Pathogenesis Of ccRCC Research Articles

CRISPR/Cas9-based discovery of ccRCC therapeutic opportunities through molecular mechanism and immune microenvironment analysis

IntroductionClear cell renal cell carcinoma is a common and aggressive form of renal cell carcinoma. Its incidence continues to rise, and metastatic recurrence leads to poor clinical outcomes. Current prognostic biomarkers lack reliability. We integrated multi-omics data to discover key ccRCC genes and build a prognostic model to improve risk prediction and guide treatment decisions.MethodsOur study integrated genome-wide CRISPR screening data from DepMap and transcriptomic profiles from TCGA to identify key genes associated with ccRCC pathogenesis. Initial screening identified 11 candidate genes through differential expression analysis and CRISPR functional validation. Using LASSO and Cox regression, we selected five key genes (GGT6, HAO2, SLPI, MELK, and EIF4A1) for model construction. The functional role of MELK was tested by knockdown experiments. Additional analyses included tumor mutation burden, immune microenvironment assessment, and drug response prediction.ResultsThe model stratified patients into high-risk and low-risk groups with distinct survival outcomes. High-risk cases showed higher mutation loads, immunosuppressive features, and activated cytokine pathways, whereas low-risk cases displayed metabolic pathway activity. MELK knockdown reduced cancer cell proliferation and migration. High-risk patients exhibited better responses to targeted drugs such as pazopanib and sunitinib.DiscussionOur study demonstrates the pivotal role of MELK in ccRCC progression. This multi-omics-driven model elucidates MELK-mediated mechanisms and their interactions with the tumor microenvironment, providing novel strategies for risk stratification and targeted therapy. Future studies will validate these findings in independent cohorts and investigate the regulatory networks of MELK to identify potential therapeutic targets.

Immunohistological Examination of HEATR1 and SLC27A2 Expression in ccRCC Samples to Evaluate Their Potential as Prognostic Markers—A Preliminary Study

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is a common kidney cancer with limited therapeutic options. This study investigated the expression of HEAT repeat-containing protein 1 (HEATR1) and solute carrier family 27 member 2 (SLC27A2) in ccRCC and their potential as prognostic markers and therapeutic targets. Methods: Analysis of a public proteomic dataset (CPTAC) and immunohistochemistry (IHC) validation in an independent cohort of 52 ccRCC patients was performed. HEATR1 and SLC27A2 expression were correlated with survival outcomes. Reactome pathway analysis was conducted to explore the functional roles of HEATR1 and SLC27A2. Results: The analysis showed that HEATR1 is upregulated and associated with poor prognosis, while SLC27A2 is downregulated and similarly linked to shorter progression-free survival. High HEATR1 expression and low SLC27A2 expression correlated with shorter progression-free survival (PFS) and overall survival (OS) in patients with high-grade ccRCC. Reactome analysis indicated HEATR1's involvement in RNA metabolism and SLC27A2's role in lipid metabolism, particularly peroxisomal lipid metabolism and fatty acyl-CoA biosynthesis. HEATR1 exhibited a dual localization in both the cytoplasm and nucleus, while SLC27A2 was primarily observed at the cell membrane and the nucleus. This different subcellular distribution suggests multifaceted roles for both proteins in ccRCC pathogenesis. Conclusions: HEATR1 and SLC27A2 are potential prognostic markers in ccRCC. Further research is needed to validate these findings in larger, more diverse cohorts and elucidate their roles in ccRCC progression.

LMO2 confers value as a potential immunotherapy marker in pan-cancer analysis and inhibits progression of Clear Cell Renal Cell Carcinoma.

LMO2 confers value as a potential immunotherapy marker in pan-cancer analysis and inhibits progression of Clear Cell Renal Cell Carcinoma.

