RÉSUMÉ
Membrane-type metalloproteinases (including MMP-14 and MMP-15) are enzymes involved in the degradation of extracellular matrix components. In cancer, they are involved in processes such as cellular invasion, angiogenesis and metastasis. Therefore, the aim of this study was to evaluate the expression, content and activity of MMP-14 and MMP-15 in human renal cell carcinoma. Samples of healthy kidney tissue (n = 20) and tissue from clear-cell kidney cancer (n = 20) were examined. The presence and contents of the MMPs were assessed using Western blot and ELISA techniques, respectively. Their activity-both actual and specific-was evaluated using fluorimetric analysis. Both control and cancer human kidney tissues contain MMP-14 and MMP-15 enzymes in the form of high-molecular-weight complexes. Moreover, these enzymes occur in both active and latent forms. Their content in cancer tissues is very similar, but with a noteworthy decrease in content with an increase in the kidney cancer grade for both membrane-type metalloproteinases. Even more notable is the highest content of the investigated enzymes represented by MMP-14 in the control tissues. Considering the actual and specific activity outcomes, MMP-14 dominates over MMP-15 in all of the investigated tissues. Nevertheless, we also noted a significant enhancement of the activity of both metalloproteinases with an increase in the grade of renal cancer. The expression and activity of both enzymes were detected in all examined renal cancer tissues. However, our findings suggest that transmembrane metalloproteinase 14 (MMP-14) plays a much more significant and essential role than MMP-15 in the studied renal carcinoma tissues. Therefore, it seems that MMP-14 could be a promising target in the diagnosis, prognosis and therapy of renal cell carcinoma.
Sujet(s)
Néphrocarcinome , Tumeurs du rein , Matrix metalloproteinase 14 , Matrix metalloproteinase 15 , Humains , Matrix metalloproteinase 14/métabolisme , Tumeurs du rein/anatomopathologie , Tumeurs du rein/métabolisme , Tumeurs du rein/enzymologie , Néphrocarcinome/métabolisme , Néphrocarcinome/anatomopathologie , Néphrocarcinome/enzymologie , Matrix metalloproteinase 15/métabolisme , Matrix metalloproteinase 15/génétique , Femelle , Mâle , Adulte d'âge moyen , Sujet âgé , AdulteRÉSUMÉ
DICER1 tumor predisposition syndrome results from pathogenic variants in DICER1 and is associated with a variety of benign and malignant lesions, typically involving kidney, lung, and female reproductive system. Over 70% of sarcomas in DICER1 tumor predisposition syndrome occur in females. Notably, pediatric cystic nephroma (pCN), a classic DICER1 tumor predisposition syndrome lesion, shows estrogen receptor (ER) expression in stromal cells. There are also renal, hepatic, and pancreatic lesions unassociated with DICER1 tumor predisposition syndrome that have an adult female predominance and are characterized/defined by ER-positive stromal cells. Except for pCN, the expression of ER in DICER1-associated lesions remains uninvestigated. In the present study, ER expression was assessed by immunohistochemistry in 89 cases of DICER1-related lesions and 44 lesions lacking DICER1 pathogenic variants. Expression was seen in stromal cells in pCN and pleuropulmonary blastoma (PPB) types I and Ir, whereas anaplastic sarcoma of kidney and PPB types II and III were typically negative, as were other solid tumors of non-Müllerian origin. ER expression was unrelated to the sex or age of the patient. Expression of ER showed an inverse relationship to preferentially expressed antigen in melanoma (PRAME) expression; as lesions progressed from cystic to solid (pCN/anaplastic sarcoma of kidney, and PPB types I to III), ER expression was lost and (PRAME) expression increased. Thus, in DICER1 tumor predisposition syndrome, there is no evidence that non-Müllerian tumors are hormonally driven and antiestrogen therapy is not predicted to be beneficial. Lesions not associated with DICER1 pathogenic variants also showed ER-positive stromal cells, including cystic pulmonary airway malformations, cystic renal dysplasia, and simple renal cysts in adult kidneys. ER expression in stromal cells is not a feature of DICER1 perturbation but rather is related to the presence of cystic components.
