Taurine inhibits neuron apoptosis in hippocampus of diabetic rats and high glucose exposed HT-22 cells via the NGF-Akt/Bad pathway.

Type 2 Diabetes causes learning and memory deficits that might be mediated by hippocampus neuron apoptosis. Studies found that taurine might improve cognitive deficits under diabetic condition because of its ability to prevent hippocampus neuron apoptosis. However, the effect and mechanism is not clear. In this study, we explore the effect and mechanism of taurine on inhibiting hippocampus neuron apoptosis. Sixty male Sprague-Dawley rats were randomly divided into control, T2D, taurine treatment (giving 0.5%, 1%, and 2% taurine in drinking water) groups. Streptozotocin was used to establish the diabetes model. HT-22 cell (hippocampus neurons line) was used for in vitro experiments. Morris Water Maze test was used to check the learning and memory ability, TUNEL assay was used to measure apoptosis and nerve growth factor (NGF); Akt/Bad pathway relevant protein was detected by western blot. Taurine improved learning and memory ability and significantly decreased apoptosis of the hippocampus neurons in T2D rats. Moreover, taurine supplement also inhibited high glucose-induced apoptosis in HT-22 cell in vitro. Mechanistically, taurine increased the expression of NGF, phosphorylation of Trka, Akt, and Bad, as well as reduced cytochrome c release from mitochondria to cytosol. However, beneficial effects of taurine were blocked in the presence of anti-NGF antibody or Akt inhibitor. Taurine could inhibit hippocampus neuron apoptosis via NGF-Akt/Bad pathway. These results provide some clues that taurine might be efficient and feasible candidate for improvement of learning and memory ability in T2D rats.

Sorafenib induces renal cell carcinoma apoptosis via upregulating activating transcription factor 4.

Previous studies have shown sorafenib to function as a multitargeted tyrosine kinase inhibitor in different tumors. However, whether sorafenib improves renal cell carcinoma (RCC) through activating transcription factor 4 (ATF4) has never been explored. In the current study, we showed that sorafenib could suppress RCC cell viability in a time- and dose-dependent manner. Furthermore, sorafenib is demonstrated to enhance the mRNA and protein levels of ATF4. Meanwhile, overexpression of ATF4 was demonstrated to induce ACHN cell cycle arrest and cell apoptosis. Moreover, treatment with sorafenib could enhance the expression of CCAAT/enhancer-binding protein-homologous protein (CHOP) and p53 upregulated modulator of apoptosis (PUMA), thereby leading to ACHN cell apoptosis. More importantly, silencing of ATF4 could largely abolish sorafenib-induced upregulation of CHOP and PUMA in ACHN cells. Meanwhile, sorafenib-induced cell apoptosis may be dependent on the activation of ATF4 since knockdown of ATF4 partially reversed sorafenib-induced ACHN cell apoptosis. In summary, the present study demonstrates that sorafenib activates ATF4-CHOP-PUMA pathway in RCC cells, resulting in enhanced ER stress-related cell apoptosis.

MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor PDCD4 and promotes cell transformation, proliferation, and metastasis in renal cell carcinoma.

