Combining MTI-31 with RAD001 inhibits tumor growth and invasion of kidney cancer by activating autophagy.

At most of the times, patients who are diagnosed with kidney cancer should be provided with systemic treatment as drug resistance is a challenging issue in the treatment of this disease. The progression of the cancer can be inhibited with the help of mTOR inhibitors namely RAD001 (everolimus) and MTI-31. In literature, it has been revealed that these mTOR inhibitors have the potential to stimulate autophagy. This degradation pathway boosts the survival rate of the cancerous cells that are subjected to anti-cancer therapy. In this study, CCK8, colony formation assays, and ethynyl deoxyuridine (EdU) analysis were conducted to detect cell proliferation. Furthermore, Transwell assays were also conducted for cell migration analysis. In addition to these, the researchers also performed the flow cytometry process to identify the cells that are undergoing apoptosis. In vivo, experiments were conducted to measure the growth of tumors and metastasis. In this study, the treatment provided through a combination of MTI-31 and RAD001 significantly inhibited the kidney cancer cells' proliferation and tumor growth. Furthermore, there was a notable reduction in the migration and invasion of kidney cancer cells upon the neighboring cells. The outcomes from the mechanistic studies infer that the combination of MTI-31 and RAD001 increases the LC3 levels, which in turn translates into the activation of autophagy. To conclude, the combination of MTI-31 and RAD001 improves the anti-cancerous impact produced by RAD001 in vivo through the promotion of autophagy.

Protective Autophagy Attenuates the Cytotoxicity of MTI-31 in Renal Cancer Cells by Activating the ERK Pathway.

The mammalian target of rapamycin (mTOR) is a key regulatory molecular target to treat cancer, and MTI-31 is a potent mTOR inhibitory agent for the therapeutically target of the renal cell carcinoma (RCC). However, the therapeutic efficacy of MTI-31 is limited by multiple factors, including autophagy. MTI-31 can activate cells to generate autophagy, which may in turn indirectly affect cell proliferation and apoptosis. We aimed to observe changes in cell protective autophagy via the ERK pathway and explore the potential mechanism underlying drug resistance of RCC cells to MTI-31. Different concentrations of 786-O and RCC4 cells were co-cultured with MTI-31 for distinct durations. The result of autophagy marker detection by Western blot showed that MTI-31 could induce RCC cells to produce autophagy in a dose and time-dependent manner. After treating the RCC cells with the autophagy inhibitor chloroquine (CQ), CCK8 and Western blot assays demonstrated that CQ could effectively enhance cell apoptosis induced by MTI-31 and that the autophagy induced by MTI-31 was cytoprotective. In addition, CCK8 and Western blot demonstrated that MTI-31 exerted its effect by activating the ERK pathway rather than the JNK or p38 pathway. The use of the ERK inhibitor AZD6244 to block the ERK pathway could effectively promote cell apoptosis induced by MTI-31. AZD6244 attenuated the autophagy induced by MTI-31 and increased the cytotoxicity of MTI-31. Western blot also demonstrated that MTI-31-induced autophagy was mediated by the downstream regulators of ERK pathways, including Beclin-1 and Bcl-2. It demonstrated that the MTI-31 mediated activation ERK pathway is associated with the induction of autophagy, and autophagy can attenuate the cytotoxicity of MTI-31 on RCC cells. In summary, inhibition of ERK pathway-mediated autophagy can rectify drug resistance to MTI-31 effectively.

Overexpression of Ubiquitin-Conjugating Enzyme E2C Is Associated with Worsened Prognosis in Prostate Cancer.

