ATXN3 promotes prostate cancer progression by stabilizing YAP.

BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract.

Clinical implications of 3D printing technology in preoperative evaluation of partial nephrectomy. / 3D打印技术应用于肾部分切除术术前评估中的临床意义.

OBJECTIVES: Renal cancer is a common malignancy of the urinary system, and the partial nephrectomy is a common surgical modality for early renal cancer. 3D printing technology can create a visual three-dimensional model by using 3D digital models of the patient's imaging data. With this model, surgeons can perform preoperative assessment to clarify the location, depth, and blood supply of the tumor, which helps to develop preoperative plans and achieve better surgical outcomes. In this study, the R.E.N.A.L scoring system was used to stratify patients with renal tumors and to explore the clinical application value of 3D printing technology in laparoscopic partial nephrectomy. METHODS: A total of 114 renal cancer patients who received laparoscopic partial nephrectomy in Xiangya Hospital from June 2019 to December 2020 were enrolled. The patients were assigned into an experimental group (n=52) and a control group (n=62) according to whether 3D printing technology was performed, and the differences in perioperative parameters between the 2 groups were compared. Thirty-nine patients were assigned into a low-complexity group (4-6 points), 32 into a moderate-complexity group (7-9 points), and 43 into a high-complexity group (10-12 points) according to R.E.N.A.L score, and the differences in perioperative parameters between the experimental group and the control group in each score group were compared. RESULTS: The experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (all P<0.05), less intraoperative blood loss (P=0.047), and smaller postoperative blood creatinine change (P=0.032) compared with the control group. In the low-complexity group, there were no statistically significant differences between the experimental group and the control group in operation time, renal ischemia time, intraoperative blood loss, postoperative blood creatinine changes, and postoperative hospital stay (all P>0.05). In the moderate- and high- complexity groups, the experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (P<0.05 or P<0.001), less intraoperative blood loss (P=0.022 and P<0.001, respectively), and smaller postoperative blood creatinine changes (P<0.05 and P<0.001, respectively) compared with the control group. CONCLUSIONS: Compared with renal tumor patients with R.E.N.A.L score<7, renal cancer patients with R.E.N.A.L score≥7 may benefit more from 3D printing assessment before undergoing partial nephrectomy.

Tamsulosin as a Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: Tamsulosin is widely administered as a medical expulsive therapy to facilitate stone passage in patients with ureteral calculi. Recently several large, multicenter, randomized controlled trials revealed conflicting results, which led to considerable uncertainty about the efficacy of tamsulosin in the management of ureteral stones. The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of tamsulosin in the management of ureteral stones. MATERIALS AND METHODS: We searched MEDLINE®, Embase®, Web of Knowledge, Google Scholar™ and the Cochrane Central Search Library databases up to June 2018. Two reviewers independently evaluated eligible randomized controlled trials of the efficacy of tamsulosin to treat ureteral stones. Study quality was assessed with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Subgroup analyses were performed to explore heterogeneity. RESULTS: Included in study were 56 randomized controlled trials in a total of 9,395 patients. The observed treatment effect indicated that tamsulosin was associated with a higher stone expulsion rate (RR 1.44, 95% CI 1.35-1.55, p <0.01), a shorter stone expulsion time (weighted mean difference -0.73, 95% CI -1.00--0.45, p <0.01), a lesser incidence of ureteral colic (weighted mean difference -0.81, 95% CI -1.24--0.39, p <0.01) and fewer incidences of requiring subsequent intervention (RR 0.68, 95% CI 0.50-0.93, p = 0.017). Treatment with tamsulosin did not differ from a control group in the overall incidence of side effects (RR 1.14, 95% CI 0.86-1.51, p = 0.36). On subgroup analysis we observed a significant benefit in the stone expulsion rate for tamsulosin among patients with stones greater than 5 mm (RR 1.44, 95% CI 1.22-1.68, p <0.01) but no effect for stones 5 mm or less (RR 1.08, 95% CI 0.99-1.68, p <0.01). CONCLUSIONS: Our current meta-analysis results indicate that tamsulosin is effective and relatively safe in patients with ureteral stone as a medical expulsive therapy to facilitate stone passage. It is suggested to administer it selectively in patients with 5 to 10 mm ureteral stones.