OBJECTIVES: MiR-21 induces neoplastic transformation, cell proliferation, and metastasis and downregulates programmed cell death4 (PDCD4) in some cancers. The aim of this study was to investigate the roles and interactions of PDCD4 and miR-21 in human renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 32 paired tumor and normal tissue specimens from RCC patients as well as three renal cancer cell lines (786-O, A498, caki-1) and one normal epithelial kidney cell line (HK-2) were studied. The expression levels of PDCD4 (protein and mRNA) and miR-21 were examined by Western blot analysis and by qRT-PCR and luciferase reporter assays. Furthermore, we transfected 786-O cells with pre-miR-21 (mimics) and anti-miR-21 (inhibitor) and then again analyzed the expression of PDCD4 protein and mRNA, and determined cell proliferation and transformation capabilities by EDU and soft agar colony formation assay. RESULTS: MiR-21 expression was significantly upregulated in RCC, metastatic RCC specimens and renal cancer cell lines (A498, 786-O, caki-1) compared to normal non-metastatic RCC specimens and HK-2 cells (P<0.05). In contrast, PDCD4 protein expression significantly decreased (P<0.05), whereas PDCD4 mRNA expression remained unaltered (P>0.05). Moreover, we observed a significant reduction in PDCD4 protein levels in miR-21mimic-transfected cells, but a significant increase in miR-21inhibitor-transfected cells (P<0.05), whereas PDCD4 mRNA was practically unaltered (P>0.05). Furthermore, miR-21mimic-transfected cells exhibited increased cell proliferation and transformation capacity according to EDU analysis and soft agar formation assay, whereas miR-21inhibitor-transfected cells exhibited the opposite phenomenon(P<0.05). CONCLUSIONS: MiR-21 not only promoted cancer cell hyperplasia and contributed to tumor cell transformation and metastasis, but also post-transcriptionally downregulated PDCD4 protein expression. PDCD4 and miR-21 expression levels potentially play an important role in renal cell cancer.

Deciphering the role of neddylation in tumor microenvironment modulation: common outcome of multiple signaling pathways.

Neddylation is a post-translational modification process, similar to ubiquitination, that controls several biological processes. Notably, it is often aberrantly activated in neoplasms and plays a critical role in the intricate dynamics of the tumor microenvironment (TME). This regulatory influence of neddylation permeates extensively and profoundly within the TME, affecting the behavior of tumor cells, immune cells, angiogenesis, and the extracellular matrix. Usually, neddylation promotes tumor progression towards increased malignancy. In this review, we highlight the latest understanding of the intricate molecular mechanisms that target neddylation to modulate the TME by affecting various signaling pathways. There is emerging evidence that the targeted disruption of the neddylation modification process, specifically the inhibition of cullin-RING ligases (CRLs) functionality, presents a promising avenue for targeted therapy. MLN4924, a small-molecule inhibitor of the neddylation pathway, precisely targets the neural precursor cell-expressed developmentally downregulated protein 8 activating enzyme (NAE). In recent years, significant advancements have been made in the field of neddylation modification therapy, particularly the integration of MLN4924 with chemotherapy or targeted therapy. This combined approach has demonstrated notable success in the treatment of a variety of hematological and solid tumors. Here, we investigated the inhibitory effects of MLN4924 on neddylation and summarized the current therapeutic outcomes of MLN4924 against various tumors. In conclusion, this review provides a comprehensive, up-to-date, and thorough overview of neddylation modifications, and offers insight into the critical importance of this cellular process in tumorigenesis.

Frontiers in sarcopenia: Advancements in diagnostics, molecular mechanisms, and therapeutic strategies.

The onset of sarcopenia is intimately linked with aging, posing significant implications not only for individual patient quality of life but also for the broader societal healthcare framework. Early and accurate identification of sarcopenia and a comprehensive understanding of its mechanistic underpinnings and therapeutic targets paramount to addressing this condition effectively. This review endeavors to present a cohesive overview of recent advancements in sarcopenia research and diagnosis. We initially delve into the contemporary diagnostic criteria, specifically referencing the European Working Group on Sarcopenia in Older People (EWGSOP) 2 and Asian Working Group on Sarcopenia (AWGS) 2019 benchmarks. Additionally, we elucidate comprehensive assessment techniques for muscle strength, quantity, and physical performance, highlighting tools such as grip strength, chair stand test, dual-energy X-ray Absorptiometry (DEXA), bioelectrical impedance analysis (BIA), gait speed, and short physical performance battery (SPPB), while also discussing their inherent advantages and limitations. Such diagnostic advancements pave the way for early identification and unequivocal diagnosis of sarcopenia. Proceeding further, we provide a deep-dive into sarcopenia's pathogenesis, offering a thorough examination of associated signaling pathways like the Myostatin, AMP-activated protein kinase (AMPK), insulin/IGF-1 Signaling (IIS), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Each pathway's role in sarcopenia mediation is detailed, underscoring potential therapeutic target avenues. From a mechanistic perspective, the review also underscores the pivotal role of mitochondrial dysfunction in sarcopenia, emphasizing elements such as mitochondrial oxidative overload, mitochondrial biogenesis, and mitophagy, and highlighting their therapeutic significance. At last, we capture recent strides made in sarcopenia treatment, ranging from nutritional and exercise interventions to potential pharmacological and supplementation strategies. In sum, this review meticulously synthesizes the latest scientific developments in sarcopenia, aiming to enhance diagnostic precision in clinical practice and provide comprehensive insights into refined mechanistic targets and innovative therapeutic interventions, ultimately contributing to optimized patient care and advancements in the field.