Multi-omics analysis reveals the role of ribosome biogenesis in malignant clear cell renal cell carcinoma and the development of a machine learning-based prognostic model

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer, marked by high molecular heterogeneity and limited responsiveness to targeted or immune therapies. Ribosome biogenesis (Ribosis), a central regulator of cell growth and metabolism, has emerged as a driver of tumor aggressiveness. However, its role in ccRCC pathogenesis and prognosis remains poorly defined.MethodsWe integrated bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics sequencing data to dissect the biological functions and clinical relevance of Ribosis-related genes in ccRCC. Through pseudotime trajectory analysis and metabolic flux inference, we examined malignant progression and metabolic reprogramming. A prognostic model based on a Ribosis-related signature (RBRS) was built using 118 machine learning algorithm combinations and validated in internal and external cohorts. A web-based calculator was also developed. We further analyzed immune infiltration, genomic alterations, tumor microenvironment features, and drug sensitivity. Expression of five core Ribosis-related genes (RPL38, RPS2, RPS14, RPS19, RPS28) was validated by qRT-PCR.ResultsWe identified a Ribosis-high malignant subpopulation with enhanced stemness, poor prognosis, and elevated oxidative phosphorylation. These cells showed increased metabolic activity, especially in the pyruvate–lactate axis, potentially facilitating immune evasion. The RBRS model outperformed 32 published signatures (C-index = 0.68). High-risk patients exhibited an “immune-activated yet immunosuppressed” microenvironment, with increased CD8+ T-cell infiltration and elevated regulatory T cells, myeloid-derived suppressor cells, and immune checkpoint expression (e.g., PDCD1, CTLA-4). Despite active antigen presentation and immune cell recruitment, terminal tumor-killing capacity was impaired. High-risk tumors also showed higher mutation burden, frequent copy number loss of tumor suppressor genes, and resistance to common targeted therapies. The five RBRS genes were significantly upregulated in tumor tissues, consistent with bulk RNA-seq data.ConclusionWe reveal Ribosis as a key driver of ccRCC progression. The RBRS model demonstrates robust prognostic value and translational utility, linking Ribosis to metabolism, immune dysfunction, and therapy resistance, offering new insights for risk stratification and precision treatment in ccRCC.

FOXM1 could serve as a bridge mediating prognosis and immunity for clear cell renal cell carcinoma via single-cell and bulk RNA-sequencing

BackgroundIn the development of several cancers, the Forkhead Box M1 (FOXM1) is crucial. The relationship between the immune system and FOXM1 in renal cell carcinoma (ccRCC), which has been verified by bulk RNA sequencing and scRNA sequencing, is the primary subject of this research.MethodPublicly available data related to FOXM1 and ccRCC were extracted from The Cancer Genome Atlas (TCGA) database. The impact of FOXM1 on the prognosis of ccRCC was examined using Cox regression analysis. Results were verified by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Additionally, single-cell sequencing data were analyzed.ResultsWhen compared to para-carcinoma tissues, the expression of FOXM1 was considerably higher in ccRCC tissues. Patients with elevated FOXM1 expression had lower survival rates. FOXM1 may be a standalone prognostic factor for ccRCC, according to results of univariate and multivariate Cox regression studies. Reduced FOXM1 expression was linked to higher immunotherapy sensitivity, according to immunocorrelation analysis. This suggests FOXM1 may mediate immunotherapy resistance in ccRCC. Additionally, FOXM1 showed strong associations with tumor mutation load, microsatellite instability, and antitumor immunity. These results imply FOXM1 may regulate antitumor immunity in the ccRCC microenvironment. Consistent results from immunohistochemistry, PCR, and single-cell RNA sequencing confirmed upregulated FOXM1 expression in ccRCC.ConclusionsAccording to the findings, FOXM1 might be used as a stand-alone prognostic biomarker for ccRCC. Moreover, FOXM1 has exhibited robust correlations with microsatellite instability, tumor mutation burden, immune response, and immunotherapy efficacy. FOXM1 may promote ccRCC pathogenesis partly by suppressing antitumor immunity and mediating immunotherapy resistance.

