Rv1 cells lines were subsequently selected to establish prostate cancer models, and ATM knockout cells were established via lentivirus infection. The results of the present study demonstrated that the migration and epithelial­mesenchymal transition (EMT) of ATM knockout cells were significantly decreased, which suggested that ATM is closely associated with CRPC cell migration and EMT. To further investigate the mechanisms underlying this process, programmed cell death 1 ligand 1 (PD­L1) expression was investigated in ATM knockout cells. In addition, inhibitors of Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3; Stattic) were added to C4­2­Sc and CWR22Rv1­Sc cells, and the results demonstrated that PD­L1 expression was significantly decreased following the addition of JAK inhibitor 1; however, no significant change was observed following the addition of Stattic. Furthermore, a PD­L1 antibody and JAK inhibitor 1 were added to C4­2­Sc and CWR22Rv1­Sc cells, and it was revealed that cell migration ability was significantly decreased and the expression of EMT­associated markers was effectively reversed. The results of the present study suggested that via inhibition of the ATM­JAK­PD­L1 signaling pathway, EMT, metastasis and progression of CRPC may be effectively suppressed, which may represent a novel therapeutic approach for targeted therapy for patients with CRPC.

Combined inhibition of JAK1,2/Stat3­PD­L1 signaling pathway suppresses the immune escape of castration­resistant prostate cancer to NK cells in hypoxia.

Castration­resistant prostate cancer (CRPC) is difficult to treat in current clinical practice. Hypoxia is an important feature of the CRPC microenvironment and is closely associated with the progress of CRPC invasion. However, no research has been performed on the immune escape of CRPC from NK cells. The present study focused on this subject. Firstly, when the CRPC cell lines C4­2 and CWR22Rv1 were induced by hypoxia, the expression of the UL16 binding protein (ULBP) ligand family of natural killer (NK) group 2D (NKG2D; ULBP­1, ULBP­2 and ULBP­3) and MHC class I chain­related proteins A and B (MICA/MICB) decreased. NKG2D is the main activating receptor of NK cells. Tumor cells were then co­cultured with NK cells to conduct NK cell­mediated cytotoxicity experiments, which revealed the decreased immune cytolytic activity of NK cells on hypoxia­induced CRPC cells. In exploring the mechanism behind this observation, an increase in programmed death­ligand 1 (PD­L1) expression in CRPC cells induced by hypoxia was observed, while the addition of PD­L1 antibody effectively reversed the expression of NKG2D ligand and enhanced the cytotoxic effect of NK cells on CRPC cells. In the process of exploring the upstream regulatory factors of PD­L1, inhibition of the Janus kinase (JAK)1,2/signal transducer and activator of transcription 3 (Stat3) signaling pathway decreased the expression of PD­L1 in CRPC cells. Finally, it was observed that combined inhibition of JAK1,2/PD­L1 or Stat3/PD­L1 was more effective than inhibition of a single pathway in enhancing the immune cytolytic activity of NK cells. Taking these results together, it is thought that combined inhibition of the JAK1,2/PD­L1 and Stat3/PD­L1 signaling pathways may enhance the immune cytolytic activity of NK cells toward hypoxia­induced CRPC cells, which is expected to provide novel ideas and targets for the immunotherapy of CRPC.

ELL2 regulates DNA non-homologous end joining (NHEJ) repair in prostate cancer cells.

ELL2 is an androgen-responsive gene that is expressed by prostate epithelial cells and is frequently down-regulated in prostate cancer. Deletion of Ell2 in the murine prostate induced murine prostatic intraepithelial neoplasia and ELL2 knockdown enhanced proliferation and migration in C4-2 prostate cancer cells. Here, knockdown of ELL2 sensitized prostate cancer cells to DNA damage and overexpression of ELL2 protected prostate cancer cells from DNA damage. Knockdown of ELL2 impaired non-homologous end joining repair but not homologous recombination repair. Transfected ELL2 co-immunoprecipitated with both Ku70 and Ku80 proteins. ELL2 could bind to and co-accumulate with Ku70/Ku80 proteins at sites of DNA damage. Knockdown of ELL2 dramatically inhibited Ku70 and Ku80 recruitment and retention at DNA double-strand break sites in prostate cancer cells. The impaired recruitment of Ku70 and Ku80 proteins to DNA damage sites upon ELL2 knockdown was rescued by re-expression of an ELL2 transgene insensitive to siELL2. This study suggests that ELL2 is required for efficient NHEJ repair via Ku70/Ku80 in prostate cancer cells.

Physical and Functional Interactions between ELL2 and RB in the Suppression of Prostate Cancer Cell Proliferation, Migration, and Invasion.

Elongation factor, RNA polymerase II, 2 (ELL2) is expressed and regulated by androgens in the prostate. ELL2 and ELL-associated factor 2 (EAF2) form a stable complex, and their orthologs in Caenorhabditis elegans appear to be functionally similar. In C. elegans, the EAF2 ortholog eaf-1 was reported to interact with the retinoblastoma (RB) pathway to control development and fertility in worms. Because RB loss is frequent in prostate cancer, ELL2 interaction with RB might be important for prostate homeostasis. The present study explored physical and functional interaction of ELL2 with RB in prostate cancer. ELL2 expression in human prostate cancer specimens was detected using quantitative polymerase chain reaction coupled with laser capture microdissection. Co-immunoprecipitation coupled with deletion mutagenesis was used to determine ELL2 association with RB. Functional interaction between ELL2 and RB was tested using siRNA knockdown, BrdU incorporation, Transwell, and/or invasion assays in LNCaP, C4-2, and 22Rv1 prostate cancer cells. ELL2 expression was downregulated in high-Gleason score prostate cancer specimens. ELL2 could be bound and stabilized by RB, and this interaction was mediated through the N-terminus of ELL2 and the C-terminus of RB. Concurrent siRNA knockdown of ELL2 and RB enhanced cell proliferation, migration, and invasion as compared to knockdown of ELL2 or RB alone in prostate cancer cells. ELL2 and RB can interact physically and functionally to suppress prostate cancer progression.

Suppression of STIM1 inhibits the migration and invasion of human prostate cancer cells and is associated with PI3K/Akt signaling inactivation.

Store-operated calcium entry (SOCE) plays an important role in the invasion and migration of cancer cells. Stromal-interacting molecule 1 (STIM1) is a critical component in the SOCE. STIM1 has been attracting more and more attention due to its oncogenic potential. STIM1 inhibition suppresses cell proliferation, migration and invasion in a variety of cancer models both in vitro and in vivo. However, the role of STIM1 in prostate carcinogenesis, in particular, in tumor migration and invasion is unclear. Herein, we downregulated STIM1 in prostate cancer cells by lentivirus-mediated short hairpin (shRNA), and then studied its impacts on cell migration and invasion. We found that migration and invasion of prostate cancer cells were significantly inhibited after the suppression of STIM1. Furthermore, we demonstrated that the PI3K/Akt signaling pathway was inactivated by STIM1 knockdown. The PI3K inhibitor LY294002 synergized with STIM1 knockdown to inhibit cell motility. Our results revealed that STIM1 may act as a novel regulator to promote migration and invasion of prostate cancer cells and is associated with the activation of the PI3K/Akt signaling pathway.