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Protein kinase C eta is associated with progression of renal cell carcinoma (RCC).

BACKGROUND: The expression of all eleven PKC-isoforms in clear cell RCCs (ccRCC) and in the corresponding normal renal tissue was quantified. A possible association of PKC-isoforms with histopathological parameters was examined. MATERIALS AND METHODS: Proteins were isolated from tumor and normal tissue of 43 patients with ccRCC. Expression of PKC-isoforms were quantified by Western blot analysis. RESULTS: In both, ccRCCs and the corresponding normal renal tissue, all PKC-isoforms apart from PKC gamma and theta were detectable. Striking associations between PKC-isoforms and histopathological parameters were observed: (i) a 3-fold increase in PKC eta of grade 3 and 4 versus grade 1 and 2 tumors (p = 0.025), (ii) a decrease of PKC alpha in tumor versus normal tissue of 18% (p = 0.020) and (iii) a 20% increase of PKC zeta in grade 3 and 4 versus grade 1 and 2 tumors (p = 0.092). CONCLUSION: The major result is a clear correlation of PKC eta expression with tumor progression. This observation-is in agreement with the known oncogenic properties of PKC eta. Similarly, oncogenic PKC zeta also increased with tumor progression. PKC alpha, with known tumor-suppressor properties, was decreased in ccRCC versus normal tissue. These findings may become important for both classification and treatment of ccRCC.

Blotting, Western↗

PubMed2004

[Mutation of von Hippel-Lindau gene and expression of vascular endothelial growth factor in sporadic clear cell renal cell carcinoma and their relationships to angiogenesis].

OBJECTIVE: To evaluate the relationship between the mutation of the von Hippel-Lindau (VHL) gene and expression of vascular endothelial growth factor (VEGF) in sporadic clear cell renal cell carcinoma (CCRCC) and angiogenesis. METHODS: Polymerase chain reaction (PCR) was used to detect the mutation of VHL gene in the specimens of cancerous tissue and normal tissues away from tumor from 77 patients with CCRCC. Immunohistochemistry was used to examine the expression of VEGF. CD34 staining was used to measure the microvascular density (MVD). RESULTS: VHL gene mutations were detected in 40 cases (51.9%). The expression rate of VEGF was 79.2% (61 cases). The positive rate of VEGF in the cases with VHL mutation was 92.5%, significantly higher than that in the cases without VHL mutation (64.9%, P = 0.003). The levels of MVD was higher in the cases with VHL mutation and those with VEGF expression were 760.80/mm2 and 715.95/mm2 respectively, both significantly higher than those in the cases without VHL-mutation and those without VEGF expression (547.03/mm2 and 437.44/mm2 respectively, all P = 0.001). The cases with expression of VEGF were divided into two groups according the presence or absence of VHL gene mutations or not. The MVD of the cases with VEGF expression and VHL mutation was 760.80 mm2, significantly higher than that of the cases with VEGF expression and without VHL mutation (547.03 mm2, P = 0.011). CONCLUSION: The mutation rate of VHL gene is high among the Chinese with sporadic CCRCC. VHL gene mutation increases significantly the VEGF expression, thus, and perhaps via other mechanism too, promoting the angiogenesis in tumor. The high level of MVD of the cases with VHL gene mutation may be related to the high malignant potential of CCRCC.

Adenocarcinoma, Clear Cell↗

PubMed2006

[Expression of hypoxia-inducible factor-1-alpha, hypoxia-inducible factor-2alpha and vascular endothelial growth factor in sporadic clear cell renal cell renal cell carcinoma and their significance in the pathogenesis thereof].