To evaluate the role of ubiquitin-conjugating enzyme E2C (UBE2C) in prostate cancer (PCa) progression and prognosis, the TCGA and our PCa tissue microarray cohort were included in the study. Weighted gene co-expression network analysis (WGCNA) and non-negative matrix factorization were used to cluster patients and to screen genes that play a vital role in PCa progression (hub gene). Immunohistochemistry staining was used to evaluate the protein level of UBE2C in prostatic tissues. Through WGCNA, we found a gene co-expression module (named the purple module) that is strongly associated with the Gleason score, pathologic T stage, and biochemical recurrent status. Genes in the purple module are enriched in cell cycle and P53 signaling and help us to cluster patients into two groups with distinctive biochemical recurrent survival rates and TP53 mutation statuses. Further analysis showed UBE2C served as a hub gene in the purple module. The expression of UBE2C in PCa was significantly higher than that in paracancerous tissues and was remarkably associated with pathologic grade, Gleason score, and prognosis in PCa patients. To conclude, UBE2C is a PCa-progress-related gene and a biomarker for PCa patients. Therapy targeting UBE2C may serve as a promising treatment of PCa in the future.

Repair of the Urethral Mucosa Defect Model Using Adipose-Derived Stem Cell Sheets and Monitoring the Fate of Indocyanine Green-Labeled Sheets by Near Infrared-II.

Treatment of urethral mucosa defects is a major challenge in urology. Synthetic materials or autologous mucosa does not provide satisfactory treatment options for long-term or large urethral mucosa defects. In response to this problem, we used autologous adipose-derived stem cells (ADSCs) to synthesize cell sheets in vitro for repairing urethral mucosa defect models. In order to monitor the localization and distribution of cell sheets in vivo, cells and sheets were labeled with indocyanine green (ICG) and the second near-infrared (NIR-II) fluorescence imaging was performed. ICG-based NIR-II imaging can successfully track ADSCs and sheets in vivo up to 8 W. Then, rabbit urethral mucosa defect models were repaired with ICG-ADSCs sheets. At 3 months after operation, retrograde urethrography showed that ADSC sheets could effectively repair urethral mucosa defect and restore urethral patency. Histological analysis showed that in ADSC sheet groups, continuous epithelial cells covered the urethra at the transplantation site, and a large number of vascular endothelial cells could also be seen. In the cell-free sheet group, there was no continuous epithelial cell coverage at the repair site of the urethra, and the expression of pro-inflammatory factor TNF-α was increased. It shows that the extracellular matrix alone without cells is not suitable for repairing urethral defects. Surviving ADSCs in the sheets may play a key role in the repair process. This study provides a new tracing method for tissue engineering to dynamically track grafts using an NIR-II imaging system. The ADSC sheets can effectively restore the structure and function of the urethra. It provides a new option for the repair of urethral mucosa defects.

m6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer.

Prostate cancer (PCa) is one of the most common cancers in men. Usually, most PCas at initial diagnosis are localized and hormone-dependent, and grow slowly. Patients with localized PCas have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive PCa is still dismal. N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m6A regulators. A few studies have shown that the abnormal expression of m6A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in PCa remain unclear. Here, we examined the expression profiles and methylation levels of 21 m6A regulators across the Cancer Genome Atlas (TCGA), 495 PCas by consensus clustering, and correlated the expression of m6A regulators with PCa progression and immune cell infiltration. Consensus clustering was applied for subtyping Pca samples into clusters based on the expression profiles of m6A regulators. Each subtype's signature genes were obtained by a pairwise differential expression analysis. Featured pathways of m6A subtypes were predicted by Gene Ontology. The m6A score was developed to predict m6A activation. The association of the m6A score with patients' survival, metastasis and immune cell infiltration was also investigated. We identified three distinct clusters in PCa based on the expression profiles of 21 m6A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m6A regulators involved in metabolic processes and immune responses in PCa. Moreover, we developed an m6A score to evaluate the m6A regulator activation for PCa. The m6A score is significantly associated with Gleason scores and metastasis in PCa. The predictive capacity of the m6A score on PCa metastasis was also validated in another independent cohort with an area under the curve of 89.5%. Hence, our study revealed the critical role of m6A regulators in PCa progression and the m6A score is a promising predictive biomarker for PCa metastasis.

Immunological Characteristics of Alternative Splicing Profiles Related to Prognosis in Bladder Cancer.

