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Immunotherapy has emerged as a vital component in the contemporary landscape of cancer treatment. Recent studies have indicated that CEP55 plays an oncogenic role; however, its specific mechanisms in promoting tumor proliferation and its potential value in prognosis and immunotherapy prediction across various cancers remain to be elucidated. CEP55 was significantly overexpressed in 22 cancer types compared with their adjacent normal tissues. Elevated CEP55 expression was positively correlated with younger onset age, worse tumor stage, lower response rate to the first treatment, lower tumor-free survival rate, and poorer overall survival (OS) and disease-free survival (DFS) prognosis in most cancers. Moreover, CEP55 expression was positively correlated with its binding and related genes, such as KIF11 (R = 0.83, P < 0.001), CDK1 (R = 0.77, P < 0.001) and CCNA2 (R = 0.76, P < 0.001), and the classic proliferation markers, including MKI67 and PCNA. Enrichment analyses indicated that CEP55 was predominantly associated with cell division, cell cycle activities and proliferation. Immune cell infiltration analysis by TIMER2.0 revealed that CEP55 expression was positively correlated with many kinds of infiltrating cells, such as Th2 cells and some CD4 + T cell subsets. The CEP55 expression was positively associated with increased MSI and TMB in various cancers. Our analyzation indicated that the CEP55 expression level in patients with complete remission (CR) or partial remission (PR) to anti-PDL1 therapy was significantly higher than patients with stable disease (SD) or progressive disease (PD) based on IMvigor210 cohort. We also used Gene Set Cancer Analysis (GSCA) to predict a serious of small molecule CEP55 targeted drugs, such as AZ628, SB52334, SB590885, A-770,041, AZD7762, Elesclomol, panobinostat, BRD-A94377914, and LRRK2-IN-1. Furthermore, the patients with high level of CEP55-posivie tumor epithelial cells had inferior overall survival in ccRCC according to single-cell analysis. Finally, our wet lab experiments verified that the CEP55-positive rate in ccRCC tissues (19/30, 63.3%) was significantly higher than that in renal adjacent tissues (10/30, 33.3%). The clinicopathologic analysis revealed that CEP55 protein level was significantly associated with tumor size (P = 0.044), histology grade (P < 0.001) and stage (P = 0.034). Our study indicated that CEP55 overexpression in most caner types was associated with poor prognosis. Notably, CEP55 was closely relevant to immune cell infiltration and impacted the response to immunotherapy and small molecule drugs against cancers., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Clear cell renal cell carcinoma (ccRCC), a predominant form of urinary malignancy, requires the identification of reliable biomarkers to enhance both prognostic outcomes and therapeutic developments specific to ccRCC. NSUN5, a member of the NOL1/NOP2/SUN domain (NSUN) family, plays a critical role in RNA stabilization and exhibits widespread expression across various tumor types. However, the exact function of NSUN5 in ccRCC remains insufficiently understood. Data were collated from cohorts of ccRCC patients who underwent nephrectomy, including those from the Cancer Genome Atlas (TCGA) and the Sun Yat-sen University Cancer Center (SYSUCC), to evaluate the clinical relevance of NSUN5. Integrative models based on NSUN5 expression were subsequently developed to predict the prognosis of ccRCC within the TCGA and SYSUCC cohorts. Furthermore, the impact of NSUN5 on RCC cells and its association with cellular senescence were corroborated through in vitro experimental analyses. NSUN5 exhibited elevated expression in both ccRCC patients and renal cancer cell lines, whose upregulation significantly correlated with age, tumor size, TNM stage, WHO/International Society of Urological Pathology (ISUP) grade, presence of necrosis, and a poor prognosis. An accessible nomogram, incorporating NSUN5 along with various clinicopathological parameters, was adept at predicting outcomes for ccRCC patients. Additionally, in vitro findings indicated that reduced expression of NSUN5 enhanced tumor cell senescence and simultaneously inhibiting cell proliferation and migration. These observations suggest that elevated NSUN5 expression is linked to poorer overall survival (OS) and progression-free survival (PFS), positioning NSUN5 as a viable diagnostic and prognostic biomarker in ccRCC., Competing Interests: Declarations Competing interests The authors have no relevant financial or non-financial interests to disclose. The authors declare no competing interests. Ethical approval This study has been approved by the Institute Research Medical Ethics Committee of Sun Yat-sen University Cancer Center. (Document: SL-B2022-288-01) Consent to participate Our research is not involving human subjects, so informed consent was not written. Consent to publish Our manuscript contains any individual person’s data in any form., (© 2024. The Author(s).)

Background: Clear cell renal cell carcinoma (ccRCC) remains a deadly disease with a poor prognosis. Here, we identified the ETS homologous factor (EHF) and its target Filamin-B (FLNB) as molecules related to immune evasion in ccRCC. We also explored the upstream modifier that manipulates EHF in ccRCC., Design: Cell proliferation and apoptosis assay, wound healing assay, and Transwell assay were designed to analyze the effects of EHF or FLNB knockdown on the biological activity of ccRCC cells. The growth of differently treated ccRCC cells was assessed by orthotopic tumors. ccRCC cells with different treatments were co-cultured with macrophages, and the role of the lysine-specific demethylase 5B (KDM5B)/EHF/FLNB axis on macrophage polarization or ccRCC progression was characterized by detecting the expression of M2 macrophage markers in the co-culture system or tumor tissues of tumor-bearing mice., Results: The expression of EHF and FLNB was higher, while KDM5B was lower in HK2 cells than in ccRCC cells. EHF overexpression inhibited the biological behavior of ccRCC cells and tumor growth in mice. EHF activated FLNB transcription. Knockdown of FLNB supported the biological activity of ccRCC cells and tumor growth and reversed M2 macrophage polarization in tumor tissues of mice in the presence of EHF. KDM5B inhibited EHF expression by H3K4me3 demethylation, and EHF knockdown potentiated M2 macrophage polarization and tumor growth in vivo repressed by KDM5B knockdown., Conclusions: KDM5B inhibited the expression of EHF by repressing H3K4me3 modification and the transcription of FLNB by EHF to promote immune evasion and progression of ccRCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Renal cell carcinoma (RCC) represents a significant portion of genitourinary cancers, marked by challenging prognosis and high metastasis rates. Immunotherapy has been applied in managing advanced renal cell carcinoma, but the therapeutic outcomes are unsatisfactory. In this study, we order to construct a Janus kinase/signal transduction and activator transcriptional (JAK/STAT)-related signature linked to kidney patient outcomes for better predicting the efficacy to immune checkpoint inhibitors (ICIs) and to provide guidance for effective combination therapy. We screened 25 differentially expressed genes (DEGs) that exhibited high expression in RCC samples and were enriched in the JAK-STAT signaling pathway. Among these genes, 11 key genes were identified and correlated with the expectation of Kidney Clear Cell Carcinoma (KIRC) patients and all these genes was significantly elevated in RCC tumor tissues and cancer cells compared to para-cancer tissues and normal renal cells. Utilizing these 11 genes, we divided RCC patients into high-risk and low-risk groups. We found a clear correlation between the clinicopathologic factors of KIRC patients and the JAK-STAT-related risk score. And the IHC results shown that the JAK3 and STAT4 expression of tumor was significantly higher than normal tissue in RCC patients, the level of JAK3 and STAT4 was positively related to the T stage of RCC patients. In addition, high-risk patients had a poorer prognosis and greater protumor immune cell infiltration, and benefitted less from immunotherapy than did low-risk patients. Furthermore, the JAK-STAT-related risk score can predict disease-free survival (DFS) in RCC patients according to the nomogram, which constructed in combination with other clinical features such as age, TNM-staging and stage. Our study demonstrated the JAK-STAT signaling pathway's important regulatory function in RCC tumor immunity. This insight not only enhances our ability to accurately predict the survival rate of RCC patients, but also underscores a potential therapeutic alternative for RCC, involving the combined targeting of the JAK-STAT pathway and immune checkpoints., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