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing.

BACKGROUND: Neddylation, a post-translational modification process, plays a crucial role in various human neoplasms. However, its connection with kidney renal clear cell carcinoma (KIRC) remains under-researched. METHODS: We validated the Gene Set Cancer Analysis Lite (GSCALite) platform against The Cancer Genome Atlas (TCGA) database, analyzing 33 cancer types and their link with 17 neddylation-related genes. This included examining copy number variations (CNVs), single nucleotide variations (SNVs), mRNA expression, cellular pathway involvement, and methylation. Using Gene Set Variation Analysis (GSVA), we categorized these genes into three clusters and examined their impact on KIRC patient prognosis, drug responses, immune infiltration, and oncogenic pathways. Afterward, our objective is to identify genes that exhibit overexpression in KIRC and are associated with an adverse prognosis. After pinpointing the specific target gene, we used the specific inhibitor MLN4924 to inhibit the neddylation pathway to conduct RNA sequencing and related in vitro experiments to verify and study the specificity and potential mechanisms related to the target. This approach is geared towards enhancing our understanding of the prognostic importance of neddylation modification in KIRC. RESULTS: We identified significant CNV, SNV, and methylation events in neddylation-related genes across various cancers, with notably higher expression levels observed in KIRC. Cluster analysis revealed a potential trade-off in the interactions among neddylation-related genes, where both high and low levels of gene expression are linked to adverse prognoses. This association is particularly pronounced concerning lymph node involvement, T stage classification, and Fustat score. Simultaneously, our research discovered that PSMB10 exhibits overexpression in KIRC when compared to normal tissues, negatively impacting patient prognosis. Through RNA sequencing and in vitro assays, we confirmed that the inhibition of neddylation modification could play a role in the regulation of various signaling pathways, thereby influencing the prognosis of KIRC. Moreover, our results underscore PSMB10 as a viable target for therapeutic intervention in KIRC, opening up novel pathways for the development of targeted treatment strategies. CONCLUSION: This study underscores the regulatory function and potential mechanism of neddylation modification on the phenotype of KIRC, identifying PSMB10 as a key regulatory target with a significant role in influencing the prognosis of KIRC.

Erratum: The potential value of cuprotosis (copper-induced cell death) in the therapy of clear cell renal cell carcinoma.

[This corrects the article on p. 3947 in vol. 12, PMID: 36119838.].

[Retracted] Isoquercitrin inhibits bladder cancer progression in vitro and in vivo by regulating the PI3K/Akt and PKC signaling pathways.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the agarose gel electrophoretic bands shown in Fig. 4A for PKC were strikingly similar to bands that had already appeared in another article written by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 36: 165­172, 2016; DOI: 10.3892/or.2016.4794].

Zinc sensitizes prostate cancer cells to sorafenib and regulates the expression of Livin.