Forkhead Box R2 Knockdown Decreases Chemoresistance to Cisplatin via MYC Pathway in Bladder Cancer.

BACKGROUND Bladder cancer is a very common urological cancer globally, and cisplatin- or gemcitabine-based chemotherapy is essential for advanced bladder cancer patients. Many patients with bladder cancer have a relatively poor response to chemotherapy, leading to failure of clinical treatment. We mined the GSE77883 GEO dataset, identifying FoxR2 as being a significantly upregulated gene in T24 chemoresistant cells. Herein, we assessed how FoxR2 functions in bladder cancer cell chemoresistance. MATERIAL AND METHODS Cisplatin-resistant T24 (T24/DDP) cells were constructed by administering increasing concentrations of cisplatin, and differences in expression of FoxR2 were examined in T24/DDP and T24 cells. FoxR2 loss- and gain-of-function cells models were established in T24/DDP and T24 cells, respectively. Cell survival, clone formation, cell cycle, and cell apoptosis were assessed, and the MYC pathway was verified. RESULTS FoxR2 was significantly upregulated in T24/DDP cells compared to T24 cells. Knockdown of FoxR2 in T24/DDP cells, survival rate, and clone formation were decreased, G1/S phase transition was suppressed, and cell apoptosis was promoted. These results were reversed by restoration of FoxR2 levels in T24 cells. We found that FoxR2 knockdown enhanced sensitivity to cisplatin, whereas MYC overexpression antagonized chemosensitivity in T24/DDP cells. CONCLUSIONS FoxR2 knockdown decreases chemoresistance to cisplatin via the MYC pathway in bladder cancer cells, and this may be a target for overcoming chemoresistance in bladder cancer.

Anterior versus posterior approach laparoscopic radical cystectomy: a retrospective analysis.

OBJECTIVE: To investigate the mortality, operation time, cystectomy time, and complications of anterior approach laparoscopic radical cystectomy (ALRC) in Asian males in comparison with posterior approach laparoscopic radical cystectomy (PLRC). MATERIALS AND METHODS: One hundred forty-seven male patients with bladder cancer (cT2-3NxM0) in our hospital from May 2011 to January 2018 having undergone laparoscopic radical cystectomy were studied, including 68 patients in PLRC group and 79 patients in ALRC group. Baseline patient characteristics, operative and postoperative characteristics, and postoperative complications were retrospectively collected and analyzed between the two groups. RESULTS: Patients in these two groups exhibited similar baseline characteristics (p > 0.05). Compared with PLRC group, ALRC group required similar operation time (317.3 ± 40.9 vs 321.9 ± 37.5) and cystectomy time (64.8 ± 8.7 vs 65.6 ± 14.0). The ALRC group required less cystectomy time (67.8 ± 10.1 vs 77.4 ± 14.9) when patients' BMI > 24 or patients had large total tumor and blood clot volume (> 160 cm3). Also, estimated blood loss (EBL) of ALRC group was significantly less than that of PLRC group (477.8 ± 97.4 vs 550.4 ± 99.9). There existed no significant differences between the PLRC and ALRC groups in postoperative characteristics and complications. CONCLUSION: This study revealed that ALRC required less cystectomy time for patients with higher BMI and larger tumor, suggesting less blood loss and similar perioperative complications. ALRC is recommend for male patients, of which BMI > 24 or total tumor and blood clot volume > 160 cm3.

Preservation of the saphenous vein during laparoendoscopic single-site inguinal lymphadenectomy: comparison with the conventional laparoscopic technique.

