Global burden of bladder cancer attributable to smoking in 204 countries and territories, 1990-2019.

Bladder cancer (BCa) poses a significant medical burden worldwide. However, the epidemiological pattern of the global smoking-induced BCa burden is unclear. Our analysis of the 2019 Global Burden of Disease (GBD) database showed a significant increase in the number of BCa cases worldwide from 1990 to 2019, with a clear upward trend in both age-standardized prevalence and incidence. In contrast, age-standardized rates of mortality (ASMR) and disability-adjusted life-years (ASDR) showed a downward trend, despite an increase in the absolute number of death and disability-adjusted life years. The burden of BCa caused by smoking is greater in males, middle-aged and older adults, and people in countries with high-middle socio-demographic indices (SDI). The study highlights the continuing global health challenge posed by smoking-related BCa. Targeted health policies and interventions are critical, especially in areas with high smoking rates and low socioeconomic status.

Investigation of ENO2 as a promising novel marker for the progression of colorectal cancer with microsatellite instability-high.

BACKGROUND: Microsatellite instability-high (MSI-H) has emerged as a significant biological characteristic of colorectal cancer (CRC). Studies reported that MSI-H CRC generally had a better prognosis than microsatellite stable (MSS)/microsatellite instability-low (MSI-L) CRC, but some MSI-H CRC patients exhibited distinctive molecular characteristics and experienced a less favorable prognosis. In this study, our objective was to explore the metabolic transcript-related subtypes of MSI-H CRC and identify a biomarker for predicting survival outcomes. METHODS: Single-cell RNA sequencing (scRNA-seq) data of MSI-H CRC patients were obtained from the Gene Expression Omnibus (GEO) database. By utilizing the copy number variation (CNV) score, a malignant cell subpopulation was identified at the single-cell level. The metabolic landscape of various cell types was examined using metabolic pathway gene sets. Subsequently, functional experiments were conducted to investigate the biological significance of the hub gene in MSI-H CRC. Finally, the predictive potential of the hub gene was assessed using a nomogram. RESULTS: This study revealed a malignant tumor cell subpopulation from the single-cell RNA sequencing (scRNA-seq) data. MSI-H CRC was clustered into two subtypes based on the expression profiles of metabolism-related genes, and ENO2 was identified as a hub gene. Functional experiments with ENO2 knockdown and overexpression demonstrated its role in promoting CRC cell migration, invasion, glycolysis, and epithelial-mesenchymal transition (EMT) in vitro. High expression of ENO2 in MSI-H CRC patients was associated with worse clinical outcomes, including increased tumor invasion depth (p = 0.007) and greater likelihood of perineural invasion (p = 0.015). Furthermore, the nomogram and calibration curves based on ENO2 showed potential prognosis predictive performance. CONCLUSION: Our findings suggest that ENO2 serves as a novel prognostic biomarker and is associated with the progression of MSI-H CRC.

Bisphenol S enhances the cell proliferation ability of prostate cancer cells by regulating the expression of SDS.

Recent times have witnessed an increase in both incidence and mortality rates of prostate cancer. While some individuals with localized or metastatic cancer may progress slowly with a lower mortality risk, those with intermediate or high-risk cancer often face a higher likelihood of death, despite treatment. Bisphenol A (BPA) has been linked to various cancers, including prostate and breast cancer, yet the relationship between bisphenol S (BPS) and human health remains underexplored. In our study, we employed ssGSEA analysis to evaluate the BPS-associated score in a prostate cancer cohort. Additionally, differential expression analysis identified BPS-related genes within the same group. Through COX and LASSO regression analyses, we developed and validated a BPS-related risk model using ROC curve and survival analyses. A nomogram, integrating clinical characteristics with this risk model, was established for improved predictive accuracy, further substantiated by calibration curve validation. Molecular docking analysis suggested potential binding between SDS and BPS. We also conducted cell proliferation assays on C4-2 and LNCaP prostate cancer cells, revealing increased cell growth at a BPS concentration of 10-7 M, as evidenced by CCK8 and EdU assays. In summary, our findings shed light on the BPS-prostate cancer linkage, identifying BPS-associated genes, establishing a validated risk model, exploring SDS-BPS binding potential, and assessing BPS's effect on prostate cancer cell growth. These insights underscore the need for further investigation into BPS and its impact on human diseases.

PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking.

BACKGROUND: Bladder cancer is very common worldwide. PIGT is a subunit of the glycosylphosphatidylinositol transamidase which involves in tumorigenesis and invasiveness. m6A modification of mRNA has been linked to cell proliferation, tumor progression and other biological events. However, how PIGT is regulated and what is the function of PIGT in bladder cancer remains to be elucidated. METHODS: PIGT was silenced or overexpressed to study its role in regulating bladder cancer. Cell proliferation and invasion were examined with the Cell Counting Kit-8, colony formation and Transwell assay, respectively. Cellular oxygen consumption rates or extracellular acidification rates were detected by a XF24 Analyzer. Quantitative RT-PCR and immunoblots were performed to detect mRNA and protein levels. RESULTS: PIGT was overexpressed in bladder cancer. Silencing PIGT inhibited cell proliferation, oxidative phosphorylation, and glycolysis. Overexpressing PIGT promoted cell proliferation, oxidative phosphorylation, glycolysis in vitro and tumor metastasis in vivo by activating glucose transporter 1 (GLUT1). PIGT also promoted GLUT1 glycosylation and membrane trafficking. Wilms' tumor 1-associated protein (WTAP) mediated PIGT m6A modification, and m6A reader, insulin-like growth factor 2 mRNA-binding protein (IGF2BP2), binds to the methylated PIGT to promote the stability of PIGT, leading to up-regulation of PIGT. CONCLUSION: WTAP mediates PIGT m6A modification to increase the stability of PIGT via the IGF2BP2, which enhances cell proliferation, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking.

Comprehensive view of macrophage autophagy and its application in cardiovascular diseases.

Cardiovascular diseases (CVDs) are the primary drivers of the growing public health epidemic and the leading cause of premature mortality and economic burden worldwide. With decades of research, CVDs have been proven to be associated with the dysregulation of the inflammatory response, with macrophages playing imperative roles in influencing the prognosis of CVDs. Autophagy is a conserved pathway that maintains cellular functions. Emerging evidence has revealed an intrinsic connection between autophagy and macrophage functions. This review focuses on the role and underlying mechanisms of autophagy-mediated regulation of macrophage plasticity in polarization, inflammasome activation, cytokine secretion, metabolism, phagocytosis, and the number of macrophages. In addition, autophagy has been shown to connect macrophages and heart cells. It is attributed to specific substrate degradation or signalling pathway activation by autophagy-related proteins. Referring to the latest reports, applications targeting macrophage autophagy have been discussed in CVDs, such as atherosclerosis, myocardial infarction, heart failure, and myocarditis. This review describes a novel approach for future CVD therapies.

The stratification and prognostic importance of molecular and immune landscapes in clear cell renal cell carcinoma.

The aim of our research is to explore the various characteristics and genetic profiles of clear cell renal cell carcinoma (ccRCC) in order to discover possible predictors of prognosis and targets for treatment. By utilizing ssGSEA scores, we categorized patients with ccRCC into groups based on their phenotype, distinguishing between low and high. This categorization revealed significant variations in the expression of crucial immune checkpoint genes and Human Leukocyte Antigen (HLA) genes, suggesting the presence of a potential immune evasion tactic in different subtypes of ccRCC. A predictive model was built using genes that are expressed differently and linked to cell death, showing strong effectiveness in categorizing patient risk. Furthermore, we discovered a noteworthy correlation among risk scores, infiltration of immune cells, the expression of genes related to immune checkpoint inhibitors, and diverse clinical features. This indicates that our scoring system for risk could function as a comprehensive gauge of the severity of the disease. The examination of the mutational terrain further highlighted the predominance of particular genetic changes, including VHL and PBRM1 missense mutations. Finally, we have discovered the function of DKK1 in facilitating cell death in ccRCC, presenting an additional possibility for therapeutic intervention. The results of our study suggest the possibility of incorporating molecular information into clinical prediction, which could lead to personalized treatment approaches in ccRCC.

