New application of traditional S retractor in collecting wound flushing fluid after skin tumour resection.

After Skin tumour resection, there may be residual tumour cells on the wound surface, washing the wound surface with sterilized water can mediate tumour cell lysis and improve patient prognosis. We observed that when the patient is lying behind the operating table, both the limbs and trunk will form an inclined plane with a high centre and a low periphery. Fit the hook of the traditional S retractor onto the low end of the inclined surface, and apply appropriate pressure to make the fitting tight. This way, the flushing fluid will converge at the low end of the fitting surface and will not leak out. Combined with a negative pressure aspirator, it can reduce the splashing of flushing fluid. The traditional S retractor is common in the operating room, which is easy to operate and do not increase medical costs. The method of using a traditional S retractor to collect flushing fluid is worth further promotion.

MIR663AHG as a competitive endogenous RNA regulating TGF-ß-induced epithelial proliferation and epithelial-mesenchymal transition in benign prostate hyperplasia.

Benign prostate hyperplasia (BPH) is the most commonly seen disease among aging males. Transforming growth factor(TGF)-ß-mediated epithelial-mesenchymal transition (EMT) and epithelial overproliferation might be central events in BPH etiology and pathophysiology. In the present study, long noncoding RNA MIR663AHG, miR-765, and FOXK1 formed a competing endogenous RNAs network, modulating TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. miR-765 expression was downregulated in TGF-ß-stimulated BPH-1 cells; miR-765 overexpression ameliorated TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. MIR663AHG directly targeted miR-765 and negatively regulated miR-765; MIR663AHG knockdown also attenuated TGF-ß-induced EMT and epithelial overproliferation in BPH-1 cells, whereas miR-765 inhibition attenuated MIR663AHG knockdown effects on TGF-ß-stimulated BPH-1 cells. miR-765 directly targeted FOXK1 and negatively regulated FOXK1. FOXK1 knockdown attenuated TGF-ß-induced EMT and epithelial overproliferation and promoted autophagy in BPH-1 cells, and partially attenuated miR-765 inhibition effects on TGF-ß-stimulated BPH-1 cells. In conclusion, this study provides a MIR663AHG/miR-765/FOXK1 axis modulating TGF-ß-induced epithelial proliferation and EMT, which might exert an underlying effect on BPH development and act as therapeutic targets for BPH treatment regimens.

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.

Prevention of Recurrent Bladder Tumors after Nephroureterectomy for Primary Upper Urinary Tract Urothelial Carcinoma: An Individualized Selection Strategy Based on Patient Risk Stratification Is Needed.

OBJECTIVE: To evaluate the efficacies of different chemotherapy regimens in different risk sub-groups for the prevention of bladder recurrence after radical nephroureterectomy (RNU). MATERIALS AND METHODS: Between 2004 and 2012, we recruited 685 patients who underwent RNU for upper tract urothelial carcinoma at 4 Chinese institutions. We assessed whether the type of intravesical chemotherapy regimen affected the bladder recurrence rate in patients with different risk levels after RNU. RESULTS: For all patients, the bladder recurrence rate was lower with intravesical chemotherapy than without, but no significant differences were found between the 2 intravesical chemotherapy regimens (single dose or relatively long-term therapy). We used multivariate analysis to define the risk factors for bladder recurrence and stratified patients into low-, intermediate-, and high-risk sub-groups accordingly. The bladder recurrence rate in the low-risk patients was not significantly different between patients with or without intravesical chemotherapy. However, in the intermediate-risk and high-risk patients, the rate was greater in patients without intravesical chemotherapy than in patients with. Furthermore, the rate was not significantly different between the 2 intravesical chemotherapy regimens in the intermediate-risk patients, while the efficacy of the relatively long-term regimen in high-risk patients remains unclear. CONCLUSIONS: Our study showed that an individualized strategy based on patient risk stratification is needed.

[Treatment of varicocele combined with asthenospermia by microsurgical shunt: 3 cases report].

To investigate the clinic value of microsurgical shunt for the treatment of varicocele combined with asthenspermia, the clinical data and therapeutic method for 3 patients, who conducted the microscope spermatic vein high ligation combined with superficial epigastric vein flow, were retrospectively analyzed. No postoperative complications were found, and the original symptoms and signs were disappeared. All patients were conducted scrotal ultrasound and semen routine after 3 months, and all indexes, including maximum internal diameter of the cord vein (erect position), sperm density, sperm survival rate, sperm deformity rate and sperm forward movement rate, were gradually improved. Consequently, high ligation of spermatic vein combined with vascular bypass surgery under the microscope can block the countercurrent venous blood and establish a new return channel to the testis. Meanwhile, it can also protect the testicular artery and lymph-vessel. It is worth to be spread for the treatment of varicocele combined with asthenospermia.