dCTP pyrophosphatase 1 (DCTPP1) is widely expressed in tumors and the immune system and plays a critical role in human cancer progression. However, multi-omics characterization of DCTPP1 and its role in prognosis and immune microenvironment of tumor patients has not been explored. We collected data from 33 cancers and comprehensively analyzed the aberrant expression, prognostic role, pathway enrichment, immune microenvironment, and association with drug sensitivity of DCTPP1 in cancers, as well as the prediction of patients' immunotherapeutic response to ICIs and targeted small molecule drugs. Finally, we experimentally confirmed the role of DCTPP1 in renal clear cell carcinoma. We discovered that DCTPP1 has a differentiable expression and a diagnostic biomarker significance in cancer. Additionally, we discovered that DCTPP1 is important for the tumor microenvironment and pan-cancer. TMB and MSI are frequent immunological checkpoints that are significantly correlated with DCTPP1 expression. Patients who express high levels of DCTPP1 have greater rates of survival and therapeutic response following immunotherapy. Ultimately, it was discovered that renal clear cell carcinoma cells' invasion and proliferation were suppressed by DCTPP1 knockdown. Our findings demonstrate the significant potential of DCTPP1 as a biomarker for prognosis and immunotherapeutic response, which may pave the way for more investigation into the mechanism of tumor infiltration and DCTPP1's potential for cancer therapy., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The crosstalk between cuproptosis and the tumor immune microenvironment (TIME) is vital during clear cell renal cell carcinoma (ccRCC) malignant progression. However, the underlying molecular mechanisms regulate this cross-talk remain elusive. Through tailored machine learning, we analyze clinical ccRCC data from The Cancer Genome Atlas (TCGA) to explore the critical factors that regulate the interaction among cuproptosis, TIME, and tumor progression. We found that rhomboid-like 2 (RHBDL2), critical gene affecting this process, might inhibit cuproptosis-related genes (CRGs) and promotes ccRCC progression through the Wnt/β-catenin pathway. Next, knocking down RHBDL2 expression increased the cuproptosis-related genes ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS) levels but reduced forkhead box P3 (FOXP3) levels and tumor growth in vivo and in vitro models. By employing HLY78, Wnt/β-catenin pathway activator, we rescued the expression of CRGs and the malignant proliferation and metastasis capacity in ccRCC cells with RHBDL2 knockdown. Mechanistically, RHBDL2 inhibits cuproptosis and promotes malignant progression of ccRCC through the Wnt/β-catenin pathway. Abnormal RHBDL2 expression may cause the suppressive TIME formation by regulating Treg-cell infiltration, thus triggering immune escape. In summary, our results indicated that RHBDL2 is an oncogene that induces tumorigenesis and targeting RHBDL2 may be novel therapeutic direction for metastatic ccRCC., (© 2024. The Author(s).)

Clinically, the body mass index remains the most frequently used metric of overall obesity, although it is flawed by its inability to account for different adipose (i.e., visceral, subcutaneous, and inter/intramuscular) compartments, as well as muscle mass. Numerous prior studies have demonstrated linkages between specific adipose or muscle compartments to outcomes of multiple diseases. Although there are no universally accepted standards for body composition measurement, many studies use a single slice at the L3 vertebral level. In this study, we use computed tomography (CT) studies from patients in The Cancer Genome Atlas (TCGA) to compare current L3-based techniques with volumetric techniques, demonstrating potential limitations with level-based approaches for assessing outcomes. In addition, we identify gene expression signatures in normal kidney that correlate with fat and muscle body composition traits that can be used to predict sex-specific outcomes in renal cell carcinoma., (© 2024. The Author(s).)

The present study investigated the Zinc finger BED-type containing 3 (ZBED3) mRNA expression levels, diagnostic and prognostic values, co-expressed and differentially expressed genes, immune infiltration, and functional enrichment analysis in patients with kidney renal clear cell carcinoma (KIRC) using various public databases such as The Cancer Genome Atlas, Genotype-Tissue Expression Project, LinkedOmics, Gene Set Enrichment Analysis databases, and the Xiantao academic tool. Through extensive data mining, our study revealed differential expression of ZBED3 in various tumor and paired normal tissues. Specifically, ZBED3 expression was found to be significantly decreased in KIRC, particularly in advanced pathologic stages and histologic grades, when compared to corresponding control tissues. Our analysis revealed that the overexpression of ZBED3 is associated with a favorable overall survival outcome in KIRC patients. Moreover, functional enrichment analysis identified key pathways related to inflammation response and DNA methylation of ZBED3 in KIRC. Additionally, our findings suggest that the upregulation of ZBED3 leads to the inhibition of cell proliferation by modulating cell-cycle progression in KIRC cell lines. Taken together, these results suggest that ZBED3 may serve as a promising biomarker and prognostic indicator for individuals diagnosed with KIRC., (© 2024. The Author(s).)

Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy characterized by dysregulated cellular metabolism leading to aberrant glucose metabolism, fatty acid accumulation, and excessive reactive oxygen species production. ccRCC cells exhibit an augmented oxidative stress response. Complex interactions between iron metabolism and lipid homeostasis in ccRCC cells require a counteracting response that enables ferroptosis evasion and survival maintenance. Additionally, abnormal GA-binding protein transcription factor subunit alpha (GABPA) expression is associated with ccRCC occurrence and development, but its impact on ferroptosis-related molecular mechanisms remains unclear. Herein, we examined the impact of the GABPA-ACSL4 pathway on ferroptosis in ccRCC through bioinformatics analysis, as well as in vitro and in vivo experiments. In contrast to that in adjacent normal tissues, GABPA expression was significantly downregulated in ccRCC tissues, and this downregulation was linked to poor overall survival. Increased GABPA expression suppressed ccRCC cell proliferation, migration, and invasion. Moreover, GABPA overexpression increased the susceptibility of ccRCC cells to ferroptosis. Additionally, GABPA directly bound to the promoter region of ACSL4, promoting ferroptosis. Thus, inducing the GABPA-ACSL4 pathway activates ferroptosis, inhibits proliferation or metastasis, and exerts anticancer activity in ccRCC. These findings have important implications for regulating ccRCC occurrence and development., (© 2024. The Author(s).)

The tumour immunological microenvironment is involved in the development of clear cell renal cell carcinoma (ccRCC). Nevertheless, the role of the immunological microenvironment in ccRCC has not been thoroughly investigated. In this study, we combined six ccRCC cohorts into a large cohort and quantified the expression matrix into 53 immunological terms using the ssGSEA algorithm. Five immune terms related to prognosis were screened through 1000 iterations of L1-penalised (lasso) estimation and Cox regression analysis for immune-related risk score (IRS) calculation. The IRS showed satisfactory prognosis prediction efficacy in ccRCC. We then compared the clinical and genomic characteristics of two IRS subgroups. Patients with low IRS showed a high level of tumour mutational burden (TMB) and a low level of copy number variation (CNV), indicating that low IRS group patients have a higher probability of responding to immunotherapy. We employed TIDE and subclass mapping analyses to corroborate our results, and the findings demonstrated that patients with a low IRS had a significantly greater percentage of immunotherapy response. According to the Genomics of Drug Sensitivity in Cancer (GDSC), patients with a high IRS had a decreased IC50 for sunitinib, which is the first-line treatment for ccRCC patients. As a result, the immune characteristics of the microenvironment of ccRCC tumours have been explored, and a signature has been constructed. Analysis demonstrated that our signature could effectively predict prognosis and immunotherapy response rate., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objectives: To analyze the diagnostic and prognostic potential of the BOLA gene family in kidney renal clear cell carcinoma (KIRC)., Methods: This study is an observational study. The whole study was carried out at Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia from January to November 2023. As it involves in silico and in vitro methods, ethical consent was not required. Various in silico and molecular experimental techniques were employed in this study., Results: Significant up-regulation and hypomethylation of BOLA1, BOLA2, and BOLA3 were observed across 12 KIRC cell lines. Retrospective analysis of the cancer genome atlas program (TCGA)-KIRC cohorts confirmed hypomethylation of these genes in KIRC tissues. The cBioPortal analysis showed minimal genetic alterations, with amplification being the most common. Kaplan-Meier plotter data revealed that high BOLA1, BOLA2, and BOLA3 expression correlated with shorter overall survival and relapse-free survival in KIRC. Tumor-immune system interactions database analysis linked BOLA1 expression to immune and molecular subtypes. Gene silencing of BOLA1, BOLA2, and BOLA3 in 786-0 cells reduced cell growth and proliferation, enhancing wound healing capacity., Conclusion: BOLA genes may serve as diagnostic and prognostic markers in KIRC, offering insights into therapeutic targets and disease progression., (Copyright: © Saudi Medical Journal.)