In prostate carcinogenesis, normal zinc-accumulating epithelial cells are transformed into malignant cells that do not accumulate zinc. Increased levels of zinc have been shown to induce apoptosis through a caspase-dependent mechanism with down-regulated anti-apoptotic proteins in prostate cancer cells. Our previous study showed that, as a member of the inhibitor of apoptosis proteins (IAPs) family, Livin could play an important role in the initiation of human prostate cancer and promote cell proliferation by altering the G1-S cell cycle transition. In the present study, we measured the apoptosis sensitivity of prostate cancer cells to zinc and sorafenib and found that zinc sensitized prostate cancer cells to sorafenib-induced apoptosis. Surprisingly, we also found that, unlike its counterparts Survivin and cIAP2, Livin was not decreased all the time; instead, it was compensatively increased in zinc-mediated apoptosis at 48 h in prostate cancer cells. Our results offer potential treatment combinations that may augment the effect of sorafenib, and also reveal, for the first time, that increased Livin expression may play a role in the early cell death response of prostate cancer cells to zinc.

Can tamsulosin facilitate expulsion of ureteral stones? A meta-analysis of randomized controlled trials.

OBJECTIVES: To determine the efficacy and safety of the adrenergic alpha-antagonist tamsulosin in facilitating ureteral stones expulsion. METHODS: A literature search was carried out using the PubMed database, Medline via Ovid, Embase and the Cochrane Library database to identify randomized controlled trials evaluating the efficiency of tamsulosin in the treatment of ureteral stones. Meta-analysis and forest plots were carried out by use of Review Manager version 5.1 software (Cochrane Collaboration). RESULTS: Compared with the control group, the tamsulosin group had an increase in expulsion rate of 51% and a decrease in expulsion time of 2.63 days. Furthermore, tamsulosin was found to reduce the risk of ureteral colic during treatment by 40% and also the risk of requirement of auxiliary procedures during follow up by 60%. In terms of safety, the tamsulosin group had a 117% increase in the incidence of side-effects compared with the control group, especially for incidence of dizziness. CONCLUSION: Tamsulosin facilitates the expulsion of ureteral calculi by providing a higher expulsion rate, a shorter expulsion time, a lower incidence of ureteral colic during treatment and a lower requirement of auxiliary procedures. However, the incidence of dizziness occurring during tamsulosin treatment is significantly higher in this setting.

Tumor Vaccines: Unleashing the Power of the Immune System to Fight Cancer.

This comprehensive review delves into the rapidly evolving arena of cancer vaccines. Initially, we examine the intricate constitution of the tumor microenvironment (TME), a dynamic factor that significantly influences tumor heterogeneity. Current research trends focusing on harnessing the TME for effective tumor vaccine treatments are also discussed. We then provide a detailed overview of the current state of research concerning tumor immunity and the mechanisms of tumor vaccines, describing the complex immunological processes involved. Furthermore, we conduct an exhaustive analysis of the contemporary research landscape of tumor vaccines, with a particular focus on peptide vaccines, DNA/RNA-based vaccines, viral-vector-based vaccines, dendritic-cell-based vaccines, and whole-cell-based vaccines. We analyze and summarize these categories of tumor vaccines, highlighting their individual advantages, limitations, and the factors influencing their effectiveness. In our survey of each category, we summarize commonly used tumor vaccines, aiming to provide readers with a more comprehensive understanding of the current state of tumor vaccine research. We then delve into an innovative strategy combining cancer vaccines with other therapies. By studying the effects of combining tumor vaccines with immune checkpoint inhibitors, radiotherapy, chemotherapy, targeted therapy, and oncolytic virotherapy, we establish that this approach can enhance overall treatment efficacy and offset the limitations of single-treatment approaches, offering patients more effective treatment options. Following this, we undertake a meticulous analysis of the entire process of personalized cancer vaccines, elucidating the intricate process from design, through research and production, to clinical application, thus helping readers gain a thorough understanding of its complexities. In conclusion, our exploration of tumor vaccines in this review aims to highlight their promising potential in cancer treatment. As research in this field continues to evolve, it undeniably holds immense promise for improving cancer patient outcomes.

Review and prospect of immune checkpoint blockade therapy represented by PD-1/PD-L1 in the treatment of clear cell renal cell carcinoma.