Sujet(s)
Marqueurs biologiques tumoraux , DEAD-box RNA helicases , Immunohistochimie , Récepteurs des oestrogènes , Ribonuclease III , Humains , Ribonuclease III/génétique , DEAD-box RNA helicases/génétique , Femelle , Mâle , Récepteurs des oestrogènes/métabolisme , Récepteurs des oestrogènes/analyse , Enfant , Adulte , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/analyse , Adolescent , Adulte d'âge moyen , Enfant d'âge préscolaire , Jeune adulte , Tumeurs du rein/anatomopathologie , Tumeurs du rein/génétique , Tumeurs du rein/enzymologie , Blastome pulmonaire/anatomopathologie , Blastome pulmonaire/génétique , Blastome pulmonaire/enzymologie , Prédisposition génétique à une maladie , Nourrisson , Sujet âgéRÉSUMÉ
Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and is associated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.
Sujet(s)
Antigènes CD3 , Néphrocarcinome , Maladies des chiens , Facteurs de transcription Forkhead , Granzymes , Tumeurs du rein , Lymphocytes TIL , Animaux , Chiens , Néphrocarcinome/médecine vétérinaire , Néphrocarcinome/immunologie , Néphrocarcinome/enzymologie , Antigènes CD3/analyse , Antigènes CD3/métabolisme , Maladies des chiens/immunologie , Maladies des chiens/enzymologie , Facteurs de transcription Forkhead/analyse , Facteurs de transcription Forkhead/métabolisme , Granzymes/métabolisme , Granzymes/analyse , Immunohistochimie/médecine vétérinaire , Tumeurs du rein/médecine vétérinaire , Tumeurs du rein/immunologie , Tumeurs du rein/enzymologie , Lymphocytes TIL/immunologie , Études rétrospectivesRÉSUMÉ
The aim of this study was to examine the impact of Resveratrol nanoparticles on migration/invasion capacity of renal cell carcinoma (RCC) cells and its mechanism. Human RCC cells were exposed to dimethyl sulfoxide or gradient concentrations of Resveratrol nanoparticles respectively, and U0126 were also added in some experiments. We examined renal cell viability by MTT assay, and wound healing test and Transwell assays were used detect invasion and migration capability of RCC cells. We used Western blotting assay to analyze the protein levels in extracellular signal-regulated kinase (ERK) signaling. We also detected the enzymatic capacity of matrix metalloproteinase 2 (MMP-2) in cells by gelatin enzymatic profiling. Resveratrol nanoparticles treatment significantly suppressed cell viability to migrate and invade RCC cells in a dose-dependent manner. Also, notably were reduced MMP-2 activity and expression, and elevated TIMP-2 level were observed in RCC cells exposed with Resveratrol nanoparticles. Further, Resveratrol nanoparticles treatment significantly decreased only the expression of p-ERK1/2, but not p-p38 and p-JNK. Moreover, U0126, which is the ERK inhibitor, exerted similar role as Resveratrol nanoparticles did. Of note was that, combined use of U0126 and Resveratrol nanoparticles displayed a more intense suppression of MMP-2 activity and expression, and also the viability to migrate and invade the RCC cells, compared with Resveratrol nanoparticles treatment alone. The Resveratrol nanoparticles inhibited RCC cells migration and invasion by regulating MMP2 expression and ERK pathways.