OBJECTIVE: To investigate the expression of hypoxia-inducible factor (HIF)-1-alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) in sporadic clear cell renal cell carcinoma (CCRCC) and to analyze the relationship among them. METHODS: Samples of CCRCC were obtained from 107 patients during resection. Immunohistochemistry was used to detect the expression of HIF-1-alpha, HIF-2alpha, and VEGF in the tumor tissues and normal kidney tissues distant from the tumor. The microvessel density (MVD) was observed by microscopy. RESULTS: HIF-1-alpha and HIF-2alpha were not expressed in the normal kidney tissues. However, in the tumor tissues the HIF-1-alpha positive rate was 69.2% (74/107), significantly lower than that of the HIF-2-alpha (80.5%, 88/107, P = 0.001), the VEGF positive rate was 78.5% (84/107). The VEGF positive rate of the HIF-1-alpha-positive group was 90.5%, significantly higher than that of the HIF-1-alpha-negative group (51.5%, P = 0.001). The VEGF positive rate of the HIF-2-alpha-positive group was 89.8%, significantly higher than that of the HIF-1-alpha-negative group (26.3%, P = 0.001). The MVD of the 64 HIF-1alpha, HIF-2alpha, and VEGF positive samples was 697, significantly higher than that of the 13 HIF-1alpha, HIF-2alpha, and VEGF negative samples (391, P = 0.001). The MVD of the HIF-2alpha positive samples was 678 +/- 324, significantly higher than that of the HIF-2alpha negative samples (383 +/- 293, P = 0.001). The MVD of the VEGF positive samples was 692 +/- 325, significantly higher than that of the VEGF negative samples (384 +/- 269, P = 0.001). Spearman correlation analysis showed that MVD was strongly positively correlated with HIF-2alpha and VEGF. Mann-Whitney U test showed that HIF-1alpha and HIF-2alpha were not correlated with the staging of CCRCC. CONCLUSION: HIF-2alpha is expressed more frequently in sporadic CCRCC than HIF-1alpha. Both HIF-1alpha and HIF-2alpha upregulate the VEGF expression and angiogenesis, especially HIF-2alpha.

Adult↗

PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗

PubMed2002

Loss of tumor suppressor protein PTEN during renal carcinogenesis.

The tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) encodes a dual specific protein and phospholipid phosphatase that affects cell proliferation, apoptosis and migration. In our study, we examined protein expression of PTEN in renal carcinogenesis. PTEN protein levels were examined in 42 clear cell renal cell carcinomas (ccRCC) and oncocytomas as well as in the corresponding normal renal tissue of the same patients using Western blot analysis. Cellular localization was analyzed by immunohistochemistry. PTEN was highly expressed in all investigated normal renal tissue specimens. Immunohistochemical analysis showed an almost exclusive staining of proximal tubulus epithelial cells known to be precursor cells of ccRCC. Within the proximal tubulus cells, PTEN exhibited a membrane predominant immunostaining pattern. In ccRCCs PTEN expression was markedly reduced to an average of less than 10% compared with normal tissue as evidenced by Western blot analysis (p < 0.001). The degree of reduction was similar in highly differentiated (G1) carcinomas and in less differentiated (G2-G4) carcinomas. These observations were reproduced by immunohistochemical studies, which revealed a loss of the characteristic membrane predominant immunostaining pattern in ccRCC. In contrast to the PTEN positive proximal tubulus epithelial cells, the distal tubulus epithelial cells, which are precursor cells of the benign oncocytomas, exhibited only a very weak PTEN expression. Compared with the distal tubulus epithelial cells, no downregulation of PTEN was seen in oncocytomas. We conclude that PTEN expression and PTEN membrane localization are lost during early renal cell carcinogenesis and may therefore be a valuable RCC tumor marker.

Adenoma, Oxyphilic↗

PubMed2006

Lower expression levels of the transforming growth factor beta receptor type II protein are associated with a less aggressive tumor phenotype and improved survival among patients with clear cell renal cell carcinoma.