Several studies have found that pathological imbalance of alterative splicing (AS) events is associated with cancer susceptibility. carcinogenicity. Nevertheless, the relationship between heritable variation in AS events and carcinogenicity has not been extensively explored. Here, we downloaded AS event signatures, transcriptome profiles, and matched clinical information from The Cancer Genome Atlas (TCGA) database, identified the prognostic AS-related events via conducting the univariate Cox regression algorism. Subsequently, the prognostic AS-related events were further reduced by the least absolute shrinkage and selection operator (LASSO) logistic regression model, and employed for constructing the risk model. Single-sample (ssGSEA), ESTIMATE, and the CIBERSORT algorithms were conducted to evaluate tumor microenvironment status. CCK8, cell culture scratch, transwell invasion assays and flow cytometry were conducted to confirm the reliability of the model. We found 2751 prognostic-related AS events, and constructed a risk model with seven prognostic-related AS events. Compared with high-risk score patients, the overall survival rate of the patients with low-risk score was remarkably longer. Besides, we further found that risk score was also closely related to alterations in immune cell infiltration and immunotherapeutic molecules, indicating its potential as an observation of immune infiltration and clinical response to immunotherapy. In addition, the downstream target gene (DYM) could be a promising prognostic factor for bladder cancer. Our investigation provided an indispensable reference for ulteriorly exploring the role of AS events in the tumor microenvironment and immunotherapy efficiency, and rendered personalized prognosis monitoring for bladder cancer.

Exosome-derived circTRPS1 promotes malignant phenotype and CD8+ T cell exhaustion in bladder cancer microenvironments.

Circular RNAs (circRNAs) play critical roles in different diseases. Exosomes are important intermediates of intercellular communication. While both have been widely reported in cancers, exosome-derived circRNAs are rarely studied. In this work, we identified the differently expressed circRNAs in bladder cancer (BCa) tissue and exosomes through high-throughput sequencing. RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays were used to investigate the interactions between specific circRNAs, microRNAs (miRNAs), and mRNAs. Wound-healing, Transwell, Cell Counting Kit-8 (CCK8), and colony-formation assays were used to study the biological roles in vitro. Metabolomics were used to explore the mechanism of how specific circRNAs influenced BCa cell behavior. Flow cytometry was used to study how specific circRNAs affected the function of CD8+ T cells in tumor microenvironments. We identified that exosome-derived hsa_circ_0085361 (circTRPS1) was correlated with aggressive phenotypes of BCa cells via sponging miR-141-3p. Metabolomics and RNA sequencing (RNA-seq) identified GLS1-mediated glutamine metabolism was involved in circTRPS1-mediated alterations. Exosomes derived from circTRPS1 knocked down BCa cells, prevented CD8+ T cells from exhaustion, and repressed the malignant phenotype of BCa cells. In conclusion, exosome-derived circTRPS1 from BCa cells can modulate the intracellular reactive oxygen species (ROS) balance and CD8+ T cell exhaustion via the circTRPS1/miR141-3p/GLS1 axis. Our work may provide a potential biomarker and therapeutic target for BCa.

Transcriptome subtyping of metastatic Castration Resistance Prostate Cancer (mCRPC) for the precision therapeutics: an in silico analysis.