As a common tumor of the urinary system, the morbidity and mortality related to renal carcinoma, are increasing annually. Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell carcinoma, accounting for approximately 75% of the total number of patients with renal cell carcinoma. Currently, the clinical treatment of ccRCC involves targeted therapy, immunotherapy, and a combination of the two. In immunotherapy, PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment. However, as treatment progresses, some patients gradually develop resistance to immunotherapy. Meanwhile, other patients experience great side effects after immunotherapy, resulting in a survival status far lower than the expected survival rate. Based on these clinical problems, many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results. We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.

Livin regulates prostate cancer cell invasion by impacting the NF-κB signaling pathway and the expression of FN and CXCR4.

Prostate cancer (PCa) has the second highest mortality rate of all tumor-related diseases for males in Western countries, and the incidence of PCa in China is increasing. Previous studies have proven that inhibitor of apoptosis proteins (IAPs) can regulate tumor cell invasion and metastasis. Livin is the most recently identified IAP. Our previous study showed that Livin might play an important role in the initiation of human PCa and that Livin-α might promote cell proliferation by regulating the G1-S cell cycle transition. However, whether Livin, as an IAP, can regulate the invasive ability of PCa cells remains unknown. In this study, we found that the expression of Livin was higher in metastatic PCa tissues than in nonmetastatic tissues and that the expression of Livin was downregulated/upregulated by small interfering RNA/vector, which could inhibit/promote PC-3/LNCaP cell invasion. This action was related to the impact of Livin on nuclear factor-κB (NF-κB) and its downstream signaling pathway, including FN and CXCR4. Together, our findings suggested that Livin might regulate tumor cell invasion in PCa directly, and that Livin might be an ideal candidate for preventing tumor cell invasion.

Development of a Novel Sphingolipid Signaling Pathway-Related Risk Assessment Model to Predict Prognosis in Kidney Renal Clear Cell Carcinoma.

This study aimed to explore underlying mechanisms by which sphingolipid-related genes play a role in kidney renal clear cell carcinoma (KIRC) and construct a new prognosis-related risk model. We used a variety of bioinformatics methods and databases to complete our exploration. Based on the TCGA database, we used multiple R-based extension packages for data transformation, processing, and statistical analyses. First, on analyzing the CNV, SNV, and mRNA expression of 29 sphingolipid-related genes in various types of cancers, we found that the vast majority were protective in KIRC. Subsequently, we performed cluster analysis of patients with KIRC using sphingolipid-related genes and successfully classified them into the following three clusters with significant prognostic differences: Cluster 1, Cluster 2, and Cluster 3. We performed differential analyses of transcription factor activity, drug sensitivity, immune cell infiltration, and classical oncogenes to elucidate the unique roles of sphingolipid-related genes in cancer, especially KIRC, and provide a reference for clinical treatment. After analyzing the risk rates of sphingolipid-related genes in KIRC, we successfully established a risk model composed of seven genes using LASSO regression analysis, including SPHK1, CERS5, PLPP1, SGMS1, SGMS2, SERINC1, and KDSR. Previous studies have suggested that these genes play important biological roles in sphingolipid metabolism. ROC curve analysis results showed that the risk model provided good prediction accuracy. Based on this risk model, we successfully classified patients with KIRC into high- and low-risk groups with significant prognostic differences. In addition, we performed correlation analyses combined with clinicopathological data and found a significant correlation between the risk model and patient's M, T, stage, grade, and fustat. Finally, we developed a nomogram that predicted the 5-, 7-, and 10-year survival in patients with KIRC. The model we constructed had strong predictive ability. In conclusion, we believe that this study provides valuable data and clues for future studies on sphingolipid-related genes in KIRC.

Potential Application of Pyroptosis in Kidney Renal Clear Cell Carcinoma Immunotherapy and Targeted Therapy.