Background/aim: Renal cell carcinoma (RCC) is highly heterogeneous, with distinct patient management between clear cell RCC (ccRCC) and non-ccRCC groups. Previous bioinformatics and machine learning techniques identified fatty acid binding protein 7 (FABP7) as a potential ccRCC biomarker. However, FABP7 expression studies between ccRCC and non-ccRCC were incomplete. This study aimed to assess FABP7 as a biomarker for distinguishing between ccRCC and non-ccRCC tissue samples., Patients and Methods: FABP7 expression was evaluated via immunohistochemical staining in 58 RCC cases, including 43 ccRCC and 15 non-ccRCC cases. Staining results were interpreted using H-scores; scores above the cut-off were deemed positive. The correlation between FABP7 expression and clinicopathological RCC features was investigated., Results: FABP7 positivity was 48.8% in ccRCC and only 13.3% in non-ccRCC cases, with weak positivity in non-ccRCC tissues. FABP7 expression significantly differed between ccRCC and non-ccRCC (p<0.05). This finding was confirmed in a TCGA dataset. However, FABP7 expression was not correlated with other RCC clinicopathological features in our dataset. TCGA results linked FABP7 expression to tumor stage and disease-free survival in patients with ccRCC., Conclusion: This study preliminarily evaluated FABP7 as a differential diagnostic biomarker in RCC subtyping, showing higher expression in ccRCC than non-ccRCC. FABP7 may serve as a potential diagnostic and prognostic biomarker for ccRCC., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, accounting for approximately 75% of kidney cancers. The objective of this study was to identify novel progression markers for ccRCC based on proteomics, with the goal of stage determination and early diagnosis of kidney cancer patients., Materials and Methods: We performed quantitative global proteomics coupled with Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and high-resolution tandem mass spectrometry on kidney-derived cells, including HEK-293, 786-O (primary ccRCC), and Caki-1 (metastatic ccRCC) cells, to investigate the novel progression factors of ccRCC., Results: In this study, a total of 1,106 proteins were quantified. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted for differentially expressed proteins (DEPs) that were increased in ccRCC cells compared to HEK-293 cells. Ultimately, 99 DEPs including 75 up-regulated and 24 down-regulated proteins, that were significantly altered in both ccRCC cells, were identified. Among DEPs, vimentin was identified as the most significantly changed protein. Its increased expression in ccRCC was verified through immunoblotting in ccRCC cell lines and immunohistochemistry in kidney tumors., Conclusion: From the global proteomics data detected in ccRCC, we propose 99 DEPs including vimentin as progression factors., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Alternative pre-mRNA splicing (AS) is a biological process that results in proteomic diversity. However, implications of AS alterations in cancer remain poorly understood. Herein, we performed a comprehensive AS analysis in cancer driver gene transcripts across fifteen cancer types and found global alterations in inclusion rates of the PBAF SWI/SNF chromatin remodeling complex subunit Polybromo 1 (PBRM1) exon 27 (E27) in most types of cancer tissues compared with those in normal tissues. Further analysis confirmed that PBRM1 E27 is excluded by the direct binding of RBFOX2 to intronic UGCAUG elements. In addition, the E27-included PBRM1 isoform upregulated PD-L1 expression via enhanced PBAF complex recruitment to the PD-L1 promoter. PBRM1 wild-type patients with clear cell renal cell carcinoma were resistant to PD-1 blockade therapy when they expressed low RBFOX2 mRNA levels. Overall, our study suggests targeting of RBFOX2-mediated AS of PBRM1 as a potential therapeutic strategy for immune checkpoint blockade., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests., (© 2024. The Author(s).)

The prognostic value of Runt-related transcription factor 2 (Runx2) and its involvement in cell growth and motility have been reported in patients diagnosed with renal cell carcinoma (RCC). Since Runx2 may have the potential to be a target for the purpose of antitumor intervention, there is an urgent need to gain insight into its oncogenic properties. Using human 786-O, Caki-1 and ACHN RCC cells as models, the silencing of cellular Runx2 expression brought about a reduction in cyclin D1 and β-catenin expression, cell growth and migration without any significant cell death. Runx2-silenced cells turned into apoptosis vulnerable in the presence of ABT-737, a BH3 mimetic Bcl-2 inhibitor. Data from biochemical and molecular studies have revealed a positive correlation between Runx2 expression and Akt phosphorylation, Mcl-1 expression, and fibronectin expression. Results of genetic silencing studies have indicated the potential involvement of Mcl-1 and fibronectin in the decision of RCC cell ABT-737 resistance and sensitivity. The regulatory roles of the PI3K/Akt axis in the expression of Mcl-1 and fibronectin were suggested by means of the results taken from experiments involving pharmacological study of the PI3K/Akt. Since overexpression and prognostic roles of Runx2, activated Akt, Mcl-1, fibronectin, cyclin D1, and β-catenin have been revealed in RCC, it is important to explore the precise mechanisms underlying Runx2 oncogenic effects. Although the linking details between Runx2 and PI3K/Akt have yet to be identified, our findings suggest that Mcl-1 and fibronectin are downstream effectors of Runx2 via a regulatory axis of the PI3K/Akt and their promotion of cell growth, migration, and ABT-737 resistance in RCC cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Renal cell carcinoma (RCC) is one of the most frequent urological cancers globally that has a good prognosis in the early tumor stages. However, there is a poor prognosis in metastatic RCC patients. Therefore, it is needed to evaluate the molecular biology of RCC progression to introduce the efficient diagnostic and therapeutic markers in these patients. Long non-coding RNAs (lncRNAs) have key roles in regulation of molecular mechanisms during RCC progression. In the present study, we assessed the levels of LINC00365 expressions in RCC patients to suggest that as a tumor marker in these patients., Methods: Fifty fresh RCC tumor tissues and their normal margins were collected to assess the levels of LINC00365 expressions and probable correlations with clinicopathological features of RCC patients., Results: There was significant LINC00365 up regulation in females compared with males (p=0.050). Among the RCC patients with total nephrectomy, there was a significant LINC00365 up regulation in advanced stage compared with primary stage tumors (p=0.035). RCC patients older than 60 years old who were undergone the total nephrectomy had also significant LINC00365 up regulation compared with RCC patients younger than 60 years old (p=0.039)., Conclusions: given the significant increase in LINC00365 expression in advanced stage RCC tumors and patients over 60 years old who had total nephrectomy; it could serve as a useful diagnostic marker in screening programs for old high-risk individuals. It was also noticed that female RCC patients had elevated levels of LINC00365 expressions in their tumor samples, suggesting its potential use as a gender-specific diagnostic marker for high-risk females. Nevertheless, evaluating the levels of LINC00365 in serum samples of RCC patients is necessary to suggest that as a reliable diagnostic marker in clinical settings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Over the past decade, the realm of immunotherapy-based combination therapy has witnessed rapid growth for renal cell carcinoma (RCC), however, success has been constrained thus far. This limitation primarily stems from the absence of biomarkers essential for identifying patients likely to derive benefits from such treatments., Methods: In this study, the immunotherapy-based combination associated score (IBCS) was established using single-sample gene set enrichment analysis (ssGSEA) based on the genes identified in the key modules extracted by weighted correlation network analysis (WGCNA) in the IMmotion151 dataset, a randomized, global phase III trial., Results: High IBCS patients showed better responses to immunotherapy-based combinations and had longer progression-free survival (PFS). Further transcriptomic analysis revealed that IBCS was negatively correlated to TIDE score, identifying a subset of RCC patients characterized by enrichment of T-effector and moderate cell-cycle/angiogenesis gene expression. Our analysis of hub genes unveiled a novel molecule that could potentially serve as a target antigen in RCC. Validation through multiplex immunofluorescence assays on tissue microarrays (TMAs) containing 180 samples confirmed the pivotal role of this hub gene in immunoregulation. Furthermore, we developed an independent risk score model, which is significant for prognostic evaluation and patient stratification. Notably, we devised a forecasting nomogram using this risk score model, surpassing the IMDC score (a widely accepted risk score for predicting survival in patients undergoing VEGF-targeted therapy) in prognostic accuracy for patients treated with immunotherapy-based combinations., Conclusion: This study has collectively developed an immunotherapy-based combination associated score, pinpointed effective biomarkers for prognostic and responsiveness of kidney cancer patients to immunotherapy-based combinations, and delved into their potential biological mechanisms, offering promising targets for further exploration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: With the development of modern medicine and the application of multimodal treatment strategies, the survival rate after childhood malignant tumors as well as the incidence of Secondary malignant neoplasm (SMN) have increased. Case report: Patient is a Chinese girl. Initially diagnosed with Wilms tumor affecting her left kidney at the age of 6, she was later found to have TFE3 -rearranged renal cell carcinoma (rRCC) affecting her right kidney at the age of 12. Employing NGS technology on specimens obtained from the TFE3 -rRCC, we uncovered a significant somatic mutation within PRSS8 gene. This discovery sheds new light on the intricate genetic landscape underlying her condition, paving the way for further exploration and personalized treatment strategies. Conclusion: We consider that the etiology of SMN may be the result of chemoradiotherapy.