Extraperitoneal and transperitoneal laparoscopic partial cystectomy for benign non-urothelial bladder tumors: an initial experience.

OBJECTIVE: This study presents our initial experience with extraperitoneal and transperitoneal laparoscopic partial cystectomy (LPC) in the treatment of benign non-urothelial bladder tumors. METHODS: Eleven patients with benign non-urothelial bladder tumors underwent extraperitoneal or transperitoneal LPC. The five cases with tumors located on the anterior/anterolateral bladder wall received the extraperitoneal approach. The six cases with tumors located around the bladder dome or over the posterior bladder wall received the transperitoneal approach. Key perioperative parameters were recorded. RESULTS: All patients underwent laparoscopic resection smoothly without requiring a conversion to a traditional open procedure, and no patient displayed perioperative complications. Pathology showed benign non-urothelial bladder tumors with normal margins in all eleven patients, including five leiomyoma cases, three pheochromocytoma cases, two paraganglioma cases and one inflammatory fibrous histiocytoma case. Follow-up cystoscopy and imaging studies in all eleven patients (mean follow-up period 32 months) revealed neither residual nor local recurrence. CONCLUSIONS: LPC is safe and feasible in select patients with benign non-urothelial bladder tumors and yields satisfactory oncological and functional results. Extraperitoneal LPC should be preferred for lesions located on the anterior/anterolateral bladder wall, while transperitoneal LPC should be preferred for lesions around the bladder dome or over the posterior bladder wall.

miR-150 modulates cisplatin chemosensitivity and invasiveness of muscle-invasive bladder cancer cells via targeting PDCD4 in vitro.

BACKGROUND: Chemotherapeutic insensitivity and tumor cell invasiveness are major obstacles to effectively treating muscle-invasive bladder cancer (MIBC). Recent reports show that microRNAs (miRNAs) play an important role in the chemotherapeutic response and disease progression of MIBC. Therefore, here we investigated the role of miR-150 in MIBC cells in vitro. MATERIAL AND METHODS: miR-150 expression was quantified by qRT-PCR in two MIBC cell lines (5637 and T24). After successful miR-150 inhibition by transfection, MTS and transwell assays were used to assess the MIBC's cisplatin sensitivity and cell invasiveness, respectively. The TargetScan database and a luciferase reporter system were used to identify whether the programmed cell death 4 protein (PDCD4) is a direct target of miR-150 in MIBC cells. RESULTS: miR-150 expression was found to be significantly increased in both MIBC cell lines, and treatment with a miR-150 inhibitor significantly sensitized MIBC cells to cisplatin and inhibited MIBC cell invasiveness. PDCD4 was identified as a direct target of miR-150 in MIBC cells, and increased PDCD4 expression via transfection with the pLEX-PDCD4 plasmid efficiently sensitized MIBC cells to cisplatin chemotherapy and inhibited MIBC cell invasiveness. CONCLUSIONS: This study provides novel evidence that miR-150 functions as a tumor promoter in reducing chemosensitivity and promoting invasiveness of MIBC cells via targeting PDCD4. Thus, modulation of the miR-150-PDCD4 axis shows promise as a therapeutic strategy for MIBC.

Predicting the Prognosis of Bladder Cancer Patients Through Integrated Multi-omics Exploration of Chemotherapy-Related Hypoxia Genes.

Bladder cancer is a prevalent malignancy with high mortality rates worldwide. Hypoxia is a critical factor in the development and progression of cancers. However, whether and how hypoxia-related genes (HRGs) could affect the development and the chemotherapy response of bladder cancer is still largely unexplored. This study comprehensively explored the complex molecular landscape associated with hypoxia in bladder cancer by analyzing 260 hypoxia genes based on transcriptomic and genomic data in 411 samples. Employing the 109 dysregulated hypoxia genes for consensus clustering, we delineated two distinct bladder cancer clusters characterized by disparate survival outcomes and distinct oncogenic roles. We defined a HPscore that was correlated with a variety of clinical features, including TNM stages and pathologic grades. Tumor immune landscape analysis identified three immune clusters and close interactions between hypoxia genes and the various immune cells. Utilizing a network-based method, we defined 129 HRGs exerting influence on apoptotic processes and critical signaling pathways in cancer. Further analysis of chemotherapy drug sensitivity identified potential drug-target HRGs. We developed a Risk Score model that was related to the overall survival of bladder cancer patients based on doxorubicin-target HRGs: ACTG2, MYC, PDGFRB, DHRS2, and KLRD1. This study not only enhanced our understanding of bladder cancer at the molecular level but also provided promising avenues for the development of targeted therapies, representing a significant step toward the identification of effective treatments and addressing the urgent need for advancements in bladder cancer management.