Renal cell carcinoma (RCC) is a type of cancer with an increasing rate of morbidity and mortality and is a serious threat to human health. The treatment of RCC, especially kidney renal clear cell carcinoma (KIRC), has always been the focus of clinical treatment. Using The Cancer Genome Atlas (TCGA) database as a starting point, we explored the feasibility of applying the pyroptosis mechanism to KIRC treatment by searching for cancer markers associated with pyroptosis and cancer treatment signatures. The obtained samples were clustered using unsupervised clustering analysis to define the different KIRC subtypes with different pyroptosis expression levels. Based on this, a gene expression analysis was performed to explore the carcinogenic mechanism that is markedly related to pyroptosis. The Genomics of Drug Sensitivity in Cancer database and single sample gene set enrichment analysis (ssGSEA) algorithm were used to analyze the different treatment methods of the current prominent KIRC to determine whether pyroptosis plays a role. Finally, LASSO regression was used to screen for related genes and construct a model to predict patient prognosis. The expression levels of GSDME, CASP3, CASP4, CASP5, CHMP3, and CHMP4C were incorporated into the model construction. After verification, the prediction accuracy of the 3-, 5-, 7- and 10 years survival rates of our prognostic model were 0.66, 0.701, 0.719, and 0.728, respectively. Through the above analysis, we demonstrated the feasibility of pyroptosis in the clinical treatment of KIRC and provided novel ideas and suggestions for the clinical treatment of KIRC.

Application of Regulatory Cell Death in Cancer: Based on Targeted Therapy and Immunotherapy.

The development of cancer treatment methods is constantly changing. For common cancers, our treatment methods are still based on conventional treatment methods, such as chemotherapy, radiotherapy, and targeted drug therapy. Nevertheless, the emergence of tumor resistance has a negative impact on treatment. Regulated cell death is a gene-regulated mode of programmed cell death. After receiving specific signal transduction, cells change their physical and chemical properties and the extracellular microenvironment, resulting in structural destruction and decomposition. As research accumulates, we now know that by precisely inducing specific cell death patterns, we can treat cancer with less collateral damage than other treatments. Many newly discovered types of RCD are thought to be useful for cancer treatment. However, some experimental results suggest that some RCDs are not sensitive to cancer cell death, and some may even promote cancer progression. This review summarizes the discovered types of RCDs, reviews their clinical efficacy in cancer treatment, explores their anticancer mechanisms, and discusses the feasibility of some newly discovered RCDs for cancer treatment in combination with the immune and tumor microenvironment.

Lipid metabolism in ferroptosis and ferroptosis-based cancer therapy.

Ferroptosis refers to iron-dependent, specialized, and regulated-necrosis mediated by lipid peroxidation, which is closely related to a variety of diseases, including cancer. Tumor cells undergo extensive changes in lipid metabolism, including lipid peroxidation and ferroptosis. Changes in lipid metabolism are critical for the regulation of ferroptosis and thus have important roles in cancer therapy. In this review, we introduce the characteristics of ferroptosis and briefly analyze the links between several metabolic mechanisms and ferroptosis. The effects of lipid peroxides, several signaling pathways, and the molecules and pathways involved in lipid metabolism on ferroptosis were extensively analyzed. Finally, our review highlights some ferroptosis-based treatments and presents some methods and examples of how these treatments can be combined with other treatments.

Analysis of genomes and transcriptomes of clear cell renal cell carcinomas identifies mutations and gene expression changes in the TGF-beta pathway.

The occurrence of clear cell renal cell carcinoma (ccRCC) is related to changes in the transforming growth factor-ß (TGF-ß) signaling pathway. In this study, we adopted an integrated approach to identify and verify the effects of changes in this pathway on ccRCC and provide a guide for identifying new therapeutic targets. We performed transcriptome analysis of 539 ccRCC cases from The Cancer Genome Atlas (TCGA) and divided the samples into different TGF-ß clusters according to unsupervised hierarchical clustering. We found that 76 of the 85 TGF-ß pathway genes were dysregulated, and 55 genes were either protective or risk factors affecting the prognosis of ccRCC. The survival time of patients with tumors with low TGF-ß scores was shorter than that of patients with tumors with high TGF-ß scores. The overall survival (OS) of patients with ccRCC with high TGF-ß scores was better than that of patients with low TGF-ß scores. The TGF-ß score correlated with the expression of key ccRCC and deacetylation genes. The sensitivity of tumor patients to targeted drugs differed between the high and low TGF-ß score groups. Therefore, a prognostic model based on the TGF-ß gene pathway can predict the prognosis of ccRCC patients. Grouping patients with ccRCC according to their TGF-ß score is of great significance for evaluating the prognosis of patients, selecting targeted drugs, and identifying new therapeutic targets.