OBJECTIVE: To prospectively study the surgical strategies and clinical efficacy of laparoendoscopic single-site (LESS) inguinal lymphadenectomy compared with conventional endoscopic inguinal lymphadenectomy for the management of inguinal nodes. PATIENTS AND METHODS: A total of 12 patients with squamous cell carcinoma of the penis who underwent penectomy between February and July 2013 were enrolled in the study. All 12 patients underwent bilateral inguinal lymphadenectomy (LESS inguinal lymphadenectomy in one limb and conventional endoscopic inguinal lymphadenectomy in the other) with preservation of the saphenous vein. All lymphatic tissue in the boundaries of the adductor longus muscle (medially), the sartorius muscle (laterally), 2 cm above the inguinal ligament (superiorly), the Scarpa fascia (superficially) and femoral vessels (deeply) was removed in both surgical techniques. All 24 procedures were performed by one experienced surgeon. RESULTS: All 24 procedures (12 LESS and 12 conventional endoscopic inguinal lymphadenectomies) were completed successfully without conversion to open surgery. For LESS inguinal lymphadenectomy and conventional endoscopic inguinal lymphadenectomy groups, the mean ± sd operating time was 94.6 ± 14.8 min and 90.8 ± 10.6 min, respectively (P = 0.145). No significant differences in the incidence of postoperative complications (skin-related problems, hecatomb, lower extremity oedema, lymphatic complications and overall complications) were noted between the two groups (P > 0.05). No lower extremity oedema occurred in any limbs of the two groups. No significant differences were observed in either lymph node clearance rate or detection rate of histologically positive lymph nodes (P > 0.05). The patient satisfaction rate with scar appearance and cosmetic results was significantly better in the LESS inguinal lymphadenectomy group than in the conventional endoscopic inguinal lymphadenectomy group of (75 vs 25%; P = 0.039). CONCLUSIONS: This preliminary study suggests that both LESS inguinal lymphadenectomy and conventional endoscopic inguinal lymphadenectomy are safe and feasible procedures for inguinal lymphadenectomy. Preservation of the saphenous vein during LESS inguinal lymphadenectomy/conventional endoscopic inguinal lymphadenectomy can effectively reduce the incidence of postoperative lower extremity oedema. LESS inguinal lymphadenectomy seems to provide better cosmetic results than conventional endoscopic inguinal lymphadenectomy.

CXCR4 expression in bladder transitional cell carcinoma and its relationship with clinicopathological features.

OBJECTIVE: To elucidate the role of CXCR4 in the metastasis of bladder transitional cell carcinoma (BTCC) by examining CXCR4 expression in BTCC tissue and its correlation with clinicopathological features. METHODS: The expression of CXCR4 was assessed in bladder tissues from 70 BTCC patients and 18 normal controls, respectively, using immunohistochemistry. The correlation of CXCR4 expression with lymph node metastasis was also examined by determining the lymphatic vessel density (LVD). RESULTS: Overexpression of CXCR4 was detected in 58/70 (82.9%) BTCC tissues, whereas only in 3/18 (16.7%) normal bladder tissues. The expression was significantly higher in BTCC than that in normal controls (p < 0.01). CXCR4 expression level was closely associated with tumor size, pathological grades, clinical stages, and pelvic lymph node metastasis (p < 0.05). Multivariate analysis indicated that CXCR4 expression and lymph node metastasis were independent predictors for disease-free survival (both p < 0.05). The disease-free survival rate among the patients with high CXCR4 expression level was remarkably lower than that among the patients with no or low level expression (p < 0.01). CONCLUSION: Highly expressed in BTCC tissues, CXCR4 may play a critical role in the metastasis of BTCC, and the expression level in biopsy specimens might be a good indicator of lymph node metastasis.

[Effect of electroacupuncture on the expression of Iba-1 in spinal dorsal horn and hippocampus of chronic pain rats with knee osteoarthritis].