Loss of expression of the transforming growth factor beta type II receptor (TbetaRII) has been implicated as an important event in renal carcinogenesis; however, its role as a potential prognostic factor remains poorly understood. Using archived tumor samples and long-term follow-up on a cohort of 280 clear cell renal cell carcinoma (ccRCC) patients treated with surgery from 1980 to 1998, we evaluated the association of TbetaRII expression and cancer-specific survival in both a univariate and multivariate setting. Low tumor expression of TbetaRII is associated with a less aggressive tumor phenotype at time of surgery. Moreover, those patients with lower levels of TbetaRII expression experience better cancer-specific survival than patients with higher levels of TbetaRII expression (log rank P = .034). Based on a Cox proportional hazard model adjusting for age, patients with tumors showing low (hazard ratio, 0.49; 95% confidence interval, 0.27-0.88) and moderate (hazard ratio, 0.7; 95% confidence interval, 0.40-1.23) TbetaRII expression are at decreased risk of RCC death compared with patients with tumors having high levels of TbetaRII expression. Adjustment for well-known pathologic predictors of RCC outcome attenuates the association of TbetaRII expression and ccRCC survival. Of interest, the association with TbetaRII expression appears more pronounced among those patients with tumors showing less aggressive phenotypes. Data from this investigation are the first to suggest that loss of TbetaRII expression is associated with improved ccRCC patient survival, especially among those patients with less aggressive disease profiles at time of surgery.

Adult↗

PubMed2003

The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas.

By positional cloning, we identified two breakpoint-spanning genes in a familial clear cell renal cell carcinoma (CCRCC)-associated t(1;3)(q32.1;q13.3): LSAMP and NORE1 (RASSF1 homolog). Both genes are downregulated in 9 of 9 RCC cell lines. While the NORE1A promoter predominantly presents partial methylation in 6 of the cell lines and 17/53 (32%) primary tumors, the LSAMP promoter is completely methylated in 5 of 9 cell lines and in 14/53 (26%) sporadic and 4 familial CCRCCs. Expression of LSAMP and NORE1A proteins in CCRCC cell lines inhibited cell proliferation. These characteristics indicate that LSAMP and NORE1A may represent new candidate tumor suppressors for CCRCC.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Nucleostemin mRNA is expressed in both normal and malignant renal tissues.

Nucleostemin (NS), a p53-binding protein, has been shown essential for stem and cancer cell proliferation and implicated in oncogenesis. To explore potential contributions of NS to the development of clear cell renal cell carcinomas (ccRCCs), we determined NS expression in ccRCC cell lines, and in paired normal and malignant renal tissues from 31 patients with ccRCC. Nucleostemin mRNA and/or protein expression was observed in all four cell lines and 27 of 31 (87%) tumour specimens. Surprisingly, 16 of 31 (52%) adjacent normal renal samples also expressed NS mRNA and its levels in four of them were comparable with those in paired tumour tissues. Three of the patients had detectable NS mRNA in their normal renal tissues whereas lacked its expression in the matched tumours. Compared to the oncogene c-MYC expression in these same samples, NS expression showed a much less specificity for ccRCC. We further demonstrated that NS mRNA expression was closely associated with cellular proliferation in normal fibroblasts or T lymphocytes and renal cell carcinoma cell lines. Collectively, NS expression widely occurs in normal and malignant renal tissues, and is likely a proliferation marker rather than a unique regulator of cell proliferation and survival in stem and cancer cells.

Adult↗

PubMed2004

Strict regulation of CAIX(G250/MN) by HIF-1alpha in clear cell renal cell carcinoma.

Renal cell carcinoma of the clear cell type (ccRCC) is associated with loss of functional von Hippel-Lindau (VHL) protein and high, homogeneous expression of the G250MN protein, an isoenzyme of the carbonic anhydrase family. High expression of G250MN is found in all ccRCCs, but not in most normal tissues, including normal human kidney. We specifically studied the mechanism of transcriptional regulation of the CAIXG250 gene in RCC. Previous studies identified Sp1 and hypoxia-inducible factor (HIF) as main regulatory transcription factors of G250MN in various non-RCC backgrounds. However, G250MN regulation in RCC has not been studied and may be differently regulated in view of the HIF accumulation under normoxic conditions due to VHL mutations. Transient transfection of different G250MN promoter constructs revealed strong promoter activity in G250MN -positive RCC cell lines, but no activity in G250MN -negative cell lines. DNase-I footprint and band-shift analysis demonstrated that Sp1 and HIF-1alpha proteins in nuclear extracts of RCC cells bind to the CAIX promoter and mutations in the most proximal Sp1 binding element or HIF binding element completely abolished CAIX promoter activity, indicating their critical importance for the activation of G250 expression in RCC. A close correlation between HIF-1alpha expression and G250MN expression was observed. In contrast, no relationship between HIF-2alpha expression and G250MN was seen. The participation of cofactor CBP/p300 in the regulation of G250 transcription was shown. In conclusion, HIF-1alpha and Sp1, in combination with CBP/p300, are crucial elements for G250MN expression in ccRCC, and CAIXG250 can be regarded as a unique HIF-1alpha target gene in ccRCC.