BACKGROUND: Men with metastatic prostate cancer who are treated with androgen deprivation therapy (ADT) typically develop therapeutic resistance eventually and have a dismal outcome. Moreover, the limited survival benefit observed in only a proportion of patients receiving novel therapeutics including immune checkpoint blockade and PARP inhibitors suggests the biological heterogeneity of mCRPCs. METHODS: To understand the heterogeneity of mCRPC, we analyzed the transcriptome of 231 mCRPCs and identified four disparate biological subtypes (Basal, Homologous Recombination Repair (HRR), Neuroendocrine and Luminal). The package "randomForest" was used to construct a Random Forest model. Circular plots were used for visualization of TMPRSS2-ERG fusion in each subtype. RESULTS: The Luminal subtype of mCRPCs has higher Androgen Receptor (AR) expression and copy number alterations as compared with the other subtypes. Genes in HRR pathway are relatively downregulated in most subtypes regardless of the genetic alterations, except for the HRR and NE subtypes, suggesting potential resistance of the HRR and NE mCRPCs to PARP inhibitor treatment. The HRR subtype has relatively more immune cell infiltration and higher expression of immune checkpoints, highlighting that the efficacy of immunotherapy should be evaluated in this particular subtype. TMPRSS2-ERG fusion is the most frequent gene fusion in all mCRPCs, and the Basal subtype has a higher frequency of this fusion than the other subtypes. CONCLUSIONS: Our results reveal that the stratification of mCRPC according to transcriptome is informative of personalized therapeutics in the treatment of mCRPCs. The predictive capacity of the transcriptome subtyping of mCRPC warrants further exploration in the future.

DNA Methylation Modification Map to Predict Tumor Molecular Subtypes and Efficacy of Immunotherapy in Bladder Cancer.

Background: Considering the heterogeneity and complexity of epigenetic regulation in bladder cancer, the underlying mechanisms of global DNA methylation modification in the immune microenvironment must be investigated to predict the prognosis outcomes and clinical response to immunotherapy. Methods: We systematically assessed the DNA methylation modes of 985 integrated bladder cancer samples with the unsupervised clustering algorithm. Subsequently, these DNA methylation modes were analyzed for their correlations with features of the immune microenvironment. The principal analysis algorithm was performed to calculate the DMRscores of each samples for qualification analysis. Findings: Three DNA methylation modes were revealed among 985 bladder cancer samples, and these modes are related to diverse clinical outcomes and several immune microenvironment phenotypes, e.g., immune-desert, immune-inflamed, and immune-excluded ones. Then patients were classified into high- and low-DMRscore subgroups according to the DMRscore, which was calculated based on the expression of DNA methylation related genes (DMRGs). Patients with the low-DMRscore subgroup presented a prominent survival advantage that was significantly correlated to the immune-inflamed phenotype. Further analysis revealed that patients with low DMRscores exhibited less TP53 wild mutation, lower cancer stage and molecular subtypes were mainly papillary subtypes. In addition, an independent immunotherapy cohort confirmed that DMRscore could serve as a signature to predict prognosis outcomes and immune responses. Conclusion: Global DNA methylation modes can be used to predict the immunophenotypes, aggressiveness, and immune responses of bladder cancer. DNA methylation status assessments will strengthen our insights into the features of the immune microenvironment and promote the development of more effective treatment strategies.

Calculated identification of mutator-derived lncRNA signatures of genomic instability to predict the clinical outcome of muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is one of the most important type of bladder cancer, with a high morbidity and mortality rate. Studies have found that long non-coding RNA (lncRNA) plays a key role in maintaining genomic instability. However, Identification of lncRNAs related to genomic instability (GIlncRNAs) and their clinical significance in cancers have not been extensively studied yet. METHODS: Here, we downloaded the lncRNA expression profiles, somatic mutation profiles and clinical related data in MIBC patients from The Cancer Genome Atlas (TCGA) database. A lncRNA computational framework was used to find differentially expressed GIlncRNAs. Multivariate Cox regression analysis was used to construct a genomic instability-related lncRNA signature (GIlncSig). Univariate and multivariate Cox analyses were used to assess the independent prognostic for the GIlncSig and other key clinical factors. RESULTS: We found 43 differentially expressed GIlncRNAs and constructed the GIlncSig with 6 GIlncRNAs in the training cohort. The patients were divided into two risk groups. The overall survival of patients in the high-risk group was lower than that in the low-risk group (P < 0.001), which were further verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression showed that the GIlncSig was an independent prognostic factor. In addition, the GIlncSig correlated with the genomic mutation rate of MIBC, indicating its potential as a measure of the degree of genomic instability. The GIlncSig was able to divide FGFR3 wild- and mutant-type patients into two risk groups, and effectively enhanced the prediction effect. CONCLUSION: Our study introduced an important reference for further research on the role of GIlncRNAs, and provided prognostic indicators and potential biological therapy targets for MIBC.