Super-enhancer-associated SNHG15 cooperating with FOSL1 contributes to bladder cancer progression through the WNT pathway.

Small nucleolar RNA host gene 15 (SNHG15) plays an oncogenic role in many cancers. However, the role of SNHG15 in bladder cancer (BLCA) remains unclear. In this study, the regulation of SNHG15 on the activities of BLCA cells (T24 and RT112) was investigated. In detail, super-enhancers (SEs), differentially expressed genes, and functional enrichment were detected by bioinformatic analyses. Mutant cell lines lacking SNHG15-SEs were established using CRISPR-Cas9. Relative gene expression was detected by quantitative polymerase chain reaction (qPCR), western blot, in situ hybridization, and immunohistochemistry assays. Cell senescence, apoptosis, viability, and proliferation were measured. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter gene assays were conducted to analyze the interactions between genes. A novel super-enhancer of SNHG15 (SNHG15-SEs) was discovered in several BLCA datasets. The deletion of SNHG15-SEs resulted in a significant downregulation of SNHG15. Mechanistically, the core active region of SNHG15-SEs recruited the transcription factor FOSL1 to facilitate the SNHG15 transcription, thereby inducing the proliferation and metastasis of BLCA cells. Deletion of SNHG15-SEs inhibited the growth and metastasis of T24 and RT112 cells by inactivating the WNT/CTNNB1 pathway activation. Overexpression of FOSL1 in SNHG15-SEs restored the cell proliferation and metastasis. Next, a xenograft mouse model showed that SNHG15-SEs deletion inhibited the proliferation and metastasis of BLCA cells in vivo. Collectively, our data indicate that SNHG15-SEs recruit FOSL1 to promote the expression of SNHG15 which interacts with CTNNB1 in the nucleus to activate the transcription of ADAM12, leading to the malignance of BLCA cells.

Identification of the novel therapeutic targets and biomarkers associated of prostate cancer with cancer-associated fibroblasts (CAFs).

Globally, prostate cancer remains a leading cause of mortality and morbidity despite advances in treatment. Research on prostate cancer has primarily focused on the malignant epithelium, but the tumor microenvironment has recently been recognized as an important factor in the progression of prostate cancer. Cancer-associated fibroblasts (CAFs) play an important role in prostate cancer progression among multiple cell types in the tumor microenvironment. In order to develop new treatments and identify predictive and prognostic biomarkers for CAFs, further research is needed to understand the mechanism of action of prostate cancer and CAF. In this work, we performed the single-cell RNA sequence analysis to obtain the biomarkers for CAFs, and ten genes were finally regarded as the marker genes for CAFs. Based on the ssGSEA algorithm, the prostate cancer cohort was divided into low- and high-CAFs groups. Further analysis revealed that the CAFs-score is associated with many immune-related cells and immune-related pathways. In addition, between the low- and high-CAFs tissues, a total of 127 hub genes were discovered, which is specific in CAFs. After constructing the prognostic prediction model, SLPI, VSIG2, CENPF, SLC7A1, SMC4, and ITPR2 were finally regarded as the key genes in the prognosis of patients with prostate cancer. Each patient was assigned with the risk score as follows: SLPI* 0.000584811158157081 + VSIG2 * -0.01190627068889 + CENPF * -0.317826812875334 + SLC7A1 * -0.0410213995358753 + SMC4 * 0.202544454923637 + ITPR2 * -0.0824652047622673 + TOP2A * 0.140312081524807 + OR51E2 * -0.00136602095885459. The GSVA revealed the biological features of CAFs, many cancer-related pathways, such as the adipocytokine signaling pathway, ERBB signaling pathway, GnRH signaling pathway, insulin signaling pathway, mTOR signaling pathway and PPAR signaling pathway are closely associated with CAFs. As a result of these observations, similar transcriptomics may be involved in the transition from normal fibroblasts to CAFs in adjacent tissues. As one of the biomarkers for CAFs, CENPF can promote the proliferation ability of prostate cancer cells. The overexpress of CENPF could promote the proliferation ability of prostate cancer cells. In conclusion, we discuss the potential prognostic and therapeutic value of CAF-dependent pathways in prostate cancer.