Sujet(s)
Néphrocarcinome , Tumeurs du rein , Système de signalisation des MAP kinases , Matrix metalloproteinase 2 , Nanoparticules , Resvératrol , Néphrocarcinome/traitement médicamenteux , Néphrocarcinome/enzymologie , Néphrocarcinome/anatomopathologie , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Extracellular Signal-Regulated MAP Kinases/métabolisme , Humains , Tumeurs du rein/traitement médicamenteux , Tumeurs du rein/enzymologie , Tumeurs du rein/anatomopathologie , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Matrix metalloproteinase 2/biosynthèse , Matrix metalloproteinase 2/métabolisme , Matrix metalloproteinase 9/métabolisme , Inhibiteurs de métalloprotéinases matricielles/administration et posologie , Inhibiteurs de métalloprotéinases matricielles/pharmacologie , Nanoparticules/administration et posologie , Invasion tumorale , Resvératrol/administration et posologie , Resvératrol/pharmacologieRÉSUMÉ
Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.
Sujet(s)
Carcinome papillaire , Néphrocarcinome , Fumarates , Tumeurs du rein , Phosphohydrolase PTEN , Carcinogenèse , Carcinome papillaire/traitement médicamenteux , Carcinome papillaire/enzymologie , Carcinome papillaire/génétique , Carcinome papillaire/métabolisme , Néphrocarcinome/traitement médicamenteux , Néphrocarcinome/enzymologie , Néphrocarcinome/génétique , Néphrocarcinome/métabolisme , Cystéine/métabolisme , Résistance aux médicaments antinéoplasiques , Fumarate hydratase/génétique , Fumarate hydratase/métabolisme , Fumarates/pharmacologie , Humains , Tumeurs du rein/traitement médicamenteux , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Tumeurs du rein/métabolisme , Phosphohydrolase PTEN/antagonistes et inhibiteurs , Phosphohydrolase PTEN/génétique , Phosphatidylinositol 3-kinases/génétique , Protéines proto-oncogènes c-akt/génétique , Sunitinib/pharmacologieSujet(s)
Néphrocarcinome , Fumarate hydratase , Tumeurs du rein , Léiomyomatose , Syndromes néoplasiques héréditaires , Tumeurs de l'utérus , Néphrocarcinome/diagnostic , Néphrocarcinome/enzymologie , Néphrocarcinome/anatomopathologie , Femelle , Fumarate hydratase/déficit , Fumarate hydratase/génétique , Humains , Tumeurs du rein/diagnostic , Tumeurs du rein/enzymologie , Tumeurs du rein/anatomopathologie , Léiomyomatose/diagnostic , Léiomyomatose/enzymologie , Léiomyomatose/anatomopathologie , Syndromes néoplasiques héréditaires/diagnostic , Syndromes néoplasiques héréditaires/enzymologie , Syndromes néoplasiques héréditaires/anatomopathologie , Pronostic , Tumeurs de l'utérus/diagnostic , Tumeurs de l'utérus/enzymologie , Tumeurs de l'utérus/anatomopathologieRÉSUMÉ
OBJECTIVES: Wilms tumor is a common pediatric malignant tumor that accounts for approximately 95% of kidney tumors in children. The role of lipid metabolism in tumors has attracted increased attention in recent years. We examined the role of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), a lipid metabolism enzyme, in the pathogenesis of Wilms tumor. MATERIALS AND METHODS: In a previous study, we screened Wilms tumors and adjacent normal tissues for differentially expressed proteins by mass spectrometry and verified the results by western blot analysis. The Oncomine database and quantitative reverse transcription-polymerase chain reaction were used to verify the expression of HADHA at the genetic level. Immunohistochemistry and immunofluorescence were also used to validate the differential expression of the HADHA protein. The relationship between histopathological typing, clinical pathology, and HADHA expression was analyzed in 65 paraffin-embedded specimens from pediatric Wilms tumor patients. Kaplan-Meier survival curves were used to analyze the relationship between the expression of HADHA and patient prognosis. RESULTS: HADHA was expressed at low levels in Wilms tumor tissue compared with the corresponding normal tissue. The expression of HADHA was closely associated with histopathological typing (P = 0.030). The prognostic analysis of 65 children with Wilms tumor showed that high expression of HADHA was closely associated with poor prognosis (P = 0.046). CONCLUSIONS: HADHA expression is downregulated in Wilms tumor tissues, but high expression in tumor tissues is associated with clinical stage and the prognosis of children with this tumor.