Circulating bile acid profiles characteristics and the potential predictive role in clear cell renal cell carcinoma progression

BackgroundThe incidence of clear cell renal cell carcinoma (ccRCC) has steadily increased over the past decade, and recent studies have linked bile acid (BA) metabolism to its development. However, the metabolic profile of BAs and their potential as biomarkers in ccRCC pathogenesis remain poorly characterized, making their evaluation crucial for advancing disease understanding and management.MethodsA total of 68 newly diagnosed ccRCC patients and 63 healthy controls were enrolled. Serum bile acid (BA) profiles were measured using Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). The Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) model analyzed differences in serum BA profiles between ccRCC patients and controls. Additionally, the relationship between BA profiles and tumor heterogeneity parameters was investigated. Receiver Operating Characteristic (ROC) analysis identified potential biomarkers for ccRCC pathogenesis.ResultsThe BA profile was altered in ccRCC patients and was not influenced by sex or age. Specifically, primary and secondary unconjugated BA fractions were significantly higher in the ccRCC population. Five BA metabolite candidates exhibited the most significant differences between ccRCC patients and controls. Deoxycholic acid (DCA) was associated with pathological pTNM stage classification and grade. Chenodeoxycholic acid (CDCA) and lithocholic acid (LCA), combined with testosterone, showed potential as biomarkers for the pathogenesis of ccRCC.ConclusionAlterations in the serum BA profile are observed in ccRCC. Deoxycholic acid (DCA) correlates with pathological pTNM stage classification and tumor grade. Additionally, CDCA combined with LCA show potential as biomarkers for ccRCC pathogenesis.Clinical trial numberNot applicable.

Comparative study of [18F]AlF-NOTA-FAPI-RGD and [18F]FDG/[18F]AlF-NOTA-FAPI-04 PET/CT in renal cell carcinoma.

Renal cell carcinoma (RCC) is a significant global health concern, and the early diagnosis and accurate staging of clear cell renal cell carcinoma (ccRCC) remain major challenges. [18F]FDG PET/CT is not ideal for diagnosing ccRCC due to the low glucose metabolism potential of cancer cells. Both fibroblast activation protein (FAP) and the angiogenic integrin αvβ3 receptor are closely linked to the pathogenesis and progression of ccRCC. The aim of this study is to evaluate a novel radiopharmaceutical [18F]AlF-NOTA-FAPI-RGD (denoted as [18F]AlF-LNC1007), a dual-targeting heterodimer tracer targeting both FAP and integrin αvβ3, and to compare the diagnostic value of [18F]AlF-LNC1007 with [18F]FDG and [18F]AlF-NOTA-FAPI-04 PET/CT in RCC. Materials and Methods: A total of 35 participants, highly suspected to have RCC, were recruited. [18F]AlF-LNC1007 and [18F]AlF-NOTA-FAPI-04/[18F]FDG scans were performed at least one day apart, and both were completed within one week. The Wilcoxon signed-rank test or paired t-test was used to assess differences in tumor uptake and TBR (tumor-to-background ratio) between [18F]AlF-LNC1007 and the other two imaging agents. The Spearman correlation coefficient was used to evaluate the correlation between tumor uptake and the expression of FAP and αvβ3. Results: The detection rate, sensitivity, and positive predictive value (PPV) of [18F]AlF-LNC1007 for RCC primary lesions were significantly higher than those of [18F]FDG, at 91% vs. 76%, 100% vs. 85%, and 91% vs. 87%, respectively. Obvious advantages were also seen in metastatic lesions at 94% vs. 34%, 94% vs. 29%, and 100% vs. 100%. Compared to [18F]AlF-NOTA-FAPI-04, the corresponding detection rate, sensitivity, and PPV were 98% vs. 90%, 100% vs. 92%, and 98% vs. 98% for primary lesions, and 89% vs. 78%, 89% vs. 93%, and 100% vs. 82% for metastatic lesions. The uptake and TBR of [18F]AlF-LNC1007 in both primary and metastatic lesions were significantly higher than those of [18F]FDG (all P < 0.001). The uptake of [18F]AlF-LNC1007 showed a moderate to high positive correlation with the expression levels of αvβ3 and the combined expression of FAP and αvβ3 (r = 0.756, P = 0.0003; r = 0.678, P = 0.0002) and a low positive correlation with FAP expression alone (r = 0.389, P = 0.014). The uptake of [18F]AlF-NOTA-FAPI-04 showed a low to moderate positive correlation with FAP expression and the combined expression of FAP and αvβ3 (r = 0.570, P = 0.0002; r = 0.408, P = 0.010), and no correlation with αvβ3 expression alone (r = 0.262, P = 0.107). Conclusion: [18F]AlF-LNC1007 demonstrated significantly higher diagnostic efficacies and uptake in primary and metastatic renal cell carcinoma (RCC) compared to FDG PET/CT. Additionally, [18F]AlF-LNC1007 exhibited higher diagnostic efficacies and uptake in primary RCC than [18F]AlF-NOTA-FAPI-04 PET/CT. While these findings suggest potential diagnostic advantages, further studies are needed to fully evaluate its diagnostic efficacy compared to the standard of treatment.