A novel survival model based on a Ferroptosis-related gene signature for predicting overall survival in bladder cancer.

BACKGROUND: The effective treatment and prognosis prediction of bladder cancer (BLCA) remains a medical problem. Ferroptosis is an iron-dependent form of programmed cell death. Ferroptosis is closely related to tumour occurrence and progression, but the prognostic value of ferroptosis-related genes (FRGs) in BLCA remains to be further clarified. In this study, we identified an FRG signature with potential prognostic value for patients with BLCA. METHODS: The corresponding clinical data and mRNA expression profiles of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA). Univariate Cox regression was used to extract FRGs related to survival time, and a Cox regression model was used to construct a multigene signature. Both principal component analysis (PCA) and single-sample gene set enrichment analysis (ssGSEA) were performed for functional annotation. RESULTS: Clinical traits were combined with FRGs, and 15 prognosis-related FRGs were identified by Cox regression. High expression of CISD1, GCLM, CRYAB, SLC7A11, TFRC, ACACA, ZEB1, SQLE, FADS2, ABCC1, G6PD and PGD was related to poor survival in BLCA patients. Multivariate Cox regression was used to construct a prognostic model with 7 FRGs that divided patients into two risk groups. Compared with that in the low-risk group, the overall survival (OS) of patients in the high-risk group was significantly lower (P < 0.001). In multivariate regression analysis, the risk score was shown to be an independent predictor of OS (HR = 1.772, P < 0.01). Receiver operating characteristic (ROC) curve analysis verified the predictive ability of the model. In addition, the two risk groups displayed different immune statuses in ssGSEA and different distributed patterns in PCA. CONCLUSION: Our research suggests that a new gene model related to ferroptosis can be applied for the prognosis prediction of BLCA. Targeting FRGs may be a treatment option for BLCA.

Ureteroscopic Cryoablation for Patients with Upper Tract Urothelial Carcinoma of a Solitary Kidney: A Porcine Model and Our Pilot Clinical Experience.

PURPOSE: To investigate the safety and efficacy of ureteroscopic cryoablation by a liquid-nitrogen system in a porcine model and for patients with upper tract urothelial carcinoma (UTUC) of a solitary kidney. METHODS: In the animal experiment, the right-sided ureter was frozen in nine pigs. Eight were randomly assigned to two different groups according to the freezing duration of 60 or 90 s. The other one was designed to receive a 10-min freeze. The treated ureters were harvested at 30 min, 2 days, 4 weeks, and 3 months after cryoablation for histological evaluation. After the animal study, we conducted a pilot clinical trial that enrolled six patients who were diagnosed with UTUC of a solitary kidney and received therapeutic management with ureteroscopic cryoablation at our center. Perioperative adverse events and oncological outcomes were evaluated. RESULTS: In the porcine model, the liquid-nitrogen system was capable of forming a therapeutic ice ball which infiltrated the full-thickness ureter and induced apoptosis and necrosis from mucosa to lamina muscularis through histological examination. In the clinical trial, cryoablation was successfully performed under ureteroscopy in all the patients, without intraoperative ureteral perforation, avulsion, or active hemorrhage. No recurrence in situ was observed during a median follow-up period of 12.5 months. Hydronephrosis and ureteral stricture was observed in one patient and was managed with ureteroscopic balloon dilation. CONCLUSIONS: Ureteroscopic cryoablation induced by liquid nitrogen is a promising technique for conservative management of UTUC with benefits of improving local tumor control and preservation of a solitary kidney.

Icaritin reduces prostate cancer progression via inhibiting high-fat diet-induced serum adipokine in TRAMP mice model.

