TNIK drives castration-resistant prostate cancer via phosphorylating EGFR.

The development of castration-resistant prostate cancer (CRPC) is driven by intricate genetic and epigenetic mechanisms. Traf2- and Nck-interacting kinase (TNIK) has been reported as a serine/threonine kinase associated with tumor cell proliferation or unfavorable cancer behavior. The microarray approach revealed a substantial upregulation of TNIK expression levels, enabling us to investigate the functional behaviors of the TNIK gene in CRPC. Specifically, we discovered that AR suppresses TNIK gene transcription in LNCaP and C4-2 cells by forming a complex with H3K27me3. Following the reduction of AR levels induced by androgen deprivation therapy (ADT), TNIK is recruited to activate EGFR signaling through phosphorylation in C4-2 cells, thereby promoting CRPC progression. Our findings unveil a regulatory role of AR as a repressor for TNIK while also highlighting how TNIK activates the EGFR pathway via phosphorylation to drive CRPC progression. Consequently, targeting TNIK may represent an appealing therapeutic strategy for CRPC.

Nationwide survey of ticks on domesticated animals in Taiwan: Revealing the hidden threat to animal and public health.

Ticks are not only bloodsucking ectoparasites but also important vectors of tick-borne diseases (TBDs), posing significant threats to public and animal health. Domesticated animals serve as critical hosts for numerous ticks, highlighting the importance of understanding tick infestations in Taiwan. To address this knowledge gap, we conducted a nationwide survey to identify ticks on domesticated animals and associated environments in 2018 and 2019. A total of 6,205 ticks were collected from 1,337 host animals, revealing the presence of seven tick species, with Rhipicephalus microplus, and Rhipicephalus sanguineus being the dominant species. High infestation rates and widespread distribution of ticks were observed on domesticated animals, especially on dogs and cattle (yellow cattle and angus cattle), and the neighbouring grassland of yellow cattle. While this study has certain limitations, it provides valuable insights into the distribution and prevalence of ticks on domesticated animals in Taiwan and their implications for controlling TBDs. Further research is needed to comprehensively understand the complex interactions among ticks, hosts and pathogens.

Ferroptosis landscape in prostate cancer from molecular and metabolic perspective.

Prostate cancer is a major disease that threatens men's health. Its rapid progression, easy metastasis, and late castration resistance have brought obstacles to treatment. It is necessary to find new effective anticancer methods. Ferroptosis is a novel iron-dependent programmed cell death that plays a role in various cancers. Understanding how ferroptosis is regulated in prostate cancer will help us to use it as a new way to kill cancer cells. In this review, we summarize the regulation and role of ferroptosis in prostate cancer and the relationship with AR from the perspective of metabolism and molecular pathways. We also discuss the feasibility of ferroptosis in prostate cancer treatment and describe current limitations and prospects, providing a reference for future research and clinical application of ferroptosis.

MLKL and other necroptosis-related genes promote the tumor immune cell infiltration, guiding for the administration of immunotherapy in bladder urothelial carcinoma.