Sujet(s)
Tumeurs du rein/anatomopathologie , Métabolisme lipidique , Sous-unité alpha de la protéine trifonctionnelle mitochondriale/métabolisme , Tumeur de Wilms/anatomopathologie , Marqueurs biologiques tumoraux , Enfant , Enfant d'âge préscolaire , Femelle , Études de suivi , Humains , Nourrisson , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Mâle , Sous-unité alpha de la protéine trifonctionnelle mitochondriale/génétique , Pronostic , Taux de survie , Tumeur de Wilms/enzymologie , Tumeur de Wilms/génétiqueRÉSUMÉ
Interferon-gamma (IFN-γ) has a complex role in modulating the tumor microenvironment (TME) during renal cell carcinoma (RCC) development. To define the role of IFN-γ response genes in RCC progression, we characterized the differential gene expression, prognostic implications, and DNA variation profiles of selected IFN-γ response signatures, which exhibited a significant hazard ratio for the overall survival (OS) and progression-free survival (PFS) of papillary, chromophobia, and clear cell RCC (ccRCC) patients (n = 944). Prognostic nomograms were constructed to predict the outcomes for ccRCC patients, highlighting the prognostic implications of RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1). Interestingly, large-scale pan-cancer samples (n = 12,521) and three single-cell RNA datasets revealed that RBCK1 showed markedly differential expression between cancer and normal tissues and significantly correlated with tumor-infiltrating immune cells, tumor purity, and immune checkpoint molecules, such as PD-L1, CTLA-4, LAG-3, and TIGIT in pan-cancer samples. Notably, the TIDE score was significantly higher in the RBCK1high group compared with the RBCK1low group in both ccRCC and RCC cohorts. Besides, immunohistochemistry staining showed significantly elevated RBCK1 expression in tumors (n = 50) compared with kidney samples (n = 40) from a real-world cohort, Fudan University Shanghai Cancer Center (FUSCC, Shanghai). After RBCK1 expression was confirmed in ccRCC, we found a significantly decreased number of infiltrating CD4+ T cells, CD4+ FOXP3+ Treg cells, M1 macrophages, and CD56bight/dim NK cells in the immune-cold RBCK1high group. In addition to the distinct heterogeneous immune microenvironment, the increased expression of RBCK1 predicted a prominently worse prognosis than the RBCK1low group for 232 ccRCC patients in the FUSCC proteomic cohort. Furthermore, after transfected with siRNA in human ccRCC cells, extraordinarily decreased cell proliferation, migration capacities, and prominently elevated apoptosis tumor cell proportion were found in the siRNA groups compared with the negative control group. In conclusion, this study identified IFN-γ response clusters, which might be used to improve the prognostic accuracy of immune contexture in the ccRCC microenvironment. Immune-cold RBCK1high patients have pro-tumorigenic immune infiltration and significantly worse outcomes than RBCK1low patients based on results from multi-omics to real-world data. Our discovery of novel independent prognostic indicators for RCC highlights the association between tumor alterations and immune phenotype.