Adenocarcinoma, Clear Cell↗

PubMed2006

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex.

There is increasing evidence that polymorphisms of the adenosine 5' triphosphate membrane transporters ABCB1 (P-glycoprotein, MDR1) may affect expression and function, whereas less information is available about the impact of ABCC2 (multidrug resistance-associated protein (MRP2)) single-nucleotide polymorphisms . Particularly, their role in human kidney for drug elimination and in the etiology of renal cell carcinoma is poorly understood. ABCB1 and ABCC2 mRNA and protein expression levels were determined by real-time polymerase chain reaction or immunohistochemistry in kidney cancer and adjacent unaffected cortex tissue of 82 nephrectomized renal cell cancer (RCC) patients (63 clear-cell RCC (CCRCC), 19 non-CCRCC). The DNA of all patients was genotyped for ABCB1 -2352G>A, -692T>C, 2677G>T/A (Ala893Ser/Thr), and 3435C>T, and ABCC2 -24C>T, 1249G>A (Val417Ile) and 3972C>T. ABCB1 and ABCC2 were less expressed in CCRCC than in normal cortex on mRNA as well as on protein level. Although the overall genotype frequency distribution did not differ between the patients and a matched control group, ABCB1 2677T/A and 3435T genotypes were associated with higher (P=0.02 and P=0.04) and ABCC2 -24 T with lower mRNA levels in normal tissues (0.03). The expression of ABCB1 and ABCC2 was not related to genetic variants in RCC tissue. In a reporter gene assay in HepG2 cells, the ABCC2 -24T construct showed an 18.7% reduced activity (P=0.003). In conclusion, ABCB1 and ABCC2 genotypes modulate the expression in the unaffected renal cortex of RCC patients, possibly contributing to inter-individual differences in drug and xenobiotics elimination. Their role in RCC cancer susceptibility or chemotherapy resistance needs further elucidation.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2004

Hepatitis A virus receptor blocks cell differentiation and is overexpressed in clear cell renal cell carcinoma.

BACKGROUND: The molecular mechanisms underlying tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC) are not well understood. We aimed to identify new molecular markers to provide insight into these processes. METHODS: This work reports on the identification of human hepatitis A virus cellular receptor 1 (hHAVcr-1) as a differentially expressed gene in ccRCC using RNA-based arbitrarily primed polymerase chain reaction (RAP-PCR). Results were further confirmed by Northern and Western blot assays. Carcinoma 769-P and normal HK-2 cells derived from proximal tubule epithelial cells, grown under different culture conditions, were used to understand the putative role of hHAVcr-1 in renal malignancy. hHAVcr-1 stable transfected clones and dipeptidyl peptidase IV (DPPIV) assays allowed assessing its involvement in cell differentiation. RESULTS: The hHAVcr-1 is overexpressed in eight out of 13 ccRCC and its expression neglected in benign oncocytomas. In culture, hhavcr-1 is dramatically overexpressed in normal and tumor cell lines that, having acquired the fully differentiated phenotype, are induced to de-differentiate by means of phorbol ester phorbol 12-myristate-13-acetate (PMA) treatment. Similarly, differentiation prevention by addition of PMA to confluent cells also increases hhavcr-1 expression. hHAVcr-1 stable transfected 769-P cells proved that hhavcr-1 itself blocks differentiation. Since hhavcr-1 is expressed at higher levels in tumor cells, we used an African green monkey cell model to show that immunotoxins directed against the monkey homologue of hhavcr-1 could kill kidney cells. CONCLUSION: Our results showed that hHAVcr-1 blocks differentiation of proximal tubule epithelial cells and that it could be used as a target for therapy of kidney carcinomas.