Background: Different individuals with renal cell carcinoma (RCC) exhibit substantial heterogeneity in histomorphology, genetic alterations in the proteome, immune cell infiltration patterns, and clinical behavior., Objectives: This study aims to use single-nucleus sequencing on ten samples (four normal, three clear cell renal cell carcinoma (ccRCC), and three chromophobe renal cell carcinoma (chRCC)) to uncover pathogenic origins and prognostic characteristics in patients with RCC., Methods: By using two algorithms, inferCNV and k-means, the study explores malignant cells and compares them with the normal group to reveal their origins. Furthermore, we explore the pathogenic factors at the gene level through Summary-data-based Mendelian Randomization and co-localization methods. Based on the relevant malignant markers, a total of 212 machine-learning combinations were compared to develop a prognostic signature with high precision and stability. Finally, the study correlates with clinical data to investigate which cell subtypes may impact patients' prognosis., Results & Conclusion: Two main origin tumor cells were identified: Proximal tubule cell B and Intercalated cell type A, which were highly differentiated in epithelial cells, and three gene loci were determined as potential pathogenic genes. The best malignant signature among the 212 prognostic models demonstrated high predictive power in ccRCC: (AUC: 0.920 (1-year), 0.920 (3-year) and 0.930 (5-year) in the training dataset; 0.756 (1-year), 0.828 (3-year), and 0.832 (5-year) in the testing dataset. In addition, we confirmed that LYVE1 + tissue-resident macrophage and TOX + CD8 significantly impact the prognosis of ccRCC patients, while monocytes play a crucial role in the prognosis of chRCC patients., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a newly defined, rare subtype of renal cancer, associated with pathogenic variations in the Succinate Dehydrogenase Subunit B (SDHB) gene. Our aim is to investigate the imaging findings of SDHB-associated renal tumors, utilizing cross-sectional and FDG-PET imaging in patients with pathogenic variations in SDHB gene, to facilitate accurate tumor characterization., Methods: Twenty SDH-deficient tumors from 16 patients with pathogenic variations in SDHB gene were retrospectively evaluated using cross-sectional and FDG-PET imaging. Clinical findings such as demographics, family history, extra-renal findings and metastases were recorded. Tumor imaging characteristics on CT/MRI included were laterality, size, homogeneity, morphology, margins, internal content, T1/T2 signal intensity, enhancement features, and restricted diffusion., Results: Sixteen patients (median age 31 years, IQR 19-41, 8 males) were identified with 68.8 % of patients having a known family history of SDHB variation. 81.3 % of lesions were solitary and majority were solid (86.7 % on CT, 87.5 % on MRI) with well-defined margins in >62.5 % of lesions, without evidence of internal fat, calcifications, or vascular invasion. 100 % of lesions demonstrated restricted diffusion and avid enhancement, with degree >75 % for most lesions on CT and MRI. On FDG-PET, all renal masses showed increased radiotracer uptake. 43.8 % of patients demonstrated extra-renal manifestations and 43.8 % had distant metastasis., Conclusion: SDHB-associated RCC is predominantly noted in young patients with no gender predilection. On imaging, SDH-deficient RCC are frequently unilateral, solitary, and solid with well-defined margins demonstrating avid enhancement with variability in enhancement pattern and showing restricted diffusion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Clear cell renal cell carcinoma (ccRCC) represents a highly heterogeneous kidney malignancy associated with the poorest prognosis. The metastatic potential of advanced ccRCC tumors is notably high, posing significant clinical challenges. There is an urgent imperative to develop novel therapeutic approaches to address ccRCC metastasis. Recent investigations indicated a potential association between GBP2 and tumor immunity. However, the precise functional role of GBP2 in the progression of ccRCC remains poorly understood. The present study revealed a strong correlation between GBP2 and M2 macrophages. Specifically, our findings demonstrated that the inhibition of GBP2 significantly impedes the migratory and invasive capabilities of ccRCC cells. We observed that the presence of M2 macrophages can reverse the effects of GBP2 knockdown on tumor cell migration and invasion. Mechanistically, we demonstrated that M2 macrophages promote the expression of the GBP2/p-STAT3 and p-ERK axis in tumor cells through the secretion of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), thereby substantially enhancing the migratory and invasive capacities of the tumor cells. Simultaneously, we have identified that GBP2 promotes the polarization of macrophages to the M2 phenotype by stimulating the secretion of interleukin-18 (IL-18). In summary, our investigation anticipates that the GBP2/IL-18/M2 macrophages/IL-10 and the TGF-β/GBP2, p-STAT3, p-ERK loop plays a crucial role in ccRCC metastasis. The collective findings from our research underscore the significant role of GBP2 in tumor immunity and emphasize the potential for modulating GBP2 as a promising therapeutic strategy for targeting ccRCC metastasis., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel-Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer., (© 2024. Springer Nature Limited.)

Clear cell renal carcinoma (ccRCC) is one of the cancers that posed a severe threat to human life on a global scale. The ADAMTS family has been proven to be involved in a number of tumor types, although it is yet unknown how they relate to ccRCC. The mRNA expression matrix and other clinically relevant information of 607 ccRCC were sourced from TCGA database. The role of ADAMTS family genes in ccRCC was determined by differential gene expression analysis and gene set enrichment analysis (GSEA). Employing stage grading, gene mutation, and survival analysis, the genes most linked to the prognosis of ccRCC were identified. The influence of genes on the pathway was determined by Kyoto Encyclopedia of Genes and Genes (KEGG) analysis. Following that, the gene's impact on ccRCC was verified by qRT-PCR, WB, MTT, Transwell detection, and a wound healing assay. Bioinformatics analysis showed that ADAMTS10 was overexpressed in cancerous tissues of people with ccRCC and its expression increased with tumor grade. Mutation analysis showed that the main cause of mutation in the ADAMTS family gene was amplification. The prognosis and survival of the ADAMTS10 elevated expression group were lower than those of the poorly expressed group, as demonstrated by a survival analysis. On the basis of the findings of MRI, we examined 60 clinical patients and collected their cancer along with the surrounding tissues. The results of qPCR detection showed that the expression of ADAMTS10 was considerably higher in cancerous regions of 60 clinical users than it was in the tissues nearby. Inhibiting ADAMTS10 development prevents cancer cells from proliferating, invading, and migrating. The KEGG analysis links ADAMTS10 to the NF-κB signal pathway. WB experiment confirmed that inhibiting ADAMTS10 expression can inhibit the activation of the NF-κB signal pathway. ADAMTS10 may be a promising prognostic marker for ccRCC that can be employed independently., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The tumor suppressor gene BRCA1 associated protein-1 (BAP1) is frequently mutated in renal cell carcinoma (RCC). BAP1 loss-of-function mutations are associated with poor survival outcomes. However, personalized therapy for BAP1-mutated RCC is currently not available. Previously, we found that BAP1 loss renders RCC cells more sensitive to bromodomain and extra-terminal (BET) inhibitors, as demonstrated in both cell culture and xenografted nude mice models. Here, we demonstrate that BAP1 loss in murine RCC cells enhances sensitivity to BET inhibitors in ectopic and orthotopic allograft models. While BAP1 deletion suppresses RCC cell survival in vitro , it does not impede tumor growth in immunocompetent murine models. Thus, the effect of BAP1 loss on the interactions between tumor cells and host microenvironment plays a predominant role in RCC growth, highlighting the importance of utilizing immunocompetent animal models to assess the efficacy of potential anticancer therapies. Mechanistically, BAP1 deletion compromises DNA repair capacity, rendering RCC cells more vulnerable to DNA damage induced by BET inhibitors. Our results indicate that BET inhibitors show promise as targeted therapy for BAP1-deficient RCC., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.