Sujet(s)
Marqueurs biologiques tumoraux/génétique , Néphrocarcinome/génétique , Génomique , Interféron gamma/génétique , Tumeurs du rein/génétique , Protéomique , Facteurs de transcription/génétique , Microenvironnement tumoral , Ubiquitin-protein ligases/génétique , Marqueurs biologiques tumoraux/métabolisme , Néphrocarcinome/enzymologie , Néphrocarcinome/immunologie , Néphrocarcinome/thérapie , Lignée cellulaire tumorale , Bases de données génétiques , Techniques d'aide à la décision , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes tumoraux , Réseaux de régulation génique , Humains , Interféron gamma/métabolisme , Tumeurs du rein/enzymologie , Tumeurs du rein/immunologie , Tumeurs du rein/thérapie , Lymphocytes TIL/immunologie , Lymphocytes TIL/métabolisme , Nomogrammes , Phénotype , Survie sans progression , Cartes d'interactions protéiques , Protéome , RNA-Seq , Transduction du signal , Analyse sur cellule unique , Facteurs temps , Facteurs de transcription/métabolisme , Transcriptome , Macrophages associés aux tumeurs/immunologie , Macrophages associés aux tumeurs/métabolisme , Ubiquitin-protein ligases/métabolismeRÉSUMÉ
BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have demonstrated a survival benefit for patients with cancer. However, the clinical outcomes of subsequent tyrosine kinase inhibitors (TKIs) after ICI failure in patients with metastatic renal cell carcinoma (mRCC) remain unclear. PATIENTS AND METHODS: We retrospectively examined 38 patients with mRCC who started TKIs immediately after nivolumab with (combination group) or without ipilimumab (nivolumab group) between September 2016 and July 2019. RESULTS: Of the 38 patients, 16 and 11 achieved partial response and stable disease, respectively, resulting in a 42.1% objective response rate and 71.1% disease control rate. The median progression-free survival (PFS) from TKI initiation was 8.8 and 12.9 months in the nivolumab and combination groups, respectively. PFS and overall survival were significantly longer in patients with long-term responses to previous ICI treatment (p=0.0152 and p=0.0155, respectively). CONCLUSION: TKIs demonstrate adequate anti-tumour activity after treatment with ICIs in real-world settings.
Sujet(s)
Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Ipilimumab/usage thérapeutique , Tumeurs du rein/traitement médicamenteux , Nivolumab/usage thérapeutique , Inhibiteurs de protéines kinases/usage thérapeutique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Humains , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Tumeurs du rein/enzymologie , Tumeurs du rein/immunologie , Tumeurs du rein/mortalité , Mâle , Adulte d'âge moyen , Survie sans progression , Inhibiteurs de protéines kinases/effets indésirables , Études rétrospectives , Facteurs temps , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: This research focuses on exploring RSK4 protein expression within Clear Cell Renal Cell Carcinoma (ccRCC), based on these investigations on level of expressions coupled with the relevance to clinicopathologic features and clinical outcomes. METHODS: The expression of RSK4 in 48 ccRCC and 20 hydronephrosis samples were under the detection of immunohistochemistry; besides, its relevance to the combination of clinicopathologic features with prognosis was committed in virtue of statistical approaches. RESULTS: The 48 ccRCC samples included 36 (75%, 36/48) positive for RSK4, while the positive rate in hydronephrosis samples were 5 (25%, 5/20). Statistical analysis showed that RSK4 in ccRCC samples express higher expression the hydronephrosis samples (P < 0.05). Furthermore, the expression of RSK4 in ccRCC samples weren't correlated with ages and genders (P > 0.05), while WHO/ISUP nucleolar grade harboured relevance to low survival rate (P = 0.018). Molecular researches demonstrated that over-expression of RSK4 was able to upgrade the proliferation capability of ccRCC cell lines. CONCLUSIONS: According to the expression pattern and molecular systems featured RSK4 in ccRCCs, it performed the function of a latent independent prognostic factor performing the function of a newly built latent therapeutic aim oriented with the patients undergoing RCC. Moreover, the specific mechanism of action is expected to be revealed in the future research.