Objective: Obesity resulting from high-fat diets has a close relationship with the morbidity and mortality associated with Prostate cancer (PCa) in males. The anti-cancer role of Icaritin (ICT, a traditional Chinese herbal medicine) has been reported in several types of cancer including PCa. Adipokines are novel adipocyte-specific secretory protein, which plays a key role in the development of various diseases including obesity, diabetes, atherosclerosis, and cancer. However, the function of ICT and the molecular mechanisms underlying its role in PCa regression through modulation of adipokines have not been studied. Here, we assessed the anti-cancer properties of ICT under the influence of human epidermal growth factor receptor type 2 (HER2) pathway modulating adipokines in obese PCa models. Materials and Methods: In this study, we used transgenic adenocarcinoma of mouse prostate (TRAMP), a well-established animal model for the study of PCa pathogenesis. All the animals were fed on a high-fat diet (HFD with 40% fat) and divided into two groups, one received ICT solution of 30 mg/kg body bwt (i.p) while the other group served as control without any ICT treatment. The mortality rate, tumor formation and fat ratio were assessed by histopathological and magnetic resonance analysis at different time points of 20th, 24th and 28th weeks. The protein expression of HER2 and serum levels of adipokines were measured using western blotting, IHC and multiplex immunoassays. The PCa grade in 12 TRAMP mice were longitudinally evaluated to visualize PCa development and progression upon post-surgery using PET/CT scanning. Results: We observed that ICT treatment significantly reduces the total mortality rate of TRAMP mice (p = 0.045) and the percentage of prostate intraepithelial neoplasia (PIN) or PCa (p = 0.029). Interestingly, significantly decreased levels of leptin (p = 0.006 @20th wk) and the elevated levels of adiponectin (p = 0.030 @20th wk) were observed in different subgroups upon ICT treatment in a time-dependent manner. In addition, a decrease level of HER2 (p = 0.032 @28th wk) and an elevated level of PEA3 (p = 0.014 @28th wk) were also detected in ICT treated group. The PET/CT-based imaging showed that ICT vs non-ICT treated mice had different standard uptake value and metastasis. Discussion and Conclusion: Our results showed potent anti-cancer properties of ICT through the modulation of adipokine secretion may alter the expression and activation of HER2 pathway as an alternative mechanism to prevent PCa progression. Altogether, our findings indicate that ICT could be a promising cancer preventive agent with the potential to target and eradicate tumor cells in obese PCa patients.

FGF18 Inhibits Clear Cell Renal Cell Carcinoma Proliferation and Invasion via Regulating Epithelial-Mesenchymal Transition.

Fibroblast growth factor 18 (FGF18) is a member of the FGF family and contributes to a broad range of biological events. The important role of the overexpression of FGF18 has been identified in the progression of several types of cancers. However, there is still little information on the biological role of FGF18 on clear cell renal cell carcinoma (ccRCC), which is of interest in investigating the biological functions of FGF18 in ccRCC. Our results showed that FGF18 was lowly expressed in ccRCC tissues compared to paired normal renal tissue from the TCGA database and clinical cohort of Huashan Hospital and that high expression of FGF18 correlated with a good prognosis in ccRCC patients. In addition, overexpression of FGF18 significantly inhibited the proliferation ability of ccRCC cell lines in vitro and in vivo. Gene set enrichment analysis (GSEA) identified epithelial-mesenchymal transition (EMT) involved in a high FGF18 expression group of ccRCC patients in the TCGA cohort, which was further validated with EMT related markers in FGF18 overexpressed ccRCC cell lines. Furthermore, FGF18 overexpression significantly inhibited the PI3K/Akt pathway in ccRCC cells. Taken together, this study concludes that FGF18 is of potential value as a target for ccRCC.

First-time versus recurrent penoscrotal extramammary Paget's disease: Clinicopathological characteristics and risk factors in 164 Chinese male patients.