Purpose: This study explores the role of circular RNA derived from the Multidrug Resistance Protein 4 (MRP4/ABCC4) gene, which is markedly elevated in renal cell carcinoma (RCC). Our objective is to clarify how this circular RNA contributes to the progression and development of RCC., Methods: We quantified the presence of circular ABCC4 RNA in tissue samples, plasma and urine from patients diagnosed with RCC. In addition, the impact of this circular RNA on RCC tumour growth was assessed through studies in RCC cell lines and in animal models mimicking the disease., Results: Our findings reveal that circular ABCC4 RNA, specifically the variant containing exons 25-29 (circABCC4e), is upregulated in RCC cell lines and tissues. This upregulation correlates with advanced tumor stages in RCC patients, suggesting circABCC4e's potential as a biomarker for RCC progression. Furthermore, the reduction in circABCC4e levels following tumor resection indicates its potential utility in monitoring treatment response. The mechanism by which circABCC4e promotes RCC tumor growth through the antagonism of tumor-suppressive microRNAs highlights its significance in RCC pathogenesis. These insights may inform the development of diagnostic and therapeutic strategies for RCC., Conclusion: This study demonstrates that circABCC4e accelerates RCC progression by inhibiting tumor-suppressive microRNAs. Its role as a diagnostic and prognostic biomarker for RCC underscores its potential value in improving RCC management., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To investigate the impact of TFE3 rearrangement, analyzing clinicopathological features that influence renal cell carcinoma (RCC) recurrence, and clarify the role of immunohistochemistry (IHC) staining in diagnosis., Methods: We screened patients diagnosed of clear cell RCC (ccRCC), fluorescence in situ hybridization (FISH) was performed on all TFE3 positive IHC tumors. Clinicopathological and survival features were collected for analysis., Results: Out of 695 patients treated for renal tumors, 478 (68.7%) were ccRCC and 22 were suspected of TFE3 rearrangement based on IHC. Subsequent testing revealed 8 (1.15%) were positive in the FISH test (TFE3-rearranged-RCC) and 14 (2.01%) tested negative. No significant differences were noted in general characteristics among the three groups, except for age, TFE3-rearranged-RCC were younger than ccRCC (median age, 49 vs. 58 years, p=0.02). TFE3-rearranged-RCC exhibited a significant higher recurrence rate compared to ccRCC (50% vs 18.8%) and multivariate analysis revealed that TFE3 rearrangement, along with tumor size and metastasis, was an independent prognostic factor for recurrence (HR=4.6; 95% CI 1.1-21.2; p=0.05). Survival analysis demonstrated a significant shorter PFS (progression-free survival) for TFE3-rearranged-RCC compared to ccRCC., Conclusions: TFE3 rearrangement is an independent prognostic factor for recurrence and contributes to a worse PFS, suggesting the necessity of careful follow-up. Diagnosis should be confirmed using FISH due to low specificity of IHC. Further studies are needed to confirm TFE3 IHC staining as a prognostic factor., (© 2024. The Author(s).)

TGF-β-SMAD signaling pathway plays an important role in the progression of various cancers. However, posttranscriptional regulation such as N 6 -methyladenosine (m 6 A) of TGF-β-SMAD signaling axis remains incompletely understood. Here, we reveal that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) is low expression as well as associated with poor prognosis in clear cell renal cell carcinoma (ccRCC) patients and inhibits proliferation as well as promotes metastasis of ccRCC cells. Mechanistically, IGF2BP2 systematically regulates TGF-β-SMAD signaling family, including TGF-β1/2, TGF-βR1/2 and SMAD2/3/4, through mediating their mRNA stability in an m 6 A-dependent manner. Furthermore, the functional effects of IGF2BP2 on ccRCC cells is mediated by TGF-β-SMAD signaling downstream effector SMAD4, which is identified three m 6 A sites in 5'UTR and CDS. Our study establishes IGF2BP2-TGF-β-SMAD axis as a new regulatory effector in ccRCC, providing new insights for developing novel therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Increasing evidence highlights the important role of ubiquitination in cancer. The objective of our study is to establish a reliable marker for predicting clinical outcomes and treatment responses in patients with clear cell renal cell carcinoma (ccRCC) using genes related to ubiquitination (URGs). The URGs subtypes were identified using consensus clustering based on TCGA-KIRC, and a signature containing the prognostic differentially expressed genes of the subtypes was determined using LASSO and Cox regression analysis. To demonstrate the strength of the signature, verification analyses were performed on both E-MTAB-1980 and TCGA-KIRC test datasets. We developed a nomogram to enhance the effectiveness of our predictive tool. Risk genes expression was determined through RT-qPCR. Six genes were combined to create the URGs signature, which had a highly correlated with patient prognosis in patients with ccRCC. A nomogram was developed based on the URGs signature and clinicopathological characteristics. We found that the predictive power was substantially greater than the other individual predictors. Moreover, the study on the immune microenvironment revealed significant variations in the levels of immune cells and the expression of immune checkpoint genes among the groups categorized as high-risk and low-risk. Furthermore, it was found that immunotherapy yielded better outcomes in cohorts with low risk. The URGs signature might serve as a novel and powerful prognosis biomarker and offer a momentous reference for individualized treatment for patients in ccRCC., (© 2024. The Author(s).)

Background: Renal cell carcinoma (RCC), especially clear cell RCC (ccRCC), significantly impacts health, and results in particularly poor outcomes in patients at the advanced stage. Resistance to vascular endothelial growth factor (VEGF) pathway-targeting tyrosine kinase inhibitors (TKIs) is a major barrier in effective ccRCC treatment. Herein, we aim to explore how decitabine mediates bridging integrator 1 (BIN1) and spectrin repeat containing nuclear envelope protein 1 (SYNE1) to impact resistance of ccRCC to sorafenib., Methods: Employing bioinformatics on datasets GSE64052 and CancerSea, we identified genes linked to TKI resistance, ultimately focusing on SYNE1. We assessed influences of SYNE1 overexpression and BIN1 knockdown via quantitative real-time PCR (qRT-PCR) and Western blot. Assessment of cell viability and apoptosis was accomplished using cell counting kit-8 (CCK-8) assays and flow cytometry. The investigation into the potential interactions between SYNE1 and BIN1, as well as their impacts on sorafenib sensitivity was accomplished by Co-Immunoprecipitation (Co-IP) and Glutathione-S-transferase (GST) Pull-down., Results: SYNE1 was substantially down-regulated in sorafenib-resistant ccRCC cells, and its overexpression increased sorafenib sensitivity, decreased viability and enhanced apoptosis. Interaction between BIN1 and SYNE1 was confirmed, with BIN1 level lower in resistant cells. BIN1 knockdown reduced the beneficial effects of SYNE1 overexpression on sorafenib sensitivity. Decitabine treatment elevated both SYNE1 and BIN1, while boosting apoptosis and reducing sorafenib resistance., Conclusions: SYNE1 contributes to the modulation of sorafenib resistance in ccRCC cells through interacting with BIN1. Decitabine treatment enhances expressions of these two proteins to improve TKI response, suggesting a potential strategy for counteracting resistance and bettering patient outcomes., (© 2024 The Author(s). Published by IMR Press.)