Adult↗

PubMed2026

Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.

Resistance to HIF-2α inhibitors such as belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1/STAT3 signaling pathway. Using a genome-wide CRISPR screen in von Hippel-Lindau-deficient (VHL-deficient) ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1/STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of endothelial PAS domain-containing protein (EPAS1) that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in samples from patients with ccRCC and functionally validated using CRISPR interference (CRISPRi), which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2α-dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1/STAT3 markedly suppressed HIF-2α expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1/STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.

Basic Helix-Loop-Helix Proteins↗

PubMed2006

Pathway analysis of kidney cancer using proteomics and metabolic profiling.

BACKGROUND: Renal cell carcinoma (RCC) is the sixth leading cause of cancer death and is responsible for 11,000 deaths per year in the US. Approximately one-third of patients present with disease which is already metastatic and for which there is currently no adequate treatment, and no biofluid screening tests exist for RCC. In this study, we have undertaken a comprehensive proteomic analysis and subsequently a pathway and network approach to identify biological processes involved in clear cell RCC (ccRCC). We have used these data to investigate urinary markers of RCC which could be applied to high-risk patients, or to those being followed for recurrence, for early diagnosis and treatment, thereby substantially reducing mortality of this disease. RESULTS: Using 2-dimensional electrophoresis and mass spectrometric analysis, we identified 31 proteins which were differentially expressed with a high degree of significance in ccRCC as compared to adjacent non-malignant tissue, and we confirmed some of these by immunoblotting, immunohistochemistry, and comparison to published transcriptomic data. When evaluated by several pathway and biological process analysis programs, these proteins are demonstrated to be involved with a high degree of confidence (p values < 2.0 E-05) in glycolysis, propanoate metabolism, pyruvate metabolism, urea cycle and arginine/proline metabolism, as well as in the non-metabolic p53 and FAS pathways. In a pilot study using random urine samples from both ccRCC and control patients, we performed metabolic profiling and found that only sorbitol, a component of an alternative glycolysis pathway, is significantly elevated at 5.4-fold in RCC patients as compared to controls. CONCLUSION: Extensive pathway and network analysis allowed for the discovery of highly significant pathways from a set of clear cell RCC samples. Knowledge of activation of these processes will lead to novel assays identifying their proteomic and/or metabolomic signatures in biofluids of patient at high risk for this disease; we provide pilot data for such a urinary bioassay. Furthermore, we demonstrate how the knowledge of networks, processes, and pathways altered in kidney cancer may be used to influence the choice of optimal therapy.

Adult↗

PubMed2006

Coexpression of erythopoietin and erythopoietin receptor in sporadic clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (CCRCC) is the most common renal carcinoma and it is often associated with von Hippel-Lindau disease (VHL) gene mutations. CCRCCs with VHL mutations demonstrate hypoxia-inducible factor (HIF) overexpression as well as increased expression of vascular endothelial growth factor (VEGF). Recently, the erythropoietin (Epo) has been found to be upregulated in renal and other tumors associated with VHL disease. Furthermore, Epo and Epo receptor (EpoR) coexpression has also been reported in these tumors. The results provided strong evidence that an autocrine loop is involved in tumorigenesis in VHL disease. We investigated whether Epo and EpoR coexpression also occurs in sporadic CCRCC. Fifty-four sporadic CCRCCs were analyzed. VHL gene mutations were detected in 30 out of 54 tumors. Coexpression of Epo and EpoR was detected in 50 out of 54 tumors regardless of their VHL mutation status. The results suggest that coexpression of Epo and EpoR plays an important role in tumorigenesis of sporadic CCRCC.

Adenocarcinoma, Clear Cell↗

PubMed2026

Survival prediction for clear cell renal cell carcinoma based on deep multimodal synergistic survival network.