OBJECTIVE: To observe the effect of electroacupuncture(EA) on pain-ralated behaviors, morphology of hippocampus, concentrations of inflammatory cytokines and expression of ionized calcium binding adapter molecule 1(Iba-1) in dorsal horn of the spinal cord and the hippocampus, and brain-derived neurotrophic factor (BDNF) in hippocampus of rats with knee osteoarthritis (KOA), so as to explore the mechanism of EA in improving chronic pain of KOA. METHODS: Forty SD rats were randomly divided into blank group, saline group, model group and EA group, with 10 rats in each group. Monosodium iodoacetate(MIA, 80 mg/mL, 50 µL) was injected into the left knee joint cavity of rats in the model group and EA group to establish the chronic pain model of KOA, while the same volume of normal saline was injected into the left knee joint cavity of rats in the saline group. Rats in the EA group received EA stimulation(2 Hz/100 Hz, 1-2 mA) at left "Yanglingquan"(GB34) and "Neixiyan"(EX-LE4) for 15 min, 14 d after MIA injection. The treatment was given once daily, 5 d as 1 session and 2 sessions of treatment were required. Methanical withdrawl threshold(MWT) and weight-bearing capacity tests on left hind limbs were carried out 1 d before, 7 d，14 d, 20 d and 26 d after MIA injection. At the 27th day, rats were sacrificed and HE staining was used to observe the morphology of hippocampal CA1 area. Concentrations of interleukin(IL)-1ß and tumor necrosis factor(TNF)-α in the left L3-L5 spinal dorsal horn and hippocampal CA1 area were detected by ELISA, the expressions of Iba-1 in the spinal dorsal horn and hippo-campal CA1 area were detected by immunofluorescence, and the expression of BDNF in left hippocampal CA1 area was detected by Western blot. RESULTS: The HE staining results of the hippocampal CA1 area showed reduced number of neurons, unclear cell contour and boundary between nucleus and cytoplasm, and nuclear pyknosis in the model group, which was relatively milder in the EA group. Compared with the blank group, MWT and weight-bearing capacity of rats' left hind limbs, and expression of BDNF protein in hippocampal CA1 area were significantly decreased (P<0.01), while the contents of IL-1ß and TNF-α, the expression of Iba-1 in spinal dorsal horn and hippocampal CA1 area were significantly increased (P<0.01) in the model group. In comparison with the model group, MWT and weight-bearing capacity of rats' left hind limbs, and protein expression of BDNF in hippocampal CA1 area were significantly increased (P<0.01), while the contents of IL-1ß and TNF-α, and the expression of Iba-1 protein in spinal dorsal horn and hippocampal CA1 area were significantly decreased after EA intervention(P<0.01). CONCLUSION: EA at GB34 and EX-LE4 can alleviate the pain-related behaviors of KOA rats. The mechanism might be related to the inhibition of inflammatory reaction mediated by microglia in spinal dorsal horn and hippocampus, and the up-regulation of BDNF expression in hippocampus.

Effects of YC-1 on hypoxia-inducible factor 1 alpha in hypoxic human bladder transitional carcinoma cell line T24 cells.

OBJECTIVES: It was the aim of this study to explore the effects of 3-(5'-hydroxymethyl-2'-furyl)-l-benzyl indazole (YC-1) on transcription activity, cell proliferation and apoptosis of hypoxic human bladder transitional carcinoma cells (BTCC), mediated by hypoxia-inducible factor 1α (HIF-1α). METHODS: BTCC cell line T24 cells were incubated under normoxic or hypoxic conditions, adding different doses of YC-1. The protein expression of HIF-1α and HIF-1α-mediated genes was detected by Western blotting. RT-PCR was used to detect HIF-1α mRNA expression. Cell proliferation, apoptosis and migration activity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and transwell migration assay. The cells were pretreated by two ERK/p38 MAPK pathway-specific inhibitors, PD98059 or SB203580, and then incubated with YC-1 treatment under hypoxic condition. HIF-1α protein expression was detected by Western blotting. RESULTS: Hypoxic T24 cells expressed a higher level of HIF-1α, vascular endothelial growth factor, matrix metalloproteinases-2, B-cell lymphoma/leukemia-2 protein and HIF-1α mRNA compared with normoxic controls, in which the above-mentioned expression was downregulated by YC-1 in a dose-dependent manner. Cell proliferation and migration activity were inhibited while apoptosis was induced by YC-1 under hypoxic condition. Moreover, YC-1-downregulated HIF-1α expression was reversed by PD98059 and SB203580, respectively. CONCLUSIONS: YC-1 inhibits HIF-1α and HIF-1α-mediated gene expression, cell proliferation and migration activity and induces apoptosis in hypoxic BTCC. The ERK/p38 MAPK pathway may be involved in YC-1-mediated inhibition of HIF-1α.