Sujet(s)
Marqueurs biologiques tumoraux/métabolisme , Néphrocarcinome/enzymologie , Tumeurs du rein/enzymologie , Ribosomal Protein S6 Kinases, 90-kDa/métabolisme , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Animaux , Marqueurs biologiques tumoraux/génétique , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Lignée cellulaire tumorale , Prolifération cellulaire , Femelle , Régulation de l'expression des gènes tumoraux , Humains , Immunohistochimie , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Mâle , Souris de lignée BALB C , Souris nude , Adulte d'âge moyen , Valeur prédictive des tests , Pronostic , Ribosomal Protein S6 Kinases, 90-kDa/génétique , Charge tumorale , Régulation positiveRÉSUMÉ
PURPOSE: The purpose of this study was to compare the clinical characteristics and the survival of CHEK2 mutation positive and CHEK2 mutation negative patients diagnosed with bladder or kidney cancer. MATERIALS AND METHODS: 1016 patients with bladder and 402 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 pathogenic variant carriers using the Cox proportional hazards model. The median follow-up was 17.5 years. Covariates included age (≤60; >61 years), sex (female; male), clinical characteristics (stage: TNM, grade, histopathological type), smoking status (non-smoking; smoking) and cancer family history (negative; positive). RESULTS: We found no impact of CHEK2 mutations on bladder or kidney cancer survival. However, we observed a possible increased survival in the subgroup of patients with stage T1 bladder cancer with CHEK2 mutations but this did not meet statistical significance (HR = 0.14; 95% CI 0.02-1.04; p = 0.055). Moreover, we observed that the missense mutations were more frequent in the low grade invasive bladder cancer patient group (OR = 7.9; 95% CI 1.50-42.1; p = 0.04) and in patients with bladder cancer with stage Ta (OR = 2.4; 95% CI 1.30-4.55; p = 0.006). The different results where missense mutations occurs less often we observed among patients with high grade invasive bladder cancer (OR = 0.12; 95% CI 0.02-0.66; p = 0.04) and those with stage T1 disease (OR = 0.2; 95% CI 0.07-0.76; p = 0.01). Our investigations revealed that any mutation in CHEK2 occurs more often among patients with stage Ta bladder cancer (OR = 2.0; 95% CI 1.19-3.47; p = 0.01) and less often in patients with stage T1 disease (OR = 0.31; 95% CI 0.12-0.78; p = 0.01). In the kidney cancer patients, truncating mutations were present more often in the group with clear cell carcinoma GII (OR = 8.0; 95% CI 0.95-67.7; p = 0.05). The 10-year survival for all CHEK2 mutation carriers with bladder cancer was 33% and for non-carriers 11% (p = 0.15). The 10-year survival for CHEK2 mutation carriers with kidney cancer 34% and for non-carriers 20% (p = 0.5). CONCLUSION: CHEK2 mutations were not associated with any change in bladder or kidney cancer survival regardless of their age, sex, smoking status and family history. We observed a potentially protective effect of CHEK2 mutations on survival for patients with stage T1 bladder cancer. CHEK2 missense mutations were more common among patients with low grade invasive bladder cancer and in patients with stage Ta diease. The frequencies of the I157T CHEK2 pathogenic variant were less in patients with high grade invasive bladder cancer and those with stage T1 disease. Among patients with bladder cancer with stage Ta disease, the OR for any mutation in CHEK2 was 2.0 but for those with stage T1 disease, the OR was 0.3. We observed truncating CHEK2 mutations were associated with kidney cancer patients with GII clear cell carcinoma.
Sujet(s)
Checkpoint kinase 2/génétique , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Mutation/génétique , Tumeurs de la vessie urinaire/enzymologie , Tumeurs de la vessie urinaire/génétique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Allèles , Femelle , Humains , Estimation de Kaplan-Meier , Mâle , Adulte d'âge moyen , Analyse de survieRÉSUMÉ
Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel-Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.