Multi-dimensional characterization of apoptosis in the tumor microenvironment and therapeutic relevance in melanoma.

PURPOSE: Melanoma is widely utilized as a prominent model for the development of immunotherapy, thought an inadequate immune response can occur. Moreover, the development of apoptosis-related therapies and combinations with other therapeutic strategies is impeded by the limited understanding of apoptosis's role within diverse tumor immune microenvironments (TMEs). METHODS: Here, we constructed an apoptosis-related tumor microenvironment signature (ATM) and employ multi-dimensional analysis to understand the roles of apoptosis in tumor microenvironment. We further assessed the clinical applications of ATM in nine independent cohorts, and anticipated the impact of ATM on cellular drug response in cultured cells. RESULTS: Our ATM model exhibits robust performance in survival prediction in multiple melanoma cohorts. Different ATM groups exhibited distinct molecular signatures and biological processes. The low ATM group exhibited significant enrichment in B cell activation-related pathways. What's more, plasma cells showed the lowest ATM score, highlighting their role as pivotal contributors in the ATM model. Mechanistically, the analysis of the interplay between plasma cells and other immune cells elucidated their crucial role in orchestrating an effective anti-tumor immune response. Significantly, the ATM signature exhibited associations with therapeutic efficacy of immune checkpoint blockade and the drug sensitivity of various agents, including FDA-approved and clinically utilized drugs targeting the VEGF signaling pathway. Finally, ATM was associated with tertiary lymphoid structures (TLS), exhibiting stronger patient stratification ability compared to classical "hot tumors". CONCLUSION: Our findings indicate that ATM is a prognostic factor and is associated with the immune response and drug sensitivity in melanoma.

Super enhancer-driven core transcriptional regulatory circuitry crosstalk with cancer plasticity and patient mortality in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer. Core transcriptional regulatory circuitry (CRC) consists of autoregulated transcription factors (TFs) and their enhancers, which dominate gene expression programs and control cell fate. However, there is limited knowledge of CRC in TNBC. Herein, we systemically characterized the activated super-enhancers (SEs) and interrogated 14 CRCs in breast cancer. We found that CRCs could be broadly involved in DNA conformation change, metabolism process, and signaling response affecting the gene expression reprogramming. Furthermore, these CRC TFs are capable of coordinating with partner TFs bridging the enhancer-promoter loops. Notably, the CRC TF and partner pairs show remarkable specificity for molecular subtypes of breast cancer, especially in TNBC. USF1, SOX4, and MYBL2 were identified as the TNBC-specific CRC TFs. We further demonstrated that USF1 was a TNBC immunophenotype-related TF. Our findings that the rewiring of enhancer-driven CRCs was related to cancer immune and mortality, will facilitate the development of epigenetic anti-cancer treatment strategies.

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.

RGS20 Promotes Tumor Progression through Modulating PI3K/AKT Signaling Activation in Penile Cancer.

Regulator of G protein signaling 20 (RGS20) plays an important role in regulating neuronal G protein-coupled receptor signaling; however, its expression and oncogenic function in penile cancer (PC) remains unclear. Here, we observed high RGS20 expression in PC tissues compared to normal/adjacent penile tissues, which was closely associated with tumor stage, nodal status, and pelvic metastasis in our PC cohort. The cellular functional analysis of RGS20 revealed that manipulation of the RGS20 expression markedly affected cell viability, BrdU incorporation, soft agar clonogenesis, caspase-3 activity, and cell migration/invasion in PC cell models. Moreover, RGS20 could interact with PI3K p85α subunit and regulate PI3K/AKT signaling activation in PC cell lines. Knockdown of the PI3K p85α or p110α subunit attenuated cell viability, BrdU incorporation, soft agar clonogenesis, and cell migration/invasion in PC cell lines. In contrast, the overexpression of constitutively activated PI3K p110α mutant restored cell proliferation and cell migration/invasion caused by RGS20 depletion in PC cells. Consistent with the in vitro findings, RGS20 depletion attenuated PI3K/AKT signaling activation and suppressed tumor growth in a murine xenograft model. Importantly, the high RGS20 expression was associated with PI3K/AKT signaling activation and unfavorable progression-free/overall survival, highlighting the clinical relevance of RGS20/PI3K/AKT signaling in PC. In conclusion, the aberrant RGS20 expression may serve as a diagnostic and prognostic marker for PC. RGS20 may promote PC progression through modulating PI3K/AKT signaling activation, which may assist with the development of RGS20-targeting therapeutics in the future.