The involvement of necroptosis in the immunosuppressive tumor microenvironment has been established and has been shown to contribute to the growth of pancreatic ductal adenocarcinoma, indicating its role in promoting tumor development. However, the relationship between necroptosis and bladder urothelial carcinoma (BUC) has yet to be fully understood. To shed light on this issue, our study aimed to uncover the impact of necroptosis on immune cell infiltration and immunotherapy response in BUC patients. We conducted an analysis of 67 necroptosis genes to assess their expression and genomic changes across pan-cancer and identified 12 necroptosis genes that are prognostically relevant and associated with immune subtypes and tumor stemness in BUC. Using a public database of 1841 BUC samples, we then performed Unsupervised Cluster Analysis and discovered two distinct necroptotic phenotypes in BUC. These phenotypes showed significant differences in molecular subtypes, immune infiltration patterns, and gene mutation profiles. We confirmed this discovery in BUC through qPCR and WB experiments. To evaluate the impact of necroptosis on prognosis, chemotherapy sensitivity, and immunotherapy response (such as anti-PD-L1), we developed a principal component analysis model called NecroScore. Finally, we validated the effects of RIPK3 and MLKL through a nude mouse transplantation model for BUC. Our study has uncovered that necroptosis plays a role in shaping the tumor immune microenvironment in BUC. The high necroptosis phenotype (Cluster B) was characterized by a higher abundance of tumor immunosuppressive cells and more key biological processes driving tumor progression, while the low necroptosis group (Cluster A) had higher FGFR3 mutations. We found that the infiltration levels of immune cells, including CD8+ T cells, were significantly different between FGFR3 mutated and wild-type (WT) samples. Our results confirmed the reliability of NecroScore as a comprehensive assessment tool for evaluating the immunotherapeutic effect and prognosis of BUC patients, with high NecroScore values favoring basal-like differentiation and lower FGFR3 alterations. We also observed that high expression of MLKL had a significant inhibitory effect on tumor growth and increased neutrophil infiltration in vivo. In our study, we uncovered the regulation pattern of necroptosis in the tumor immune microenvironment of BUC. Additionally, we developed a scoring tool called NecroScore that can be utilized to predict the most suitable chemotherapy and immunotherapy strategy for bladder urothelial carcinoma patients. This tool can effectively guide the chemotherapy and immunotherapy regimens for patients with advanced BUC.

Ferroptosis involved in sevoflurane-aggravated young rats brain injury induced by liver transplantation.

Liver transplantation is the only treatment available for pediatrics with end-stage liver disease. However, neurological damage is prone to occur after liver transplantation, especially in children. Accumulating evidence has shown that sevoflurane is closely linked to brain injury induced by liver transplantation. However, the study on the role of sevoflurane in brain injury induced by liver transplantation is rare and needs to be further investigated. The study is aiming to investigate the effects of sevoflurane on brain injury induced by liver transplantation and its underlying mechanisms. The brain injury rat model was built through 70% hepatic ischemia-reperfusion (HIR) of young rats. We detected the ferroptosis and brain injury after HIR by histological, transmission electron microscope analyses, western blot, and Enzyme-linked immunosorbent assays. And we detected the level of ferroptosis in brain by using sevoflurane during HIR compared with HIR without using sevoflurane. At the same time, we use iron inhibitor deferoxamine (DFO) to verify that the brain injury was caused by ferrotosis of brain. The results indicated that the pathological injury, ferroptosis indicators, and brain injury indicators were aggravated in the sevoflurane group compared with the HIR group, the decrease in the degree of brain injury and ferroptosis was observed in the group using DFO. Collectively, the results suggest that ferroptosis may mediate sevoflurane-aggravated young rats' brain injury induced by liver transplantation. Our findings provide a potential therapeutic target for brain injury after pediatric liver transplantation.

Cathepsin K regulates the tumor growth and metastasis by IL-17/CTSK/EMT axis and mediates M2 macrophage polarization in castration-resistant prostate cancer.

A common stage of advanced prostate cancer is castration-resistant prostate cancer (CRPC), greater understanding of which is required in order to address and solve the clinically difficult challenge. Cathepsin K (CTSK) is a cysteine protease that usually has a strong activity of degrading extracellular matrix and is related to osteoclast-mediated bone destruction. However, the mechanism of CTSK-regulation in CRPC is still unclear to us. The current study aimed to analyze the expression of differentially expressed genes (DEGs) in patient samples (from localized PC and CRPC). Interestingly, we found that CTSK to be significantly up-regulated in CRPC. Through further signal pathway enrichment analysis, we found that the IL-17 signaling pathway to be highly correlated with CTSK. The oncogenic functions of CTSK and IL-17 in CRPC were proven by a series of in vivo and in vitro experiments. Possible downstream molecules of CTSK were investigated, which could serve as control elements to regulate the expression of EMT, thereby facilitating the metastasis and excessive proliferation of PC cells. Expression of CTSK was related to high concentration of M2 tumor-associated macrophages (TAMs) M2 in CRPC. A CTSK-mediated feedback circuit between TAMs and CRPC tissues was indicated in the process of transfer, proving the possibility of CTSK could be use as an available therapeutic target for CRPC.