Abstract 4664: Differential transcript usage reveals SERINC2 as a prognostic biomarker in clear cell renal cell carcinoma (ccRCC)

Abstract Background: Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, accounts for approximately 75% of cases1. While differentially expressed gene (DEG) analyses have provided valuable insights, they often neglect alternative splicing (AS), a key driver of transcriptome diversity and functional protein complexity. AS is essential in modulating tumor biology and can impact disease progression and survival outcomes2. To address this gap, we performed a differential transcript usage (DTU) analysis in ccRCC to explore the role of AS in shaping survival-associated signatures. Methods: A total of 172 tumor samples from the Dartmouth Renal Tumor Biobank were analyzed. Following quality control, transcripts expressed in &amp;gt; 0.1 TPM in at least 25% of tumor samples were retained, yielding 31,850 transcripts. DTU was assessed using DRIMSeq, while functionality was evaluated with IsoformSwitchAnalyzeR. Cox proportional hazards analysis and machine learning-based Cox-LASSO regression was applied to identify survival-associated features, followed by log-rank analysis to explore their prognostic relevance. Results: DTU analysis revealed significant transcript-level changes linked to survival outcomes. Among these, SERINC2 emerged as the most statistically significant survival-associated gene, with its transcript NM_001199039.2 exhibiting a hazard ratio (HR) of 0.5 (95% CI: 0.39-0.69). Kaplan-Meier analysis confirmed that elevated expression levels of this transcript were significantly associated with better survival outcomes (p &amp;lt; 0.05). SERINC2 is linked to membrane lipid synthesis and may be associated with lipid metabolic reprogramming, a hallmark of ccRCC pathogenesis. Notably, isoform NM_001199039.2 has the shortest N-terminus regions compared to other validated isoforms, possibly conferring unique functionality. Finally, a prognostic model based on the Cox model demonstrated AUC values of 0.68 for 3-year survival and 0.78 for 5-year survival, indicating strong predictive potential for long-term outcomes. Conclusions: Our findings identify the SERINC2 splice variant (variant 5), NM_001199039.2, as a potential biomarker for favorable outcomes. We will conduct further validation in independent datasets and experimental systems to delineate the role of this splice variant on survival outcomes in ccRCC. References. 1. Jonasch E, Walker CL, et al. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat Rev Nephrol. 2021;17(4):245-261. doi:10.1038/s41581-020-00359-22. Marques-Coelho D, Iohan L da CC, Melo de Farias AR, et al. Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains. NPJ Aging Mech Dis. 2021;7(1). doi:10.1038/s41514-020-00052-5 Citation Format: Chinaza Nnam, Minghui Zhang, Brock Christensen, Lucas Salas. Differential transcript usage reveals SERINC2 as a prognostic biomarker in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4664.