Objective.To propose a deep multimodal synergistic survival analysis framework (Deep Multimodal Synergistic Survival Network, DMSSN) to achieve accurate prognostic analysis for clear cell renal cell carcinoma (ccRCC).Methods.This study (DMSSN) utilized matched multimodal data from the Cancer Genome Atlas-KIRC database, including CT imaging data, whole slide images, copy number variation (CNV) features, and clinical data. Deep Canonical Correlation Analysis was employed to map heterogeneous modalities into a shared latent space. Contrastive learning was introduced to enhance semantic consistency across multimodal features, and a gating network was utilized for the adaptive fusion of multimodal information to achieve precise survival risk prediction for patients.Results.Experimental results demonstrated that DMSSN achieved a Concordance Index (C-index) of 0.8153 ± 0.0994, with a Log-rank testp-value of 1.6553×10-11. DMSSN exhibited significant performance advantages over traditional statistical methods like Log-rank-Cox (0.7055 ± 0.0670) and machine learning methods such as Random Survival Forest (RSF) (0.6836 ± 0.1048). Furthermore, in comparison with similar deep learning approaches, DMSSN outperformed late fusion strategies (0.7493 ± 0.1211) and discrete-time survival models such as DeepHit (0.7655 ± 0.1041) and Nnet-surv (0.7694 ± 0.0635). Notably, DMSSN still achieved the best predictive performance when compared to the classic deep survival model DeepSurv (0.7919 ± 0.0978) and advanced state-of-the-art multimodal fusion frameworks like Context-Aware Transformer (0.7735 ± 0.0818) and Multimodal Co-Attention Transformer (0.8102 ± 0.0972). Ablation studies showed that removing any single modality led to a decline in performance, with the largest numerical decrease occurring after removing CT imaging features (C-index decreased to 0.7327), validating the complementarity of multimodal data and the pivotal role of radiomic features in prognostic assessment. Module ablation experiments further confirmed the effectiveness of the core components.Conclusion:By effectively integrating imaging, pathology, genomic, and clinical features, the DMSSN framework demonstrates superior performance and robustness in the survival prediction of ccRCC.

Carcinoma, Renal Cell↗

PubMed2025

Methylated ARHGAP40 in renal cell carcinoma associated with tumor necrosis and grade: a potential biomarker for non-invasive early detection.

This study investigated the expression, methylation patterns, and clinicopathological implications of ARHGAP40 in renal cell carcinoma (RCC), the most common urinary malignancy. A total of 60 clear cell renal cell carcinomas (ccRCC), 30 papillary renal cell carcinomas (pRCC), 30 chromophobe renal cell carcinomas (chRCC), and 13 other RCC subtypes were enrolled. ARHGAP40 expression was analyzed in both RCC tissues and matched paracancerous normal tissues using immunohistochemistry (IHC). The methylation status of the ARHGAP40 promoter region was assessed in both normal and tumor samples by bisulfite sequencing PCR (BSP). Circulating tumor DNA (ctDNA) extracted from peripheral blood samples of RCC patients (20), patients with benign renal tumors (1), and healthy controls (14) was quantitatively analyzed for methylation using quantitative methylation-specific PCR (qMSP). ARHGAP40 expression was significantly downregulated in RCC compared to matched normal tissues (P < 0.001). This reduced expression correlated with tumor necrosis (P = 0.009) but showed no significant association with age, gender, tumor location, tumor diameter, TNM stage, or vascular invasion. In the ccRCC subtype, ARHGAP40 expression exhibited a progressive decrease with larger tumor diameter (P = 0.045), advancing histological grade (P = 0.032), and tumor necrosis (P = 0.011). The methylation status of ARHGAP40 was consistent with its expression level in both tumor and adjacent normal tissues. Methylated ARHGAP40 DNA was detectable only in RCC patient ctDNA samples. ARHGAP40 is epigenetically silenced in RCC through methylation-mediated downregulation, which correlates with tumor necrosis and grade. The detection of methylated ARHGAP40 in ctDNA holds promise as a potential biomarker for early RCC diagnosis.