The potential value of cuprotosis (copper-induced cell death) in the therapy of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) accounts for 75% of the total incidence of renal cancer, and every year the number of morbidity and mortality increases, posing a serious threat to public health. The current main treatment methods for kidney cancer include drug-targeted therapy and immunotherapy. Although there are many treatment options for kidney cancer, they all have limitations, including drug resistance, unsatisfied long-term benefits, and adverse effects. Therefore, it is crucial to identify more effective therapeutic targets. As a newly discovered mechanism of cell death, copper-induced cell death (cuprotosis) is closely related to changes in cell metabolism, particularly in copper metabolism. Current studies have shown that the key signaling pathway of cuprotosis, the FDX1 (Ferredoxin 1)-LIAS (Lipoic Acid Synthetase) axis, plays an important role in the regulation of cellular oxidative stress, which can directly affect cell survival via inducing or promoting cancer cell death. Therefore, we speculated that this regulatory cell death mechanism might serve as a potential therapeutic target for the clinical treatment of renal cancer. To test this, we first performed a pan-cancer analysis based on cuprotosis-related genomic and transcriptomic levels to reveal the expression of cuprotosis in cancer. Next, GSVA-clustering analysis was performed with data from the Cancer Genome Atlas (TCGA) cohort, and the cohort was divided into three clusters according to the gene enrichment levels of cuprotosis marker genes. In addition, we analyzed the potential of using cuprotosis in clinical treatment from multiple perspectives, including chemotherapeutic drug susceptibility test, immune target inhibition treatment responsiveness, and histone modification. Combining the results of multi-omics analysis, we focused on the feasibility of this novel regulatory cell death mechanism in ccRCC treatment and further constructed a prognostic model. Finally, we verified our results by integrating the patient's gene expression information and radiomics information. Our study provides new insights into the development and clinical application of targeting cuprotosis pathway.

Livin-α promotes cell proliferation by regulating G1-S cell cycle transition in prostate cancer.

BACKGROUND: Prostate cancer is the third most common cancer and the second leading cause of cancer death for males in US. Livin has recently been described as a cancer-associated member of inhibitor of apoptosis proteins family, highly expressed in prostate cancer. Livin gene encodes two splicing variants, termed Livin-α and Livin-ß. We hypothesized that deregulation of proliferation could be due in part to Livin expression. METHODS: Pathological analysis of Livin was performed in 20 prostate cancer tissues and 5 benign prostatic hyperplasia tissues. The expression of Livin isoforms was also investigated by Western blot in prostate cancer cell lines LNCaP and PC3. The role of Livin-α in vitro was further studied. Using Livin-α knockdown and overexpression models, cell cycle analysis, Ki-67 immunocytostaining, and MTT assay were performed respectively. RESULTS: Livin expression positive ratio was shown to be 5.4%, 23.6%, 52.4%, 73.4% in benign prostatic hyperplasia, low, medium, and high grade of prostate cancer respectively, and Livin was positively correlated with clinical pathological grades of prostate cancer. Livin-α was expressed in both LNCaP and PC3; meanwhile; Livin-ß was only detected in the PC3. Livin-α siRNA not only resulted in G(1)-S cell cycle arrest, but also strongly correlated with the descended proliferation index and survival rate in LNCaP. In comparison, overexpression of Livin-α resulted in an accelerated S phase entry combined with elevated proliferation index and survival in LNCaP. CONCLUSIONS: Livin-α may promote cell proliferation by regulating G(1)-S cell cycle transition and possibly play an important part in initiation of prostate cancer.