Aggressive clear cell renal cell carcinoma (ccRCC) has a bad prognosis. We seek new ccRCC biomarkers for diagnosis and treatment. We used exoRBase and The Cancer Genome Atlas Database to compare DEmRNAs, DEmiRNAs, DElncRNAs, and DEcircRNAs in ccRCC and normal renal tissues. CircRNAs and circRNAs targeting microRNAs (miRNAs) were anticipated and taken intersections, and several databases assessed the targeted link between common miRNAs and messenger RNAs (mRNAs). The Cancer Genome Atlas database was used to create a predictive mRNA signature that was validated in E-MTAB-1980. Finally, we examined competing endogenous RNA network miRNAs and long noncoding RNAs for ccRCC predictive biomarkers using overall survival analysis. We built the first competing endogenous RNA regulation network of circRNA-lncRNA-miRNA-mRNA and found that it substantially correlates with ccRCC prognosis. We unveiled ccRCC's posttranscriptional regulation mechanism in greater detail. Our findings identified novel biomarkers for ccRCC diagnosis, therapy, and prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The incidence of clear cell renal cell carcinoma (ccRCC) is increasing annually. While the cure rate and prognosis of early ccRCC are promising, the 5-year survival rate of patients with metastatic ccRCC is below 12%. Autophagy disfunction is closely related to infection, cancer, neurodegeneration and aging. Nevertheless, there has been limited exploration of the association between autophagy and ccRCC through bioinformatics analysis., Methods: A novel risk model of autophagy-related genes (ARGs) was constructed to predict the prognosis of patients with ccRCC and guide the individualized treatment to some extent. Relevant data samples were obtained from the TCGA database, and ccRCC-related ARGs were identified by Pearson correlation analysis, leading to the establishment of a risk model covering 10 ccRCC-related ARGs. Many indicators were used to assess the accuracy of the risk model., Results: Receiver operating characteristic (ROC) curve analysis showed that the risk model had high accuracy, indicating that the risk model could predict the prognosis of ccRCC patients. Moreover, the findings revealed significant differences about immune and metabolic features in low- and high-risk groups. The study also found that BAG1 within the risk model was closely related to the prognosis of ccRCC and an independent risk factor. In vitro and in vivo experiments validated for the first time that BAG1 could suppress the proliferation, migration, and invasion of ccRCC., Conclusion: The construction of ARGs risk model, can well predict the prognosis of ccRCC patients, and provide guidance for individual therapy to patients. It was also found that BAG1 has significant prognostic value for ccRCC patients and acts as a tumor suppressor gene in ccRCC. These findings have crucial implications for the prognosis and treatment of ccRCC patients., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glycogen-storing so-called clear cell kidney tubules (CCTs), precursor lesions of renal cell carcinoma, have been described in diabetic rats and in humans. The lesions show upregulation of the Akt/mTOR-pathway and the related transcription factor carbohydrate responsive element binding protein (ChREBP), which is supposedly pro-oncogenic. We investigated the effect of ChREBP-knockout on nephrocarcinogenesis in streptozotocin-induced diabetic and normoglycemic mice. Diabetic, but not non-diabetic mice, showed CCTs at 3, 6 and 12 months of age. Glycogenosis was confirmed by periodic acid schiff reaction and transmission electron microscopy. CCTs in ChREBP-knockout mice consisted of larger cells and occurred more frequently compared to wildtype mice. Progression towards kidney tumors was observed in both diabetic groups but occurred earlier in ChREBP-knockout mice. Proliferative activity assessed by BrdU-labeling was lower in 1-week-old but higher in 12-month-old diabetic ChREBP-knockout mice. Surprisingly, renal neoplasms occurred spontaneously in non-diabetic ChREBP-knockout, but not non-diabetic wildtype mice, indicating an unexpected tumor-suppressive function of ChREBP. Immunohistochemistry showed upregulated glycolysis and lipogenesis, along with activated Akt/mTOR-signaling in tumors of ChREBP-knockout groups. Immunohistochemistry of human clear cell renal cell carcinomas revealed reduced ChREBP expression compared to normal kidney tissue. However, the molecular mechanisms by which loss of ChREBP might facilitate tumorigenesis require further investigation.

Background: von Hippel-Lindau ( VHL ) harbors the highest mutational frequency in clear cell renal cell carcinoma (ccRCC). Although VHL mutational subtypes exert diverse impacts on the functionality of the VHL protein, the clinical significance of VHL mutational heterogeneity remains largely obscure., Methods: This study included a total of 1331 patients with ccRCC from localized data sets, including our localized Zhongshan Hospital (ZSHS) cohort (n=1270) and Zhongshan immune checkpoint blockade cohort (n=61), as well as 525 patients with ccRCC from two publicly available data sets with matched clinical annotation and multidimensional data. According to the putative biological effect, we subclassified VHL mutation into VHL Trunc and VHL Miss . The association of VHL status with clinical outcomes, genomic, oncogenic and immunologic characteristics was further depicted., Results: VHL Miss ccRCC was associated with reduced survival in the localized ZSHS and The Cancer Genome Atlas cohorts. Clinical benefit from immunotherapy was observed in VHL Miss patients in all immunotherapy cohorts. VHL Miss ccRCC exhibited hyper-activated cell cycle and nuclear factor kappa B (NF-κB) instead of canonical hypoxia inducible factor pathways, which might contribute to its proliferative morphology. Meanwhile, VHL Miss ccRCC featured an inflamed microenvironment with enriched tertiary lymphoid structures., Conclusions: VHL Miss mutations delineate an aggressive ccRCC subtype with distinct clinical outcomes, likely attributed to its specific oncogenic, morphologic and immunologic features., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The methyltransferase Wilms' tumor 1-associated protein (WTAP) has been reported to be dysregulated in various tumors. However, its role in renal cell carcinoma (RCC) remains elusive. Here, we explored whether WTAP was upregulated in RCC specimens compared to normal tissues. Functionally, WTAP promoted RCC cell proliferation and metastasis in vivo and in vitro. Mechanistically, WTAP act as an N6-methyladenosine transferase to regulate the m 6 A modification of long noncoding RNA TEX41. Then, the upregulated m 6 A modification destabilized TEX41 in a YTHDF2-dependent manner. Furthermore, TEX41 interacted with the SUZ12 protein and increased the histone methyltransferase activity of SUZ12, resulting in HDAC1 silencing. Totally, our study demonstrated the oncogenic the role of WTAP/TEX41/SUZ12/HDAC1 axis in RCC progression., (© 2024. The Author(s).)

Clear-cell renal cell carcinoma (ccRCC) is the most common origin of pancreatic metastases (PM). Distinct genomic aberrations, favorable prognosis, and clinical observations on high angiogenesis, and succeeding tyrosine kinase inhibitor (TKI) sensitivity have been reported in PM-ccRCC. However, no functional or single-cell studies have been conducted thus far. We recruited five PM-ccRCC patients and investigated the genomic, single-cell transcriptomic, and drug sensitivity profiles of their patient-derived cells (PDCs). The PM depicted both expected and novel genomic alterations. Further, the transcriptomics differed from both primary and metastatic ccRCC, with upregulations of the PI3K/mTOR and - supporting the clinical observations - angiogenesis pathways. Data integration at pathway level showed that transcriptomics explained drug sensitivities the best. Accordingly, PM-ccRCC PDCs shared sensitivity to many PI3K/mTOR inhibitors. Altogether, we show distinct genomic and transcriptomic signatures in PM-ccRCC, highlight the superiority of transcriptomics in interpreting drug sensitivities, and encourage the use of TKIs and PI3K/mTOR inhibitors in PM-ccRCC., (© 2024. The Author(s).)

Background: Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive., Methods: By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays., Results: Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth., Conclusion: Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment., (© 2024. The Author(s).)

Renal cell carcinoma (RCC) has diverse pathological subtypes, most of which have a poor prognosis. Patients with advanced RCC require systemic therapies for disease control. Although targeted therapies and immune checkpoint inhibitors have shown therapeutic efficacy, patients eventually succumb to disease progression. Therefore, additional therapies targeting different pathways are needed to provide more therapeutic options for sequential treatment. Our study explored the biological mechanisms and therapeutic outcomes for NPS-1034, a dual MET/AXL inhibitor, in RCC, both in vivo and in vitro. Our results showed that NPS-1034 can significantly inhibit tumor proliferation and induce cancer cell apoptosis. Besides MET and AXL, known targets of NPS-1034, we identified TNFRSF1A as another target gene inhibited by NPS-1034 via antibody arrays. This was further supported by next-generation sequencing, showing that the TNF signaling pathway is one of the most significant NPS-1034-regulated pathways. Furthermore, one of the identified target genes, GADD45A, responsible for NPS-1034 anticancer properties, was significantly associated with patient survival in RCC. GADD45A expression was significantly upregulated via NPS-1034 and downregulated via TNFRSF1A overexpression. Finally, its therapeutic efficacy was demonstrated in vivo, showing that NPS-1034 significantly alleviated the tumor burden and inhibited cell proliferation in a lung metastatic animal model. In conclusion, we explored the therapeutic mechanism of NPS-1034 and found that it targets not only MET and AXL but also TNFRSF1A. In a lung metastatic animal model, we confirmed that NPS-1034 is a potential candidate for systemic therapy in RCC.