[Diagnosis and treatment of renal oncocytoma of 6 cases and literature review].

To improve the diagnosis and treatment of renal oncocytoma and avoid unnecessary radical nephrectomy. The clinical data of 6 cases of renal oncocytoma diagnosed at the Second Xiangya Hospital Central South University from March 2005 to November 2010, including symptoms, laboratory tests, imaging, style of operation, pathological examination, and follow-up were retrospectively analyzed.There were no special symptoms and obvious abnormal laboratory tests in the patients. Two patients had relatively special imaging. Partial nephrectomy was performed in 2 cases of renal oncocytoma with typical imaging, while radical nephrectomy was performed on other patients because of misdiagnosis. No relapse and metastasis were found in the following 1 to 5 years.Renal oncocytoma is an uncommon benign tumor. Partial nephrectomy or tumor excision can be performed on patients diagnosed with renal oncocytoma according to typical imaging and intraoperative frozen section biopsy. The final diagnosis depends on pathological examination and regular follow-up is imperative for patients with renal oncocytoma.

Serum IL-6 level is associated with clinical outcome of intravesical gemcitabine therapy in T1 non-muscle-invasive bladder cancer.

PURPOSE: Serum biomarkers are valuable tools to predict the prognosis of anticancer therapies. This study aimed to evaluate the impact of serum interleukin-6 (IL-6) level on the clinical outcome of intravesical gemcitabine (GEM) therapy in non-muscle-invasive bladder cancer (NMIBC). METHODS: This retrospective study enrolled 71 patients initially diagnosed with T1 NMIBC who underwent intravesical GEM therapy between 2017 and 2019. The expression of IL-6 gene was examined by real-time PCR. Serum IL-6 level was determined by enzyme-linked immunosorbent assay (ELISA). The cell viability after gemcitabine treatment was measured by CCK-8 assay. The optimal serum IL-6 cutoff values for recurrence prediction were calculated using receiver-operating characteristic curve analysis with reference to cancer recurrence. Recurrence-free survival was compared by the log-rank test. Univariate and multivariate Cox regression analysis was conducted to identify the prognostic factors influencing recurrence-free survival after treatment with intravesical GEM. RESULTS: Increased expression and secretion of IL-6 were observed in GEM-resistant sublines compared with parental bladder cancer cell lines. Serum IL-6 level rendered a sensitivity of 82.6% and a specificity of 77.1% to correlate with the cancer recurrence after intravesical GEM. Patients with a high serum IL-6 level exhibited shorter recurrence-free survival after intravesical GEM. Moreover, serum IL-6 level in our NMIBC cohort was significantly associated with clinicopathological characteristics, such as tumor diameter, multifocality, concomitant CIS, and grade. Serum IL-6 level was an independent prognostic factor for recurrence-free survival in NMIBC patients treated with intravesical GEM. CONCLUSION: Given that it was significantly associated with clinical outcome of intravesical GEM therapy, serum IL-6 level might be used as a potential prognostic biomarker for intravesical GEM in T1 NMIBC.

Niban apoptosis regulator 1 promotes gemcitabine resistance by activating the focal adhesion kinase signaling pathway in bladder cancer.