Aldolase B attenuates clear cell renal cell carcinoma progression by inhibiting CtBP2.

Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.

Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis.

The glutathione (GSH) system is considered to be one of the most powerful endogenous antioxidant systems in the cardiovascular system due to its key contribution to detoxifying xenobiotics and scavenging overreactive oxygen species (ROS). Numerous investigations have suggested that disruption of the GSH system is a critical element in the pathogenesis of myocardial injury. Meanwhile, a newly proposed type of cell death, ferroptosis, has been demonstrated to be closely related to the GSH system, which affects the process and outcome of myocardial injury. Moreover, in facing various pathological challenges, the mammalian heart, which possesses high levels of mitochondria and weak antioxidant capacity, is susceptible to oxidant production and oxidative damage. Therefore, targeted enhancement of the GSH system along with prevention of ferroptosis in the myocardium is a promising therapeutic strategy. In this review, we first systematically describe the physiological functions and anabolism of the GSH system, as well as its effects on cardiac injury. Then, we discuss the relationship between the GSH system and ferroptosis in myocardial injury. Moreover, a comprehensive summary of the activation strategies of the GSH system is presented, where we mainly identify several promising herbal monomers, which may provide valuable guidelines for the exploration of new therapeutic approaches.

Molecular Targets of Shenqi Dihuang, A Traditional Chinese Herbal Medicine, and Its Potential Role in Renal Cell Carcinoma Therapy.

Chinese herbal medicine (CHM), which includes herbal slices and proprietary products, is widely used in China. Shenqi Dihuang (SQDH) is a traditional Chinese medicine (TCM) formula with ingredients that affect tumor growth. Despite recent advances in prognosis, patients with renal cell carcinoma (RCC) cannot currently receive curative treatment. The present study aimed to explore the potential target genes closely associated with SQDH. The gene expression data for SQDH and RCC were obtained from the TCMSP and TCGA databases. The SQDH-based prognostic prediction model reveals a strong correlation between RCC and SQDH. In addition, the immune cell infiltration analysis indicated that SQDH might be associated with the immune response of RCC patients. Based on this, we successfully built the prognostic prediction model using SQDH-related genes. The results demonstrated that CCND1 and NR3C2 are closely associated with the prognosis of RCC patients. Finally, the pathways enrichment analysis revealed that response to oxidative stress, cyclin binding, programmed cell death, and immune response are the most enriched pathways in CCND1. Furthermore, transcription regulator activity, regulation of cell population proliferation, and cyclin binding are closely associated with the NR3C2.

ARHGAP6 inhibits bladder cancer cell viability, migration, and invasion via ß-catenin signaling and enhances mitomycin C sensitivity.

The Rho/ROCK pathway regulates diverse cellular processes and contributes to the development and advancement of several types of human cancers. This study investigated the role of specific Rho GTPase-activating proteins (RhoGAP), ARHGAP6, in bladder cancer (BC). In this study, ARHGAP6 expression in BC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism ARHGAP6 of in BC. The mRNA and protein levels of ARHGAP6 significantly reduced in human BC tissues and cell lines compared with corresponding adjacent non-cancerous tissues and normal urothelial cells. In vitro, ARHGAP6 overexpression markedly decreased the viability, migration, and invasion of BC cells. Interestingly, low ARHGAP6 expression in BC strongly correlated with poor patient survival and was highly associated with metastasis and ß-catenin signaling. Furthermore, ARHGAP6 expression strongly influenced the sensitivity of BC cells to mitomycin C treatment. Together, our results demonstrate that ARHGAP6 plays critical roles in regulating the proliferation, migration, invasion, and metastasis of BC cells possibly via the modulation of ß-catenin and strongly influences the chemosensitivity of BC cells.