EVI2A has emerged as a significant biomarker in various diseases; however, its biological role and mechanism in kidney renal clear cell carcinoma (KIRC) remains unexplored. We used TCGA and GEO databases to analyze EVI2A gene expression comprehensively and performed pan-cancer assessments. Clinical relevance was evaluated through Kaplan-Meier analysis and ROC curves. The gene's immune relevance was explored through analyses of the tumor microenvironment (TME), Tumor Immune Single-cell Hub (TISCH), immune checkpoints, and immunotherapy sensitivity. Our results indicate that EVI2A expression is upregulated in KIRC, showing correlations with tumor grade and T/N/M stage. EVI2A demonstrates high diagnostic accuracy (AUC=0.906) and predicts poor overall and progression-free survival in KIRC patients. Furthermore, EVI2A expression exhibits significant associations with immunity, including TME scores and specific immune cell types such as Tfh cells, CD4 memory T cells, and CD8+ T cells. Elevated EVI2A expression suggests increased sensitivity to PD-1/CTLA-4 and tyrosine kinase inhibitors. In vitro assays confirmed the impact of EVI2A on KIRC behavior, with its knockdown resulting in reduced cell proliferation and migration. In conclusion, our comprehensive analysis identifies EVI2A as a promising biomarker and a novel therapeutic target for intervening in KIRC. These findings hold significant implications for further research and potential clinical applications., Competing Interests: The authors declare that there is no possible conflict of interest., (© 2024 The Authors.)

Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel Lindau (VHL) gene loss of function mutation, which leads to the accumulation of hypoxia-inducible factor 2α (HIF2α). HIF2α has been well-established as one of the major oncogenic drivers of ccRCC, however, its therapeutic targeting remains a challenge. Through an analysis of proteomic data from ccRCCs and adjacent non-tumor tissues, we herein revealed that Ubiquitin-Specific Peptidase 7 (USP7) was upregulated in tumor tissues, and its depletion by inhibitors or shRNAs caused significant suppression of tumor progression in vitro and in vivo. Mechanistically, USP7 expression is activated by the transcription factors FUBP1 and FUBP3, and it promotes tumor progression mainly by deubiquitinating and stabilizing HIF2α. Moreover, the combination of USP7 inhibitors and afatinib (an ERBB family inhibitor) coordinately induce cell death and tumor suppression. In mechanism, afatinib indirectly inhibits USP7 transcription and accelerates the degradation of HIF2α protein, and the combination of them caused a more profound suppression of HIF2α abundance. These findings reveal a FUBPs-USP7-HIF2α regulatory axis that underlies the progression of ccRCC and provides a rationale for therapeutic targeting of oncogenic HIF2α via combinational treatment of USP7 inhibitor and afatinib., (© 2024. The Author(s).)

Background: Our study aims to address two pivotal questions: "What are the recent advancements in understanding the etiology of urological tumors through Mendelian Randomization?" and "How can Mendelian Randomization be more effectively applied in clinical settings to enhance patient health outcomes in the future?", Methods: In our systematic review conducted in April 2023, we utilized databases like PubMed and Web of Science to explore the influence of Mendelian Randomization in urological oncological diseases. We focused on studies published from January 2018, employing keywords related to urological tumors and Mendelian Randomization, supplemented with MeSH terms and manual reference checks. Our inclusion criteria targeted original research studies, while we excluded reports and non-relevant articles. Data extraction followed a PICO-based approach, and bias risk was independently evaluated, with discrepancies resolved through discussion. This systematic approach adhered to PRISMA guidelines for accuracy and thoroughness in reporting., Results: From the initial 457 publications, we narrowed down to 43 full-text articles after screening and quality assessments. A deeper understanding of Mendelian Randomization can help us explore risk factors with a clear causal relationship to urological tumors. This insight may pave the way for future research in early diagnosis, treatment, and management of associated diseases., Conclusion: Our review underscores the value of MR in urogenital tumor research, highlighting its efficacy in establishing causality and its potential to clarify disease mechanisms. Despite challenges like large sample sizes and variant identification, MR offers new perspectives for understanding and managing these tumors, suggesting a trend towards more inclusive and diverse research approaches.

Primary cilia are present on renal tubules and are implicated to play a pivotal role in transducing signals during development; however, the oncogenic role of cilia in clear cell renal cell carcinoma (ccRCC) has not been examined. Here we show that VHL wild-type ccRCC cell lines have a high incidence of primary cilia, and a high frequency of primary cilia is positively correlated with VHL expression and poor prognosis. Besides, the depletion of KIF3A and IFT88, genes required for ciliogenesis, significantly inhibited tumor proliferation and metastasis in vitro and in vivo. Further analysis found that mutations of key genes in hedgehog signaling are enriched in VHL wild ccRCC, its downstream signaling activation depends on ciliogenesis. Moreover, depletion of primary cilia or suppression of hedgehog pathway activation with inhibitor-induced robust autophagic cell death. Collectively, our findings revealed that primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of VHL wild-type ccRCC progression. Targeting the primary cilia-hedgehog pathway may represent an effective therapeutic strategy for VHL wild-type ccRCC., (© 2024. The Author(s).)

This study aims to broaden the morphological scope of SDH-deficient renal cell carcinoma and to assist clinicians and pathologists in better understanding this entity to prevent misdiagnosis. This study used immunohistochemistry staining and the first-generation sequencing Sanger method for gene detection. It retrospectively analysed the clinical pathology, molecular characteristics, biological behaviour, and treatment information of one case of SDH-deficient renal cell carcinoma. The patient was a 57-year-old female with right back pain for more than 20 days and had no personal or family history of kidney tumours. In addition, the tumour cells had clear boundaries in morphology, and residual normal renal tubules could be seen around them. There were also ossification and adipose tissue around the tumour centre. The tumour cells were arranged in a glandular tubular and cord-like manner. Vacuolar and eosinophilic inclusion bodies could be observed in the cytoplasm. The nucleus was regular, the chromatin distribution was fine, and there were no obvious nucleoli. They were low-grade nuclei. In addition, no atypical mitosis or necrosis could been found. Furthermore, immunohistochemistry staining showed SDHB-negative and keratin 20 -positive tumour. Meanwhile, the first-generation sequencing also pointed out the presence of SDHB gene mutations in the tumour. After 12 months of follow-up, there was no evidence of disease recurrence in the patient. SDH-deficient renal cell carcinoma is a rare tumour associated with SDH gene germline mutations, and suspected cases should undergo SDHB immunohistochemistry staining. Most SDH-deficient renal cell carcinomas have a good prognosis, but undifferentiated cases require long-term follow-up., (© 2024. The Author(s).)

CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters ( Cdh16 or Pax 8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1 , and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard-of-care agent, axitinib. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2 independent., Competing Interests: Competing interests statement:W.G.K. has financial interests in Casdin Capital, Cedilla Therapeutics, Circle Pharma, Fibrogen, IconOVir Bio, LifeMine Therapeutics, Lilly Pharmaceuticals, Nextech Invest, and Tango Therapeutics. He also has a royalty interest in the HIF2 inhibitor Belzutifan, which is currently being commercialized by Merck & Co., Inc., Rahway, NJ. L.A.S. has financial interests in Blueprint Medicines. S.S. reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck & Co., Inc., Rahway, NJ, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; and receives royalties from Biogenex. E.M.V.A. is a consultant/advisory board member for Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Serinus Bio; receives research support from Novartis, BMS, Sanofi, NextPoint; reports equity from Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Syapse, Serinus Bio; intermittent legal consulting on patents for Foaley & Hoag. E.M.P. reports financial interest in Merck & Co., Inc., Rahway, NJ. D.E.L., C.Y., S.D. V.P., and E.M.P. are employees of Merck Pharmaceuticals, which provided the PT2399 used in these studies and which markets the HIF2 inhibitor Belzutifan (Welireg). S.S. reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis. E.M.V.A. receives research support from Novartis, BMS, Sanofi, NextPoint. Dr. Eliezer M. Van Allen acknowledges shared co-authorship with reviewer Dr. Arul Chinnaiyan on a review in 2020: Mateo et al., Nat. Cancer 2020; 1:1041-1053.