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.

Identification of a Novel Glycolysis-Related Gene Signature Correlates With the Prognosis and Therapeutic Responses in Patients With Clear Cell Renal Cell Carcinoma.

BACKGROUND: Accumulating evidences indicate significant alterations in the aerobic glycolysis in clear cell renal cell carcinoma (ccRCC). We aim to develop and validate a glycolysis-related genes signature for predicting the clinical outcomes of patients with ccRCC. METHODS: mRNA expression profiling of ccRCC was obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and lasso Cox regression model were performed to identify and construct the prognostic gene signature. The protein expression levels of the core genes were obtained from the Human Protein Atlas database. We used four external independent data sets to verify the predictive power of the model for prognosis, tyrosine kinase inhibitor (TKI) therapy, and immunotherapy responses, respectively. Finally, we explored the potential mechanism of this signature through gene set enrichment analysis (GSEA). RESULTS: Through the GSEA, glycolysis-related gene sets were significantly different between ccRCC tissues and normal tissues. Next, we identified and constructed a seven-mRNA signature (GALM, TGFA, RBCK1, CD44, HK3, KIF20A, and IDUA), which was significantly correlated with worse survival outcome and was an independent prognostic indicator for ccRCC patients. Furthermore, the expression levels of hub genes were validated based on the Human Protein Atlas databases. More importantly, the model can predict patients' response to TKI therapy and immunotherapy. These findings were successfully validated in the external independent ccRCC cohorts. The mechanism exploration showed that the model may influence the prognosis by influencing tumor proliferation, base mismatch repair system and immune status of patients. CONCLUSIONS: Our study has built up a robust glycolysis-based molecular signature that predicts the prognosis and TKI therapy and immunotherapy responses of patients with ccRCC with high accuracy, which might provide important guidance for clinical assessment. Also, clinical investigations in large ccRCC cohorts are greatly needed to validate our findings.

Zic Family Member 2 (ZIC2): a Potential Diagnostic and Prognostic Biomarker for Pan-Cancer.

Background: As a transcription factor, Zinc finger protein ZIC2 can interact with various DNAs and proteins. Current studies have shown that ZIC2 plays an oncogene role in various cancers. In this study, we systematically characterize the prevalence and predictive value of ZIC2 expression across multiple cancer types. Methods: We mined several public databases, including Oncomine, the Cancer Genome Atlas (TCGA), cBioPortal, Kaplan-Meier Plotter and PrognoScan to evaluated the differentially expressed ZIC2 between tumor samples and normal control samples in pan-cancner, and then explored the association between ZIC2 expression and patient survival, prognosis and clinicopathologic stage. We also analyzed the relationship between tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment, tumor- and immune-related genes and ZIC2 expression. Finally, we explored the potential signaling pathway mechanism through gene set enrichment analysis (GSEA). Results: ZIC2 expression was higher in most cancer tissues compared with adjacent normal tissues. High ZIC2 expression was associated with worse prognosis and a higher clinicopathologic stage. ZIC2 expression was strongly associated with the TMB, MSI, tumor microenvironment and tumor- and immune-related genes. The GSEA revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype. Conclusion: ZIC2 expression may be a potential prognostic molecular biomarker of poor survival in pan-cancer and may act as an oncogene with a strong effect in the processes of tumorigenesis and progression.

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.

Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer.

The rising of a highly aggressive subtype of castration-resistant prostate cancer (CRPC) named treatment-induced neuroendocrine prostate cancer (t-NEPC) after androgen deprivation therapy (ADT) is well known for its features of the neuroendocrine differentiation (NED) and androgen receptor (AR) independence. However, t-NEPC is still largely unknown. Here, we found that EHF is notably depressed in t-NEPC tumors, patient-derived xenografts, transgenic mice, and cell models. Results from cell lines uncovered that ADT represses EHF expression, which is required for the ADT-induced NED. Mechanism dissection revealed that ADT decreases the EHF transcription via relieving the AR binding to different androgen-responsive elements, which then promotes the expression and enzymatic activity of enhancer of zeste homolog 2 (EZH2), consequently catalyzing tri-methylation lysine 27 of histone H3 for transcriptional repression of its downstream genes to promote the NED. Furthermore, preclinical studies from cell and mice models proved that recovery of EHF expression or using EZH2 inhibitor can attenuate aggressive properties of CRPC cells, hinder the progression of t-NEPC, and promote the response of CPRC cells to enzalutamide. Together, we elucidate that the ADT/AR/EHF/EZH2 signaling is required for the ADT-enhanced NED and plays a critical role in the progression of t-NEPC.