Comparative single‐cell transcriptomic profiling of patient‐derived renal carcinoma cells in cellular and animal models of kidney cancer

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer that often displays resistance to conventional cancer therapies, including chemotherapy and radiation therapy. Targeted treatments, including immunotherapies and small molecular inhibitors, have been associated with improved outcomes. However, variations in the patient response and the development of resistance suggest that more models that better recapitulate the pathogenesis and metastatic mechanisms of ccRCC are required to improve our understanding and disease management. Here, we examined the transcriptional landscapes of in vitro cell culture as well as in vivo orthotopic and metastatic NOD/SCID‐γ mouse models of ccRCC using a single patient‐derived RCC243 cell line to allow unambiguous comparison between models. In our mouse model assays, RCC243 cells formed metastatic tumors, and all tumors retained clear cell morphology irrespective of model type. Notably, gene expression profiles differed markedly between the RCC243 tumor models—cell culture, orthotopic tumors, and metastatic tumors—suggesting an impact of the experimental model system and whether the tumor was orthotopic or metastatic. Furthermore, we found conserved prognostic markers between RCC243 tumor models and human ccRCC patient datasets, and genes upregulated in metastatic RCC243 were associated with worse patient outcomes.

Construction of a prognostic risk model for clear cell renal cell carcinomas based on centrosome amplification-related genes

Clear cell renal cell carcinoma (ccRCC) is the urological malignancy with the highest incidence, centrosome amplification-associated genes (CARGs) have been suggested to be associated with carcinogenesis, but their roles in ccRCC are still incompletely understood. This study utilizes bioinformatics to explore the role of CARGs in the pathogenesis of ccRCC and to establish a prognostic model for ccRCC related to CARGs. Based on publicly available ccRCC datasets, 2312 differentially expressed genes (DEGs) were identified (control vs. ccRCC). Disease samples were classified into high and low scoring groups based on CARG scores and analysed for differences to obtain 345 DEGs associated with CARG scores (S-DEGs). 137 candidate genes were obtained by taking the intersection of DEGs and S-DEGs. Six prognostic genes (PCP4, SLN, PI3, PROX1, VAT1L, and KLK2) were then screened by univariate Cox, LASSO, and multifactorial Cox regression. These genes exhibit a high degree of enrichment in ribosome-associated pathways. Both risk score and age were independent prognostic factors, and the Nomogram constructed based on them had a good predictive performance (AUC > 0.7). In addition, immunological analyses identified 6 different immune cells and 23 immune checkpoints between the high- and low-risk groups, whereas mutational analyses identified frequent VHL mutations in both high- and low-risk groups. Finally, 93 potentially sensitive drugs were identified. In conclusion, this study identified six CARGs as prognostic genes for ccRCC and established a risk model with predictive value. These findings provide insights for prognostic prediction of ccRCC, optimisation of clinical management and development of targeted therapeutic strategies.

HOGA1 Suppresses Renal Cell Carcinoma Growth via Inhibiting the Wnt/β-Catenin Signalling Pathway.

Changes in hydroxyproline metabolism are reported to promote tumorigenesis. HOGA1 is a useful marker for diagnosing primary hyperoxaluria 3, catalysing the final step of mitochondrial hydroxyproline metabolism from 4-hydroxy-2-oxoglutarate (HOG) to glyoxylate and pyruvate; however, its specific mechanism in RCC remains unclear. This study investigated the role of HOGA1 in the pathogenesis of ccRCC. The results showed that HOGA1 was decreased significantly in tumour tissues, with this low expression associated with a poor prognosis in patients with ccRCC. QTL mapping showed that Hoga1 was cis-regulated. Gene enrichment analyses showed that Hoga1 co-expressed genes were enriched in the Wnt/β-catenin signalling pathway. Furthermore, invitro and invivo assays demonstrated that HOGA1 significantly inhibited the proliferation, invasion and migration of renal carcinoma cells via the Wnt/β-catenin-c-Myc/CyclinD1 axis, probably via regulating the level of HOG. In conclusion, this study demonstrates that HOGA1 has a tumour suppressor role by inhibiting the Wnt/β-catenin signalling pathway. This finding provides new insights into the function of HOGA1 in ccRCC.