Identifying tumor antigens and immune subtypes of renal cell carcinoma for immunotherapy development.

Renal cell carcinoma (RCC) is one of the leading causes of death in men. Messenger ribonucleic acid (mRNA) vaccines may be an attractive means to achieve satisfactory results. Cancer immunotherapy is a promising cancer treatment strategy. However, immunotherapy is not widely used in renal cell carcinoma, as only a few patients show a positive response. The present study aimed to identify potential antigens associated with renal cell carcinoma to develop an anti-renal cell carcinoma mRNA vaccine. Moreover, the immune subtypes of renal cell carcinoma cells were determined. The Cancer Genome Atlas (TCGA) analysis revealed gene expression profiles and clinical information. Antigen-presenting cells infiltrated the immune system using Tumor Immune Estimation Resource (TIMER) tool (http://timer.cistrome.org/). GDSC (Genomics of Drug Sensitivity in Cancer) database were used to estimate drug sensitivity. The 13 immune-related genes discovery could be targets for immunotherapy in renal cell carcinoma patients, as they were associated with a better prognosis and a higher level of antigen-presenting cells. These immune subtypes have significant relationships with immunological checkpoints, immunogenic cell death regulators, and RCC prognostic variables. Furthermore, DBH-AS1 was identified as a potential antigen for developing an mRNA vaccine. The CCK8 assay demonstrated that the proliferative capacity of 786-O and Caki-1 cells overexpressing DBH-AS1 was higher than in the control group. In addition, transwell assay revealed that 786-O and Caki-1 cells overexpressing DBH-AS1 showed higher invasion capacity compared with control. This study provides a theoretical basis for the development of mRNA vaccines. Our findings suggest that DBH-AS1 could be potential antigens for developing RCC mRNA vaccines.

Establishment of an optimized orthotopic bladder cancer model in mice.

BACKGROUND: Bladder cancer (BC) is one of the most common malignancies of the genitourinary system. Animal models offer an important tool to explore tumour initiation, progression, and therapeutic mechanisms. Our aim is to construct an optimized orthotopic BC model which is predictable, reproducible, and convenient. METHODS: The optimized orthotopic BC model was constructed in male C57BL/6 mice utilizing microsyringes to inoculate them with a murine BC cell line (MB49). Anesthetised mice were inoculated with an MB49 cell suspension (10 µL) at approximately 5 × 106/mL. The whole process of modelling was observed and monitored every 3 days for 21 days utilizing HE staining and transabdominal ultrasonography (TUS). RESULTS: In this study, the model showed excellent success rates for tumour formation (96.67%) and metastatic rate (89.66%). Compared to the control group (sham operation), mice in the modelling group had serous cachexia, visible haematuresis and weight loss (all P < 0.05). The lungs, liver, ureter and kidneys were found to have tumour metastasis. Moreover, the average survival time (19.73 ± 1.69 d) of modelling mice was significantly shorter than that of the control mice (P < 0.05), which remained alive. CONCLUSION: Our study established a method using microsyringes to inject murine BC cells into the bladder wall, creating a stable transplantable BC model in mice.

Qici Sanling Decoction Suppresses Glutamine Consumption and Bladder Cancer Cell Growth through Inhibiting c-Myc Expression.