Although intravesical gemcitabine (GEM) chemotherapy (IGC) can effectively reduce the recurrence risk of non-muscle invasive bladder cancer (NMIBC), the development of GEM resistance may occur and result in cancer recurrence and disease progression. Herein, a label-free proteomics approach was used to characterize the proteomic profiles of primary/post-IGC recurrent NMIBC. A total of 218 proteins were found to be differentially expressed in paired primary and post-IGC recurrent NMIBC. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that multiple signaling pathways including "focal adhesion" were highly enriched in recurrent NMIBC. Niban apoptosis regulator 1 (NIBAN1) was identified as the top upregulated protein in recurrent NMIBC. Highly increased NIBAN1 expression was observed in a number of GEM-resistant cancer cell lines and in post-IGC recurrent NMIBC specimens. Manipulation of NIBAN1 expression affected the chemosensitivity to GEM in bladder cancer cell models. Moreover, NIBAN1 also regulated focal adhesion/focal adhesion kinase (FAK) signaling activation in bladder cancer cell lines. Highly elevated FAK (pY397) expression was observed in post-IGC recurrent NMIBC specimens, which was positively correlated with NIBAN1 expression. Knockdown of FAK markedly attenuated GEM resistance in GEM-resistant bladder cancer cells. In vivo studies demonstrated that knockdown of NIBAN1 disrupted FAK signaling and sensitized GEM-resistant bladder cancer cells to GEM treatment. Our findings suggest that NIBAN1 might regulate FAK signaling activation to promote GEM resistance in bladder cancer. Targeting NIBAN1/FAK signaling may help sensitize bladder cancer cells to GEM treatment.

Renal phenotypes correlate with genotypes in unrelated individuals with tuberous sclerosis complex in China.

PURPOSE: To explore the relationship between the genotype and renal phenotype in a Chinese cohort and guide clinical decision-making for treating tuberous sclerosis complex (TSC). MATERIALS AND METHODS: We reviewed 173 patients with definite TSC at three centers in China from September 2014 to September 2020. All the patients underwent TSC1 and TSC2 genetic testing as well as renal phenotypic evaluation. All analyses were performed using the SPSS software, version 19.0, with a cut-off P value of 0.05 considered statistically significant. RESULTS: We identified variants in 93% (161/173) cases, including 16% TSC1 and 77% TSC2 variants. Analysis of the relationship between the genotype and renal phenotype, revealed that those with TSC2 variants were more likely to develop severe renal AML (> 4) (P = 0.044). In terms of treatment, TSC2 variants were more likely to undergo nephrectomy/partial nephrectomy (P = 0.036) and receive mTOR medication such as everolimus (P < 0.001). However, there was no significant difference between the two groups in terms of their response to the everolimus treatment. CONCLUSION: Patients with TSC2 variants exhibit more severe renal phenotypes, especially those associated with renal angiomyolipomas (AML), and they often require nephrectomy/partial nephrectomy or mTOR medication. Detection of the genotype is helpful in TSC management.

[Diagnosis and treatment of mature adrenal teratoma].

To discuss the pathology, clinical manifestation, diagnosis, therapy and prognosis of mature teratoma in adrenal gland. We reported 2 cases of mature adrenal teratoma and summarized their characters. No local recurrence or metastasis was found in the close follow-up of the 2 patients after the radical resection. Teratomas are rare germ tumors with potential malignant character which usually occur in the testes and ovaries. Adrenal teratomas are extremely rare and the diagnosis relies on radiological examinations. Early diagnosis and early surgical resection are the key in the treatment. Whether the postoperative chemotherapy is needed depends on the pathological result. Close lifelong follow-up is recommended and the prognosis is unclear at present.

Serum CXCL5 level is associated with tumor progression in penile cancer.