High expression of ARPC1B promotes the proliferation and apoptosis of clear cell renal cell carcinoma cells, leading to a poor prognosis.

High expression of ARPC1B promotes the proliferation and apoptosis of clear cell renal cell carcinoma cells, leading to a poor prognosis.

A BRAF-activated noncoding RNA attenuates clear cell renal cell carcinoma via repression of glucose-6-phosphate dehydrogenase

Clear cell renal cell carcinoma (ccRCC) is a disease rooted in metabolic disorders, distinguished by abnormally high activity of glucose 6-phosphate dehydrogenase (G6PD). G6PD serves as a key rate-limiting enzyme in the pentose phosphate pathway. Meanwhile, BRAF-activated noncoding RNA (BANCR) has emerged as a crucial regulatory factor linked to various cancers. The expression pattern of BANCR varies across different cancer types, exhibiting apparent duality in its function. However, the precise role and underlying mechanisms of BANCR in ccRCC tumorigenesis remain incompletely understood. Our study indicated that BANCR was downregulated in ccRCC and influenced cell survival by modulating cell proliferation, apoptosis, and G6PD enzyme activity. The underlying mechanism was that BANCR could directly bind to G6PD through a long noncoding RNA–protein interaction, ultimately inhibiting G6PD activity by impeding its dimer formation. Moreover, BANCR exhibited the capability to modulate the glucose metabolic flow in ccRCC cells. Subsequent experiments demonstrated a significant inhibition of tumor growth in vivo upon overexpression of BANCR, and G6PD played a pivotal role in mediating the tumor-suppressive effect of BANCR in ccRCC cells. In conclusion, this study provides novel insights into the molecular pathogenesis of ccRCC, highlights a distinct and new regulatory mechanism responsible for the ectopic overactivation of G6PD in ccRCC progression, and suggests that BANCR-mediated suppression of G6PD activity could emerge as a potential therapeutic strategy for ccRCC treatment.

Optical genome and epigenome mapping of clear cell renal cell carcinoma

Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily captured by short-read sequencing. This study presents a novel approach for simultaneous profiling of long-range genetic and epigenetic changes in matched cancer samples, focusing on clear cell renal cell carcinoma (ccRCC). ccRCC is a common kidney cancer subtype frequently characterized by a 3p deletion and the inactivation of the von Hippel–Lindau (VHL) gene. We performed integrated genetic, cytogenetic, and epigenetic analyses on paired tumor and adjacent nontumorous tissue samples. Optical genome mapping identified genomic aberrations as structural and copy number variations, complementing exome-sequencing findings. Single-molecule methylome and hydroxymethylome mapping revealed a significant global reduction in 5hmC level in both sample pairs, and a correlation between both epigenetic signals and gene expression was observed. The single-molecule epigenetic analysis identified numerous differentially modified regions, some implicated in ccRCC pathogenesis, including the genes VHL, PRCC, and PBRM1. Notably, pathways related to metabolism and cancer development were significantly enriched among these differential regions. This study demonstrates the feasibility of integrating optical genome and epigenome mapping for comprehensive characterization of matched tumor and adjacent tissue, uncovering both established and novel somatic aberrations.

Bioinformatics analysis of mitochondrial metabolism-related genes demonstrates their importance in renal cell carcinoma

PurposeClear cell renal cell carcinoma (ccRCC) is resistant to radiotherapy and chemotherapy. Thus, it is necessary to find new diagnostic markers and therapeutic targets to increase the overall outcomes of ccRCC. Recent studies have shown that therapeutic methods that interfere with the energy transfer system can also positively affect the treatment process.MethodsThe present study is focused on finding markers associated with mitochondrial metabolic pathways that affect the outcome of ccRCC. For this purpose, we investigated various aspects of the relationship between mitochondrial metabolism and ccRCC based on analysis of gene network connections and differentially expressed genes, through assessment of protein–protein interaction, mutations, and promoter methylation on the related genes. We also investigated gene interaction with miRNAs and immune infiltration analysis.ResultsThrough these steps, we provided a list of possible diagnostic markers and therapeutic targets for ccRCC.ConclusionThe current study further proved the importance of mitochondrial metabolic pathways in the pathogenesis of ccRCC and provided a list of possible diagnostic markers and therapeutic targets from these pathways that can be used in ccRCC.