Mitogen-activated protein kinase (MAPK) signalling is vitally important in tumour development and progression. This study is the first to comprehensively analyse the role of MAPK-family genes in the progression, prognosis, immune-cell infiltration, methylation, and potential therapeutic value drug candidates in ccRCC. We identified a novel prognostic panel of six MAPK-signature genes (MAP3K12, MAP3K1, MAP3K5, MAPK1, MAPK8, MAPK9), and introduced a robust MAPK-signature risk model for predicting ccRCC prognosis. Model construction, evaluation, and external validation using datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database demonstrated its stability, as well as high sensitivity and specificity. Enrichment analysis suggested the participation of immune-mediated mechanism in MAPK dysregulation in ccRCC. Immune-infiltration analysis confirmed the relationship and revealed that the MAPK-signature risk model might stratify immunotherapy response in ccRCC, which was verified in drug sensitivity analysis and validated in external ccRCC immunotherapy dataset (GSE67501). Potential therapeutic drug predictions for key MAPKs using DSigDB, Network Analyst, CTD, and DGIdb were subsequently verified by molecular docking with AutoDock Vina and PyMol. Mendelian randomization further demonstrated the possibilities of the MAPK-signature genes as targets for therapeutic drugs in ccRCC. Methylation analysis using UALCAN and MethSurv revealed the participation of epigenetic modifications in dysregulation and survival difference of MAPK pathway in ccRCC. Among the key MAPKs, MAP3K12 exhibited the highest significance, indicating its independent prognostic value as single gene in ccRCC. Knockout and overexpression validation experiments in vitro and in vivo found that MAP3K12 acted as a promoter of tumour progression in RCC, suggesting a pivotal role for MAP3K12 in the proliferation, migration, and invasion of RCC cells. Our findings proposed the potential of MAPK-signature genes as biomarkers for prognosis and therapy response, as well as targets for therapeutic drugs in ccRCC., Competing Interests: Declaration of competing interest The authors declare no competing interest exists. The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Rho GTPase activating protein (ARHGAP) family genes play critical roles in the onset and progression of human cancer. Rho GTPase activating protein 9 (ARHGAP9) is upregulated in various tumors. However, far too little attention has been paid to the prognostic value of ARHGAP9 and correlation with immune infiltration in clear cell renal cell carcinoma (ccRCC). Our aim is to evaluate the prognostic significance of ARHGAP9 expression and its correlation with immune infiltration in ccRCC. Transcriptional expression profiles of ARHGAP9 between ccRCC tissues and normal tissues were downloaded from The Cancer Genome Atlas. The ARHGAP9 protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium. Receiver operating characteristic curve was used to differentiate ccRCC from adjacent normal tissues. The Kaplan-Meier method was conducted to assess the effect of ARHGAP9 on survival. Protein-protein interaction networks were constructed by the STRING. Functional enrichment analyses were performed using the "ClusterProfiler" package. The immune infiltration patterns were evaluated via the tumor immune estimation resource 2.0 and Tumor-Immune System Interaction Database. ARHGAP9 expression was substantially higher in ccRCC tissues than in adjacent normal tissues. Increased ARHGAP9 mRNA expression was shown to be linked to high TNM stage and lymph node metastases. The diagnostic value of ARHGAP9 gene expression data was assessed using receiver operating characteristic curve analysis. The survival analysis module of GEPIA2 and the Kaplan-Meier plotter both showed ccRCC patients with high-ARHGAP9 had a worse prognosis than those with low-ARHGAP9. Correlation analysis indicated ARHGAP9 mRNA expression was significantly correlated with tumor purity and immune infiltrates. These findings demonstrate that upregulated ARHGAP9 indicates poor prognosis and immune infiltration in ccRCC. The current findings suggest that ARHGAP9 can be an effective biomarker and potential therapeutic strategy for ccRCC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

CD8+ T lymphocytes are important elements of the tumor microenvironment, hence their involvement in the development and progression of tumors is complex. Data on the precise tumor-infiltrating lymphocytes gene signature in renal cell carcinoma (RCC) remain limited. Therefore, this study created a tumor-infiltrating lymphocytes-related predictive model for patients with RCC using data from The Cancer Genome Atlas. The most important genes associated with CD8 + T lymphocytes were identified using weighted gene co-expression network analysis. Functional categories of important genes were revealed using gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes signaling pathway analyses. A CD8 + T lymphocyte-related prognostic model with 7 important genes was simultaneously created using the least absolute shrinkage and selection operator, univariate and multivariate Cox regressions, and the 7 genes were expressed particularly in CD8 + T lymphocytes according to single-cell sequencing data obtained from the Gene Expression Omnibus. This study identified a seven-gene prognostic model associated with CD8 + T lymphocytes that may significantly influence risk stratification in patients with RCC. The genes included in the model are apolipoprotein B mRNA editing catalytic polypeptide 3G, CD3 gamma, eomesodermin, protein tyrosine phosphatase, non-receptor type 7, signal regulatory protein gamma, Fas ligand, and T-cell immunoreceptor with Ig and ITIM domains., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The potential benefit of neoadjuvant toripalimab plus axitinib in cases with clear cell renal cell carcinoma (ccRCC) and inferior vena cava tumor thrombus (IVC-TT) remains unclear. NEOTAX was a phase 2 study to investigate the efficacy and safety of neoadjuvant toripalimab plus axitinib in patients with ccRCC and IVC-TT (ChiCTR2000030405). The primary endpoint was the down-staging rate of IVC-TT level. Secondary endpoints included change in TT length, response rate, percentage change in surgical approach, surgical morbidity, progression-free survival (PFS), safety, and biomarker analyses. In all, 25 patients received study treatment, 44.0% (11/25) patients had a reduction in thrombus level, and none experienced an increase in Mayo level. The median change in tumor thrombus length was -2.3 cm (range: -7.1 to 1.1 cm). Overall, 61.9% (13/21) patients experienced changes in surgical strategy compared with planned surgery, three patients experienced major complications. The median PFS was 25.3 months (95% CI: 17.0-NE). The 1-year PFS was 89.1% (95% CI: 62.7-97.2). No any of grade 4 or 5 treatment-related adverse event was identified. Biopsy samples of non-responders exhibited increased T cytotoxic cell infiltration, but these cells were predominantly PD-1 positive. Biopsy samples of responders exhibited lower T helper cells, however, their subtype, regulatory T cells remained unchanged. In surgical samples of the TT, non-responders exhibited increased CD8T&#95;01&#95;GZMK&#95;CXCR4 subset T cells. NEOTAX met preset endpoints proving that toripalimab in combination with axitinib downstages IVC-TT in a significant proportion of patients leading to simplification in the procedure of surgery., (© 2024. The Author(s).)

Aromatic caninurine formamase (AFMID) is an enzyme involved in the tryptophan pathway, metabolizing N-formylkynurenine to kynurenine. AFMID had been found significantly downregulated in clear cell renal cell carcinoma (ccRCC) in both tissue and urine samples. Although ccRCC is characterized by a typical Warburg-like phenotype, mitochondrial dysfunction, and elevated fat deposition, it is unknown whether AFMID plays a role in tumorigenesis and the development of ccRCC. In the present study, AFMID overexpression had inhibitory effects for ccRCC cells, decreasing the rate of cell proliferation. Quantitative proteomics showed that AFMID overexpression altered cellular signaling pathways involved in cell growth and cellular metabolism pathways, including lipid metabolism and inositol phosphate metabolism. Further urine proteomic analysis indicated that cellular function dysfunction with AFMID overexpression could be reflected in the urine. The activity of predicted upregulators DDX58, TREX1, TGFB1, SMARCA4, and TNF in ccRCC cells and urine showed opposing change trends. Potential urinary biomarkers were tentatively discovered and further validated using an independent cohort. The protein panel of APOC3, UMOD, and CILP achieved an AUC value of 0.862 for the training cohort and 0.883 for the validation cohort. The present study is of significance in terms of highlighting various aspects of pathway changes associated with AFMID enzymes, discovering potential specific biomarkers for potential patient diagnosis, and therapeutic targeting.