Chemokine (C-X-C motif) ligand 5 is an important regulator of tumor progression in many cancers, and could serve as potential serum cancer biomarker. Our initial analysis identified CXCL5 as a cancer-related gene highly expressed in PC. Patients with PC exhibited markedly higher preoperative serum CXCL5 levels compared with that in healthy individuals (P<0.001). The area under the curve (AUC) was 0.880 with the sensitivity of 84.0%, and specificity of 80.4% to distinguish PC. Serum CXCL5 levels were also significantly decreased following tumor resection in patients with PC (P=0.001). Preoperative serum CXCL5 level was significantly associated with clinicopathological characteristics including T stage (P=0.001), nodal status (P<0.001), and pelvic lymph node metastasis (P=0.018). Cox regression analysis showed that serum CXCL5 level could serve as an independent prognostic factor for disease-free survival with a HR of 6.363 (95% CI: 2.185-18.531, P=0.001). CXCL5 and its receptor CXCR2 exhibited correlated expression pattern in PC tissues. Differential CXCL5 expression was observed in normal penile tissues, PC cell lines, and their culture supernatants. Furthermore, knockdown of CXCL5 or CXCR2 expression markedly suppressed malignant phenotypes (cell proliferation, clonogenesis, apoptosis escape, migration, and invasion), attenuated STAT3 and AKT signaling, and reduced MMP2/9 secretion in PC cell lines. In conclusion, our findings revealed that serum CXCL5 level might serve as a potential diagnostic and prognostic cancer biomarker for penile cancer. Autocrine CXCL5/CXCR2 signaling might activate multiple downstream oncogenic signaling pathways (STAT3, AKT, MMP2/9) to promote malignant progression of PC, which may warrant further investigation in the future.

LncRNA SNHG9 is a prognostic biomarker and correlated with immune infiltrates in prostate cancer.

BACKGROUND: Expression of Long non-coding RNA (LncRNA) small nucleolar RNA host gene 9 (SNHG9) is observed in some cancer types, while its role in prostate cancer (PCa) is unclear. We aimed to demonstrate the relationship between SNHG9 and PCa based on The Cancer Genome Atlas (TCGA) database. METHODS: Kruskal-Wallis test, Wilcoxon signed-rank test, and logistic regression were used to evaluate relationships between clinical-pathologic features and SNHG9 expression. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of SNHG9 using area under curve (AUC) score. Kaplan-Meier method and Cox regression analysis were used to evaluate factors contributing to prognosis. Gene set enrichment analysis (GSEA) and immune infiltration analysis were performed to identify the significantly involved functions of SNHG9. RESULTS: Increased SNHG9 expression in PCa was associated with N stage (P<0.001), Gleason score (P=0.002), primary therapy outcome (P=0.001), residual tumor (P<0.001) and prostate specific antigen (PSA) (P=0.007). ROC curve suggested the significant diagnostic and prognostic ability of SNHG9 (AUC =0.815). High SNHG9 expression predicted a poorer progression-free survival (PFS) (P=0.002), and SNHG9 expression (HR: 1.776; 95% CI: 1.067-2.955; P=0.027) was independently correlated with PFS in PCa patients. GSEA and immune infiltration analysis showed that SNHG9 expression was correlated with regulating the function of ribosome and some types of immune infiltrating cells. CONCLUSIONS: SNHG9 expression was significantly correlated with poor survival and immune infiltrations in PCa, and it may be a promising prognostic biomarker in PCa.

Identification of key genes and microRNA regulatory network in development and progression of urothelial bladder carcinoma.

BACKGROUND: Bladder cancer as other cancers contains multiple dynamic alterations in progression. Theoretically, large number of genes participates in cancer progression. In the present study, the interconnections of genesets defined by Gene Set Enrichment Analysis (GSEA) and tumor histopathological stages were characterized. In addition, the outcomes with genesets were discussed in bladder cancer. METHODS: Transcriptome data from 411 tissues of urothelial bladder carcinoma and 19 samples from adjacent tissues were retrieved from The Cancer Genome Atlas (TCGA) database. Single-sample GSEA (ssGSEA), cluster analysis of geneset enrichment scores and genesets as indicators in prognosis were applied to elucidate the correlations between genesets and bladder cancer progression. RESULTS: Chemical and genetic perturbations (CGP), canonical pathways (CP), CP:BIOCARTA (BioCarta gene sets), CP:KEGG (KEGG gene sets) and CP:REACTOME (Reactome gene sets) in C2 collection, upstream cis-regulatory motifs serum response factor (SRF) in C3 collection, KRAS in C6 collection and C8+ T cells in C7 collection were observed as enriched by ssGSEA. The cluster 2 identified from cluster analysis shows a more immune active microenvironment which tended to increase in stage II and decreased in stage IV indicating the crucial role in bladder cancer progression. miR-450, miR-518s, transcription factor PAX3, KRAS and PTEN were potential markers for outcomes of urothelial bladder carcinoma. Activating tumor immune microenvironment had deteriorated prognosis of patients with bladder cancer. CONCLUSIONS: Our findings demonstrated that activating tumor immune microenvironment is a negative factor for outcomes of urothelial bladder carcinoma. These data provided a potential combination strategy for patients with bladder cancer.