BACKGROUND: Penoscrotal extramammary Paget's disease is a rare, slow-growing neoplasm with high frequency of local recurrence. AIMS: The aim of this study was to investigate the difference in clinicopathological characteristics between first-time and recurrent penoscrotal Paget's disease, and to discover the potential risk factors of recurrence. METHODS: Between January 2007 and February 2014, a total of 164 Chinese patients with biopsy-proven tramammary Paget's diseaseex in penis and scrotum underwent wide local resection in our institution. Among them, 142 patients with first-time disease and other 22 patients with recurrent disease were enrolled in this retrospective analysis. RESULTS: The median duration of symptoms was much shorter in recurrent disease than in first-timers (3 vs. 24 months, P < 0.001). Patients with recurrent disease tended to have lower lesion exudation rates (27.3% vs. 51.8%, P= 0.032). In addition, patients with distant stage were more likely to obtain recurrent disease compared with first-time disease (P = 0.005). Through immunohistochemical detection of extramammary Paget's specimen, we found that HER2/neu protein expression in the recurrent group was significantly higher than first-timers (P = 0.036). LIMITATIONS: In this study, the information on familial history of most patients was insufficient. Moreover, due to the lack of follow-up data of our included cases, we were unable to evaluate the prognosis after diagnosis of extramammary Paget's disease. CONCLUSION: Patients with penoscrotal Paget's disease, especially those with shorter duration of symptoms, exudation of lesions, distant-stage, Paget cells infiltrating into adnexa, and HER2/neu expression, should be followed up more carefully after surgery, as they were more likely to suffer recurrence.

Anticancer effect of icaritin on prostate cancer via regulating miR-381-3p and its target gene UBE2C.

Prostate cancer (PCa) is one of the most common health-related issues in the male individuals of western countries. Icaritin (ICT) is a traditional Chinese herbal medicine that exhibits antitumor efficacy in variety of cancers including PCa. However, the precise function and detailed molecular mechanism of ICT in the regression of PCa remain unclear. Ubiquitin-conjugating enzyme E2C (UBE2C) is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin conjugating enzyme, which acts as an oncogene in PCa progression. The function of ICT in PCa was investigated in transgenic adenocarcinoma mouse prostate (TRAMP) mice using survival analysis, hematoxylin and eosin (HE) staining, TUNEL assay, and immunohistochemistry and in human PCa cell lines using various molecular techniques and functional assays including plasmid construction and transfection. Bioinformatic analyses were performed to identify the interaction between miRNA and UBE2C via the TargetScan algorithm. We demonstrated that ICT inhibited the development and progression of PCa in TRAMP mice by improving the survival rate and tumor differentiation. Furthermore, we found that ICT could significantly inhibit cell proliferation and invasion and induce apoptosis in PCa cells. Consistently, downregulation of UBE2C suppressed the proliferation and invasion of PCa cells. Moreover, a luciferase reporter assay confirmed that UBE2C was a direct target of miR-381-3p. Meanwhile, ICT simultaneously downregulated UBE2C expression and upregulated miR-381-3p levels in human PCa cells. Altogether, our findings provide a strong rationale for the clinical application of ICT as a potential oncotherapeutic agent against PCa via a novel molecular mechanism of regulating the miR-381-3p/UBE2C pathway.

Effects of diabetes mellitus and Metformin administration on prostate cancer detection at biopsy among Chinese men: a case-control study.