Traditional Chinese medicine (TCM) is widely used as an alternative therapy for cancer treatment in China. Glutamine catabolism plays an important role in cancer development. Qici Sanling decoction (QCSL) suppresses bladder cancer growth. However, the association between QCSL and glutamine catabolism remains unknown. In this study, different doses of QCSL were applied to T24 cells, followed by the measurements of cell viability and apoptosis using CCK-8 and Annexin V/PI assay, respectively. Furthermore, glutamine consumption was detected using the glutamine assay kit. QCSL was observed to inhibit cell growth and induced cell apoptosis in a dose-dependent manner. Analysis of glutamine consumption revealed that QCSL suppressed glutamine consumption in T24 cells. Furthermore, QCSL decreased the mRNA and protein levels of c-Myc, GLS1, and SLC1A5. All these effects induced by QCSL could be alleviated by c-Myc overexpression, indicating c-Myc was involved in the protective role of QCSL in bladder cancer. In addition, QCSL was found to inhibit tumor growth in the xenograft tumor model. The similar results were obtained in tumor samples that protein levels of c-Myc, GLS1, and SLC1A5 were decreased upon treatment with QCSL. In conclusion, QCSL suppresses glutamine consumption and bladder cancer cell growth through inhibiting c-Myc expression.

[Modified Shenqi Dihuang Decoction acts on hormone-sensitive prostate cancer by inhibiting glycolysis through the PI3K/Akt /mTOR signaling pathway].

Objective: To evaluate the effect of Modified Shenqi Dihuang Decoction (MSDD) on human hormone-sensitive LNCaP prostate cancer cells and its action mechanism. METHODS: LNCaP prostate cancer cells were treated with MSDD, followed by detection of the proliferation and apoptosis of the cells by MTT assay and flow cytometry respectively and measurement of glucose uptake and lactate production by glucose uptake assay and colorimetry respectively. The expressions of the apoptosis-related proteins Bcl-2, Bax and cleaved-caspase-3, glycolysis-related proteins HK2, GLUT1, PKM2 and LDHA, and PI3K/AKT/mTOR pathway-related proteins in the LNCaP cells were determined by Western blot. The effect of MSDD on the LNCaP cells was observed with the glycolysis inducer oligomycin and the PI3K activator 740 Y-P. RESULTS: MSDD inhibited the proliferation, induced the apoptosis, increased the levels of Bax and cleaved-caspase 3 and decreased the level of Bcl-2 in the LNCaP cells in a dose-dependent manner. After MSDD intervention, the glucose uptake and lactate production in the LNCaP cells were significantly reduced, the expressions of HK2, GLUT1, PKM2 and LDHA and the phosphorylation levels of Akt, PI3K and mTOR were markedly suppressed. Oligomycin and 740 Y-P reversed the inhibitory effect of MSDD on the proliferation of the LNCaP cells, and 740 Y-P reversed that on glucose uptake, lactic acid production and the expressions of the glycolysis-related proteins HK2, GLUT1, PKM2 and LDHA in the LNCaP cells. CONCLUSIONS: Modified Shenqi Dihuang Decoction inhibits the proliferation of LNCaP prostate cancer cells by suppressing glycolysis and the PI3K/Akt/mTOR signaling pathway.

A novel cuproptosis-related lncRNA signature predicts prognosis and therapeutic response in bladder cancer.

Bladder cancer (BC) ranks the tenth in the incidence of global tumor epidemiology. LncRNAs and cuproptosis were discovered to regulate the cell death. Herein, we downloaded transcriptome profiling, mutational data, and clinical data on patients from The Cancer Genome Atlas (TCGA). High- and low-risk BC patients were categorized. Three CRLs (AL590428.1, AL138756.1 and GUSBP11) were taken into prognostic signature through least absolute shrinkage and selection operator (LASSO) Cox regression. Worse OS and PFS were shown in high-risk group (p < 0.05). ROC, independent prognostic analyses, nomogram and C-index were predicted via CRLs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated IncRNAs play a biological role in BC progression. Immune-related functions showed the high-risk group received more benefit from immunotherapy and had stronger immune responses, and the overall survival was better (p < 0.05). Finally, a more effective outcome (p < 0.05) was found from clinical immunotherapy via the TIDE algorithm and many potential anti-tumor drugs were identified. In our study, the cuproptosis-related signature provided a novel tool to predict the prognosis in BC patients accurately and provided a novel strategy for clinical immunotherapy and clinical applications.

CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma.

Recent studies have reported that MLST8 is upregulated in many malignant tumors. Nevertheless, the underlying molecular mechanism is still unclear. The aim of this work was to investigate how MLST8 contributes to the development and progression of clear cell renal cell carcinoma (ccRCC). MLST8 is an oncogenic protein in the TCGA database and ccRCC clinical specimens. We also ascertain that MLST8 interacts with FBXW7, which was universally regarded as an E3 ubiquitin ligase. MLST8 can be degraded and ubiquitinated by tumor suppressor FBXW7. FBXW7 recognizes a consensus motif (T/S) PXX (S/T/D/E) of MLST8 and triggers MLST8 degradation via the ubiquitin-proteasome pathway. Strikingly, the activated cyclin dependent kinase 1 (CDK1) kinase engages in the MLST8 phosphorylation required for FBXW7-mediated degradation. In vitro, we further prove that MLST8 is an essential mediator of FBXW7 inactivation-induced tumor growth, migration, and invasion. Furthermore, the MLST8 and FBXW7 proteins are negatively correlated in human renal cancer specimens. Our findings suggest that MLST8 is a putative oncogene that functions via interaction with FBXW7, and inhibition MLST8 could be a potential future target in ccRCC treatment.

[Modified Shenqi Dihuang Decoction for bone metastasis of hormone-sensitive prostate cancer after castration].

OBJECTIVE: To observe the clinical effect of Modified Shenqi Dihuang Decoction (MSDD) on bone metastasis of hormone-sensitive PCa after castration. METHODS: Seventy-six hormone-sensitive PCa patients with bone metastasis were randomly divided into a control and an MSDD group of an equal number, the former treated by maximal androgen blockade (MAB) and the latter with MSDD in addition to MAB, both for 6 months. Comparisons were made between the two groups of patients in their TCM symptom scores, quality of life (QOL) scores and the incidence rates of castration resistance, bone metastasis and adverse events. RESULTS: Totally, 64 of the patients were included in the statistical analysis. Compared with the controls, the MSDD group showed significantly lower rates of castration resistance (71.87% vs 28.12%, P < 0.05) and new bone and visceral metastases (40.63% vs 18.75%, P < 0.05) and level of serum alkaline phosphatase after treatment (ï¼»328.5 ± 170.6ï¼½ vs ï¼»318.5 ± 165.8ï¼½ U/L, P < 0.05), as well as lower scores in the TCM symptoms of frequent micturition (2.05 ± 0.51 vs 1.64 ± 0.66, P < 0.05), loss of appetite (1.95 ± 0.48 vs 1.41 ± 0.39, P < 0.05), fatigue (2.59 ± 0.68 vs 1.39 ± 0.58, P < 0.05), back pain (1.76 ± 0.41 vs 1.26 ± 0.38, P < 0.05), weight loss (1.88 ± 0.75 vs 1.26 ± 0.80, P < 0.05) and self-evaluation (1.89 ± 0.58 vs 1.54 ± 0.63, P < 0.05), but a higher score in the physical status (Karnofsky Performance Scale) (70.45 ± 12.16 vs 79.87 ± 11.23, P < 0.05). There were no statistically significant differences in the Numeric Rating Scale for Pain score and the incidence of adverse events between the two groups of patients. CONCLUSIONS: Modified Shenqi Dihuang Decoction can effectively improve the QOL and TCM symptom scores of the patients with hormone-sensitive PCa after androgen castration, enhance the efficacy of modern drugs in the treatment of hormone-sensitive PCa, decrease the incidence of metastasis, improve the patient's serum indicators, reduce the pain associated with bone metastasis, and improve the patient's quality of life.

ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling.

BACKGROUND: Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin-RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression. METHODS: The expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis. RESULTS: We found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis. CONCLUSION: ROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.