The 7-Methylguanosine (m7G) methylation METTL1 acts as a potential biomarker of clear cell renal cell carcinoma progression.

The 7-Methylguanosine (m7G) methylation METTL1 acts as a potential biomarker of clear cell renal cell carcinoma progression.

FXR promotes clear cell renal cell carcinoma carcinogenesis via MMP-7-regulated EMT pathway

Renal cell carcinoma (RCC) ranks as a prevalent malignant neoplasm, with clear cell renal cell carcinoma (ccRCC, also known as KIRC) accounting for approximately 75% of all RCC cases. The farnesoid X receptor (FXR, encoded by NR1H4), functioning as a nuclear receptor, plays a crucial role in regulating gene transcription. Although the involvement of FXR in tumors of the digestive system and in acute kidney injury has been extensively studied, its specific role in the pathogenesis of ccRCC has yet to be thoroughly investigated. Consequently, the objective of our current investigation is to uncover the functional roles of FXR in ccRCC. In this study, plasmids for the overexpression of FXR were constructed, and small interfering RNA (siRNA) constructs were designed. Dual-luciferase reporter assays confirmed a direct binding interaction between FXR and the promoter of the matrix metalloproteinase 7 (MMP-7) gene. Additionally, a mouse xenograft model elucidated the regulatory effect of FXR on MMP-7 in the context of tumor growth. This study elucidates how FXR regulates the promotion of ccRCC through the MMP-7-mediated EMT pathway. Interestingly, FXR is typically regarded as a tumor suppressor gene that affects gastrointestinal tumors, providing a potential new therapeutic direction for ccRCC.

High Expression of MRPL23 Is Associated with Poor Survival in Clear-Cell Renal Cell Carcinoma.

This study aimed to investigate the expression and prognostic significance of the MRPL23 protein and mRNA in clear-cell renal cell carcinoma (ccRCC) and adjacent non-tumorous tissues. The goal was to assess the impact of MRPL23 expression on tumor behavior, progression, and patient outcomes. Using immunohistochemistry (IHC), MRPL23 protein expression was analyzed in 99 cases of ccRCC and 30 adjacent non-tumorous tissues. mRNA levels were assessed using data from The Cancer Genome Atlas (TCGA). Correlations between MRPL23 expression and clinicopathological features were examined, and survival outcomes were evaluated using Kaplan-Meier survival curves and Cox regression analyses. MRPL23 protein expression was significantly lower in ccRCC tissues compared to normal tissues. In contrast, mRNA levels of MRPL23 were significantly elevated in ccRCC tissues. Expression levels were correlated with clinicopathological features, including gender, tumor grade, pT status, and disease stage, underlining their impact on tumor progression. Elevated MRPL23 protein expression was associated with poorer overall survival (OS) in ccRCC patients and remained an independent prognostic marker for adverse outcomes after adjustment for confounding variables. While high MRPL23 mRNA expression was also linked to worse OS, it did not retain its status as an independent prognostic factor after adjustments. MRPL23 protein expression is a potential independent prognostic biomarker in ccRCC, emphasizing its utility in predicting patient outcomes and potentially guiding therapeutic decisions. These findings highlight the importance of further research into the role of MRPL23 in ccRCC pathogenesis and its potential as a therapeutic target.

In Silico Exploration of AHR-HIF Pathway Interplay: Implications for Therapeutic Targeting in ccRCC.

The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel-Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1β, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein-protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.

HADH suppresses clear cell renal cell carcinoma progression through reduced NRF2-dependent glutathione synthesis

HADH suppresses clear cell renal cell carcinoma progression through reduced NRF2-dependent glutathione synthesis