Specific classification and new therapeutic targets for neuroendocrine prostate cancer: A patient-based, diagnostic study.

Objective: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer (PC) that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. In our investigation, there appeared to be a strong correlation between neuroendocrine differentiation prostate cancer (NEDPC) and NEPC. The objectives of this study included exploring whether NEDPC is an intermediate stage in the progression of high-risk prostate cancer (HRPC) to NEPC and identifying risk factors and new targets associated with survival in the treatment of NEPC. Methods: The selected prostate cancer patients were progressed to high-risk and characterized by neuroendocrine. We collected the clinical data and characteristics of patients with three types of cancer: the incidence of metastasis, site and time of metastasis, recurrence rate, related treatment methods, etc. The similarity and differences of the three groups were compared through experiment and database. Results: By analyzing the clinical data and immunohistochemical results, we found that there seems to be a clinical feature of neuroendocrine differentiation (NED) status in between when patients progress from PC to NEPC. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC. The metastasis-free survival curve and the immunohistochemical results are informing us that NEDPC can be a pre-state for diagnosing NEPC. Conclusion: NEPC is a late PC symptom that is frequently disregarded and has a bad prognosis. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC.

The CUSUM curve combined with comprehensive complication index for assessing short-term complications of radical cystectomy.

OBJECTIVE: To evaluate the comprehensive complication index(CCI) and Clavien-Dindo classification(CDC) for short-term postoperative complications in radical cystectomy and assess cumulative surgical morbidity to compare sufficient surgical skill. METHODS: From September 30, 2010, to October 1, 2020, clinical data of patients with urothelial carcinoma who underwent radical cystectomy with urinary diversion were gathered, patients who had only a urinary diversion, bladder sparing surgery, additional abdominal surgeries at the same time were all excluded. The CDC and CCI were utilized to evaluate 30-d complications after radical cystectomy and the relevance of hospital stay was compared between CCI and CDC. The cumulative sum control models (CUSUM) were used to evaluate the overall surgical morbidity of radical cystectomy in our facility and for comparisons between surgeons. RESULTS: This study enrolled a total of 635 individuals, 548 (86.3%) of whom had 1124 problems. The incidence of severe complications (CDC≥ Grade III) was 10.2%. The average CCI was 20.2 ± 14.7. Gender, urinary diversion subtype, procedure method, and surgeon were significantly correlated with the increase of CCI (p < 0.05). The CCI demonstrated a better relationship with hospital stay (R2  = 0.429) than the CDC (R2  = 0.361). The CUSUM-CCI model demonstrated a difference and growth distribution in dynamic time between individual surgeons. CONCLUSIONS: CCI can better reflect the incidence of complications for radical cystectomy than CDC, and CCI is more strongly correlated with postoperative hospital stay. The CUSUM-CCI model can reflect the quality of surgical skill for each surgeon instantaneously.

Ubiquitin specific peptidase 11 as a novel therapeutic target for cancer management.

Ubiquitination is a critical biological process in post-translational modification of proteins and involves multiple signaling pathways in protein metabolism, apoptosis, DNA damage, cell-cycle progression, and cancer development. Deubiquitinase, a specific enzyme that regulates the ubiquitination process, is also thought to be closely associated with the development and progression of various cancers. In this article, we systematically review the emerging role of the deubiquitinase ubiquitin-specific peptidase 11 (USP11) in many cancer-related pathways. The results show that USP11 promotes or inhibits the progression and chemoresistance of different cancers, including colorectal, breast, ovarian, and hepatocellular carcinomas, via deubiquitinating several critical proteins of cancer-related pathways. We initially summarize the role of USP11 in different cancers and further discuss the possibility of USP11 as a therapeutic strategy.