Humans↗

PubMed2026

Pan-cancer multi-omics machine learning defines a lactylation-associated immune-excluded tumor state with proteomic and experimental corroboration.

BACKGROUND: Histone lactylation links lactate metabolism to chromatin regulation, but whether lactylation-program-associated transcriptional patterns delineate recurrent pan-cancer tumor states remains unclear. METHODS: We integrated mRNA, lncRNA, and miRNA profiles from 9712 TCGA tumors across 33 cancer types with GTEx references, six GEO cohorts, IMvigor210, and an institutional clear-cell renal cell carcinoma (ccRCC) cohort used for exploratory DIA-NN proteomic corroboration. Random-effects co-expression meta-analysis, multi-omics consensus clustering, regulon inference, immune deconvolution, TIDE, oncoPredict, and SHAP-based machine learning were applied. hsa-miR-431-5p was functionally evaluated as a proof-of-concept CS2-associated miRNA in bladder cancer models. RESULTS: LacCoEx-Atlas comprised 398,491 lactylation-related co-expression pairs across 24,667 RNA features under a random-effects framework (median I² = 88.6%). Consensus clustering identified two subtypes: CS2 showed glycolytic-mesenchymal-immune-excluded features, M2 macrophage enrichment, CD8⁺ T-cell depletion, elevated HDAC4/NSD3/KDM6B activity, and worse survival, whereas CS1 showed oxidative, sirtuin-active programs. CS2 had fewer predicted ICI responders (18.3% vs. 52.0%) and a lower observed ORR in IMvigor210 (15.3% vs. 24.0%). oncoPredict identified NU7441 as a hypothesis-generating CS2-associated sensitivity signal (Hedges' g = 1.17). DIA-NN proteomics in 50 ccRCC specimens provided exploratory support for CS2-associated hypoxia, ECM degradation, and metastasis programs. The 10-feature mRNA LARItools model achieved an apparent AUC of 0.9413, while a separate multi-omics model achieved 0.971; neither was independently validated. LARItools reproduced prognostic separation across six GEO cohorts. miR-431-5p promoted malignant phenotypes and EMT in bladder cancer cells, with concordant CMU4h expression findings. CONCLUSIONS: Lactylation-program-associated transcriptional patterns delineate a recurrent immune-excluded pan-cancer tumor state associated with adverse prognosis, reduced predicted immunotherapy responsiveness, exploratory single-cancer protein-level support, and testable DNA damage response-targeting hypotheses. LacCoEx-Atlas and LARItools provide open resources for lactylation-program-associated tumor-state stratification and future translational research.

Humans↗

PubMed2006

Histologic subtype of metastatic renal cell carcinoma predicts response to combined immunochemotherapy with interleukin 2, interferon alpha and 5-fluorouracil.

OBJECTIVES: Combined immunochemotherapy with interleukin 2 (IL-2), interferon alpha (IFN-alpha), and 5-fluorouracil (5-FU) is an established first-line therapy for metastatic renal cell carcinoma (RCC). However, data on histologic parameters predictive of clinical benefit are rare. In this study, we evaluated the response to immunochemotherapy in the main histologic subtypes of renal cell carcinoma and performed a subgroup analysis of inoperable patients. METHODS: From 164 patients treated with one or two cycles of combined immunochemotherapy, radical nephrectomy had revealed 22 cases of papillary RCC (pRCC; 13.4%) and 131 cases of clear cell RCC (ccRCC; 79.9%). In the remaining 11 (6.7%) their disease was inoperable. The overall response rates were evaluated according to World Health Organization criteria. RESULTS: For ccRCC and inoperable disease, responses of 34.4% and 27.3% after one cycle and 28.8% and 16.7% after two cycles, respectively, were noted. In contrast, no patient with pRCC showed any response after two cycles of combined immunochemotherapy. CONCLUSIONS: No objective response was seen in patients with pRCC. Hence, the use of immunotherapeutic agents must be questioned in this histologic subtype.

Adult↗