Competing endogenous RNA network analysis reveals pivotal ceRNAs in bladder urothelial carcinoma.

BACKGROUND: Bladder urothelial cancer (BUC) has become one of the most frequently occurring malignant tumors worldwide and it is of great importance to explore the molecular pathogenesis of bladder cancer. Emerging evidence has demonstrated that dysregulation of noncoding RNAs is critically involved in the tumorigenesis and progression of BUC. Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression and therefore form a competing endogenous RNA (ceRNA) network. ceRNA networks have been proven to play vital roles during tumorigenesis and progression. Elements involved in the ceRNA network have also been identified as potential therapeutic targets and prognostic biomarkers in various tumors. Understanding the regulatory mechanisms and functional roles of the ceRNA system will help understand tumorigenesis, progression mechanisms of BUC and develop therapeutics against cancer. METHODS: In this study, we utilized the TCGA database and analyzed the multilevel expression profile of BUC. ceRNA regulatory networks were constructed by integrating tumor progression and prognosis information. RNA immunoprecipitation (RIP) and qRT-PCR were applied to verify the identified ceRNA networks. KEGG enrichment analysis was implemented to infer the biological functions of the regulatory system. RESULTS: We identified a lncRNA-miRNA-mRNA regulatory ceRNA network containing two lncRNAs, one miRNA and 14 mRNAs. The ceRNA network we identified showed significant roles in BUC tumorigenesis, progression, and metastases. CONCLUSIONS: The proposed ceRNA network may help explain the regulatory mechanism by which lncRNAs function as ceRNAs and improve our understanding of the pathogenesis of BUC. Moreover, the candidate elements involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for BUC.

Clinicopathologic Features and Survival Outcomes for Primary Renal Neuroendocrine Neoplasms.

PURPOSE: Primary renal neuroendocrine neoplasms (NENs) are exceedingly rare. We used the Surveillance, Epidemiology, and End Results (SEER) data to summarize clinicopathologic characteristics, treatment outcomes, and prognostic factors of primary renal NENs. METHODS: Data were identified from the SEER database. Clinicopathologic characteristics were compared by the Pearson chi-square or correction test, in which continuous variables were analyzed by t test. Kaplan-Meier analyses and log-rank tests were used to compare the differences in overall survival (OS). Univariable and multivariable regression model analyses of OS were conducted using the Cox proportional hazard model. Also, we used directed acyclic graphs to guide the multivariable regression model and to try to determine the impact of each of surgery, chemotherapy, and radiotherapy on OS. RESULTS: A total of 132 patients were enrolled. There were significant differences in age, grade, tumor size, SEER stage, surgery, and chemotherapy between patients with carcinoid tumors and those with neuroendocrine carcinomas. Patients with disease with carcinoid tumors, younger age, smaller tumor size, and lower SEER exhibited better survival outcomes. Univariable and multivariable regression models analyses indicated that age, sex, tumor size, and SEER stage were independent prognostic factors for OS. Directed acyclic graphs guided the respective inclusion of variables in the multivariable regression model to assess the causal effect of surgery, chemotherapy, and radiotherapy on OS. The results showed that surgery, chemotherapy, and radiotherapy did not improve OS. CONCLUSION: Primary renal NENs are exceedingly rare and exhibit different biological behavior. Older age, male sex, larger tumor size, and tumors not confined to the renal parenchyma may indicate poor prognosis. Resection of all visible disease remains the reference-standard treatment of choice. Longer-term studies with a larger patient cohort are needed to determine systemic therapeutic options.