Deubiquitinating enzyme OTUB1 in immunity and cancer: Good player or bad actor?

OTU domain-containing ubiquitin aldehyde-binding proteins 1 (OTUB1) is the most important element of the deubiquitinase OTU superfamily, which has been identified as an essential regulator of diverse physiological processes, such as DNA damage repair and cytokines secretion. Recently, we found that the pro-carcinogenesis role of OTUB1 and the relationship between OTUB1 and immune response have gradually become the research hot-spot. OTUB1 regulates NK/CD8 T cell activation, autoimmune diseases, PD-L1 mediated immune evasion, viral or bacterial infection related immune response and the occurrence and progression of various cancers via deubiquitinating and stabilizing related proteins. This review provides a comprehensive description about the role and regulatory axis of OTUB1. We can explore the balance between immune response and defense via regulating the level of OTUB1, and targeting OTUB1 might restrain the progression of cancers. This review highlights the experimental evidence that OTUB1 is a feasible and potential therapeutic target against various cancers progression and immune diseases or disorder.

BUB1 drives the occurrence and development of bladder cancer by mediating the STAT3 signaling pathway.

BACKGROUND: The incidence of bladder urothelial carcinoma (UC), a common malignancy of the urinary tract, is approximately three times higher in men than in women. High expression of the mitotic kinase BUB1 is associated with the occurrence and development of several cancers, although the relationship between BUB1 and bladder tumorigenesis remains unclear. METHODS: Using a microarray approach, we found increased BUB1 expression in human BCa. The association between BUB1 and STAT3 phosphorylation was determined through molecular and cell biological methods. We evaluated the impact of pharmacologic inhibition of BUB1 kinase activity on proliferation and BCa progression in vitro and in vivo. RESULTS: In this study, we found that BUB1 expression was increased in human bladder cancer (BCa). We further identified through a series of molecular and cell biological approaches that BUB1 interacted directly with STAT3 and mediated the phosphorylation of STAT3 at Ser727. In addition, the findings that pharmacologic inhibition of BUB1 kinase activity significantly suppressed BCa cell proliferation and the progression of bladder cancer in vitro and in vivo were further verified. Finally, we found that the BUB1/STAT3 complex promoted the transcription of STAT3 target genes and that depletion of BUB1 and mutation of the BUB1 kinase domain abrogated this transcriptional activity, further highlighting the critical role of kinase activity in the activation of STAT3 target genes. A pharmacological inhibitor of BUB1 (2OH-BNPP1) was able to significantly inhibit the growth of BCa cell xenografts. CONCLUSION: This study showed that the BUB1 kinase drives the progression and proliferation of BCa by regulating the transcriptional activation of STAT3 signaling and may be an attractive candidate for therapeutic targeting in BCa.

Comprehensive analysis of Transcription Factors identified novel prognostic biomarker in human bladder cancer.

Background: Transcriptional factors (TFs) are responsible for regulating the transcription of pro-oncogenes and tumor suppressor genes in the process of tumor development. However, the role of these transcription factors in Bladder cancer (BCa) remains unclear. And the main purpose of this research is to explore the possibility of these TFs serving as biomarkers for BCa. Methods: We analyzed the differential expression of TFs in BCa from The Cancer Genome Atlas (TCGA) online database, identified 408 up-regulated TFs and 751down-regulated TFs. We obtained some hub genes via WGCNA model and detected the RNAs level in BCa cells and tissues. Then, the relationship between the expression and clinicopathological parameters was further investigated. Kaplan-Meier curves and the log-rank test were carried out to analyze the relationship between NFATC1, AKNA and five-TFs combination and overall survival (OS). And RT-PCR assay was conducted to further consolidate and verify these results. Results: There were significant differences in the expression of five TFs (CBX7, AKNA, HDAC4, EBF2 and NFATC1) between bladder cancer and normal bladder tissue. In BCa tissue and cell lines, the five TFs were frequently down-regulated, and closely related to poor prognosis. Moreover, the RT-PCR results of five TFs in bladder cancer and normal bladder tissue were consistent with the database results, and reduced TFs could significantly induce or restrain the transcription of many critical factors. The expression level of AKNA and NFATC1 could serve as independent biomarker to predict the overall survival (P<0.05). And the above five TFs combined detection of bladder cancer has higher sensitivity and specificity. Furthermore, differential neutrophils expression between high-risk and low-risk were found, which consolidated the role and function of the five TFs combination model in the progression of BCa. Conclusions: Our analysis effectively provides a newly TFs-associated prognostic model for bladder cancer. The combination of five identified-TFs is an independent prognostic biomarker, which could serve as a more effective therapeutic target for BCa patients.