PURPOSE: To determine the associations among diabetes status, Metformin administration and prostate cancer (PCa) detection at biopsy in Chinese population. METHODS: A case-control study was conducted among a prospectively enrolled prostate biopsy cohort of 518 patients from Jan 2013 to Dec 2014 at our institute. Diabetes status and Metformin administration were determined through medical records and self-report. Different clinical characteristics were registered and compared among different groups. Univariate and multivariate logistic regression analyses were performed to evaluate the effects of diabetes status and Metformin administration on the detection of overall as well as high-grade PCa at biopsy. RESULTS: PCa was detected in 229 (44.2%) men, and high-grade PCa (Gleason score ≥8) was detected in 65 (12.5%) men. Diabetes was observed in 96 men, and 28 of them were administered with Metformin. Both overall and high-grade cancer detection rates were significantly higher in diabetic patients (p<0.001). In multivariate analysis, diabetes status was a risk factor for high-grade cancer detection (OR 7.699, 95%CI 3.483-17.020, p<0.001), but not for total PCa detection (OR 1.774, 95%CI 0.831-3.787, p=0.138). Meanwhile, Metformin administration was proved to be a protective factor for high-grade disease (OR 0.420, 95%CI 0.201-0.879, p=0.021) in multivariate analysis, while no correlation was detected with overall cancer detection (OR 0.786, 95%CI 0.172-3.593, p=0.756). CONCLUSIONS: Diabetes status was positively associated with biopsy-mediated high-grade PCa detection in Chinese population, while the positive association would be partly compromised by Metformin administration.

Clinicopathological and prognostic significance of preoperative plasma fibrinogen level in patients with upper urinary tract urothelial carcinoma: A retrospective tumor marker prognostic study.

PURPOSE: To retrospectively evaluate the prognostic value of preoperative plasma fibrinogen to predict oncological outcome and intravesical recurrence in upper urinary tract urothelial carcinoma. METHODS: This retrospective study comprised 130 patients with non-metastatic upper urinary tract urothelial carcinoma who underwent surgery between June 2009 and June 2017 at a single center. Patients were categorized base on an optimal value of preoperative plasma fibrinogen. Progression-free and cancer-specific survival were assessed using Kaplan-Meier method. The associations between plasma fibrinogen and clinical outcomes were assessed with univariate and Multivariate analysis. RESULTS: Elevated plasma fibrinogen was associated with advance tumor stage, high tumor grade and tumor size. No significant association was found between plasma fibrinogen and intravesical recurrence. Multivariate analysis revealed that plasma fibrinogen ≥3.602 g/L was an independent prognostic indicator for progression-free survival (HR = 2.18; 95% CI: 1.17-4.06; p = 0.01) and cancer-specific survival (HR = 2.2; 95% CI: 1.13-4.28; p = 0.02), as well as pathological T stage and tumor grade. CONCLUSIONS: Elevated preoperative plasma fibrinogen is an independent unfavorable prognostic factor for oncological outcomes in patients with upper urinary tract urothelial carcinoma. However, there is no association between preoperative plasma fibrinogen and intravesical recurrence. As an effective and easily accessible biomarker, this parameter can be applied in pre-intervention risk stratification of upper urinary tract urothelial carcinoma.

Differential expressions of integrin-linked kinase, ß-parvin and cofilin 1 in high-fat diet induced prostate cancer progression in a transgenic mouse model.

High-fat diet induced obesity was associated with more aggressive prostate cancer. Recent research has demonstrated that integrin-linked kinase (ILK), ß-parvin and downstream cofilin 1 jointly affected cancer progression. Meanwhile, these proteins were also involved in energy metabolism. Therefore, the present study was conducted to investigate the potential function of ILK, ß-parvin and cofilin 1 in the high-fat diet-induced progression of prostate cancer. Transgenic mice with prostate cancer were employed, fed with different diets and sacrificed at 20 and 28 weeks. Tumor differentiation, extracapsular extension and metastasis were compared between the groups. Expression levels of ILK, ß-parvin and cofilin 1 in prostate were evaluated by immunohistochemical analysis and determined by an immunoreactivity score. Public databases were applied for analysis and validation. It was detected that high-fat diet feeding promoted cancer progression in transgenic mice with prostate cancer, with increased expressions of ß-parvin (P=0.038) and cofilin 1 (P=0.018). Higher expressions of ILK, ß-parvin and cofilin 1 were also associated with poorer cancer differentiation. Additionally, higher mRNA levels of CFL1 were correlated with a worse disease-free survival in patients of certain subgroups from The Cancer Genome Atlas database. Further studies were warranted in discussing the potential roles of ILK, ß-parvin and cofilin 1 in high-fat diet feeding induced progression of prostate cancer.