The potential diagnosis role of TP53 mutation in advanced bladder cancer: A meta-analysis.

BACKGROUND: Bladder cancer is one of the most common urological cancers all over the world, and NMIBC occupies almost 80% of recently diagnosed bladder cancer cases. Progress and recurrence of bladder cancer are the main problems during the disease. The level of TP53 mutation is obviously higher in the high stage than the lower. This meta-analysis is to evaluate the potential diagnosis feature of TP53 mutation by the expression of TP53 mutation of Ta stage vs high stage in bladder cancer. METHODS: A systematic search of databases was conducted, and some relevant articles were selected. Next, the meta-analysis was carried out according to the standard guidelines. RESULTS: There were seven researches in which 677 participants were selected at the basis of inclusion standard. TP53 mutation was associated highly with increased diagnosis of bladder cancer. We found that the high stage of bladder cancer has obviously higher level of TP53 mutation than the lower stage, and these patients of MIBC have higher expression of TP53 mutation compared with NMIBC. No significant publication bias has been observed in this meta-analysis. The expression of TP53 mutation might be a diagnose-related biomarker for lots of patients with bladder cancer. CONCLUSIONS: The results of this meta-analysis provided further evidences that the expression of TP53 mutation was associated with the diagnosis efficiency of advanced bladder cancer. Higher expression of TP53 mutation was observed in the high stage of bladder cancer or the MIBC, and lower expression of TP53 mutation in the Ta stage of bladder cancer or the NMIBC. The expression level of TP53 mutation was probably a critical diagnosed biomarker in advanced bladder cancer.

OTUB1 Promotes Progression and Proliferation of Prostate Cancer via Deubiquitinating and Stabling Cyclin E1.

Background: Prostate cancer (PCa) is currently the most common cancer among males worldwide. It has been reported that OTUB1 plays a critical role in a variety of tumors and is strongly related to tumor proliferation, migration, and clinical prognosis. The aim of this research is to investigate the regulatory effect of OTUB1 on PCa proliferation and the underlying mechanism. Methods: Using the TCGA database, we identified that OTUB1 was up-regulated in PCa, and observed severe functional changes in PC3 and C4-2 cells through overexpression or knock down OTUB1. Heterotopic tumors were implanted subcutaneously in nude mice and IHC staining was performed on tumor tissues. The relationship between OTUB1 and cyclin E1 was identified via Western blotting and immunoprecipitations assays. Results: We found that the expression of OTUB1 in PCa was significantly higher than that in Benign Prostatic Hyperplasia (BPH). Overexpression OTUB1 obviously promoted the proliferation and migration of PC3 and C4-2 cells via mediating the deubiquitinated Cyclin E1, while OTUB1 knockout has the opposite effect. The nude mice experiment further explained the above conclusions. We finally determined that OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabling Cyclin E1. Conclusions: Our findings reveal the critical role of OTUB1 in PCa, and OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabilizing Cyclin E1. Blocking OTUB1/Cyclin E1 axis or applying RO-3306 could significantly repress the occurrence and development of PCa. OTUB1/Cyclin E1 axis might provide a new and potential therapeutic target for PCa.