Sujet(s)
Néphrocarcinome/enzymologie , Heme oxygenase-1/métabolisme , Tumeurs du rein/enzymologie , Protéines mitochondriales/métabolisme , Stress oxydatif , Sirtuines/métabolisme , Protéine Von Hippel-Lindau supresseur de tumeur/métabolisme , Apoptose , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Lignée cellulaire tumorale , Régulation de l'expression des gènes tumoraux , Glutamine/déficit , Heme oxygenase-1/génétique , Humains , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Protéines mitochondriales/génétique , Phosphorylation , Espèces réactives de l'oxygène/métabolisme , Transduction du signal , Sirtuines/génétique , Protéine Von Hippel-Lindau supresseur de tumeur/génétique , p38 Mitogen-Activated Protein Kinases/métabolismeSujet(s)
Néphrocarcinome , Délétion de gène , Tumeurs du rein , Rein/métabolisme , Protein-Serine-Threonine Kinases , Protéines suppresseurs de tumeurs , Animaux , Néphrocarcinome/enzymologie , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Humains , Rein/anatomopathologie , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Souris , Souris transgéniques , Protein-Serine-Threonine Kinases/déficit , Protein-Serine-Threonine Kinases/métabolisme , Protéines suppresseurs de tumeurs/déficit , Protéines suppresseurs de tumeurs/métabolismeRÉSUMÉ
OBJECTIVE: Metastatic renal cell carcinoma (mRCC) is the important factor for patient mortality, meanwhile gene mutation constantly changes cancer prognosis in tumor process. Exploring the driver mutation in mRCC process become more and more important. MATERIALS AND METHODS: We obtained the 15 paired primary and metastatic mRCC samples and analyzed specific mutation genes in the metastatic foci (SMGs) by next generation sequencing. Moreover, we explored the Correlated networks, Pathway and Gene Ontology (GO) enrichment results, prediction analysis of AS sites and prognosis of survival. RESULTS: We identify EPCAM, TMEM127, EZH2, EXT1, CDKN2A, PRF1, AIP, CDK4, PRKARIA as SMGs and find that CDKN2A mutation sites affect the prognosis of mRCC by altering splicing elements. Based on the differential analysis for SMGs in KIRC, we found that EPCAM, PRF1 and EZH2 were differential expression in both primary tumors with metastasis compared to primary tumors without metastasis or metastatic tissues. By the AS prediction analysis, we suggest that CDKN2A mutation sites play an important role for RCC metastasis by affecting the p16/p14 expression. CONCLUSIONS: The SMGs could provide new molecular cues associated with tumor metastasis and have potential clinical implications for cancer prognosis and treatment. Definitive conclusions await further validation and follow up.
Sujet(s)
Épissage alternatif , Néphrocarcinome/génétique , Inhibiteur p16 de kinase cycline-dépendante/génétique , Tumeurs du rein/génétique , Mutation , Protéines oncogènes/génétique , Néphrocarcinome/enzymologie , Néphrocarcinome/secondaire , Inhibiteur p16 de kinase cycline-dépendante/métabolisme , Bases de données génétiques , Régulation de l'expression des gènes tumoraux , Réseaux de régulation génique , Gènes suppresseurs de tumeur , Humains , Tumeurs du rein/enzymologie , Tumeurs du rein/anatomopathologie , Protéines oncogènes/métabolismeRÉSUMÉ
PURPOSE: Fumarate hydratase-deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population. METHODS: We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan-Meier method. RESULTS: Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received "other antiangiogenics" (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for "other antiangiogenics," and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0-95.0). CONCLUSIONS: We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.
Sujet(s)
Inhibiteurs de l'angiogenèse/usage thérapeutique , Marqueurs biologiques tumoraux/génétique , Fumarate hydratase/génétique , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Tumeurs du rein/traitement médicamenteux , Inhibiteurs de protéines kinases/usage thérapeutique , Adulte , Inhibiteurs de l'angiogenèse/effets indésirables , Marqueurs biologiques tumoraux/déficit , Évolution de la maladie , Femelle , France , Fumarate hydratase/déficit , Prédisposition génétique à une maladie , Humains , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Mâle , Adulte d'âge moyen , Thérapie moléculaire ciblée , Phénotype , Inhibiteurs de protéines kinases/effets indésirables , Études rétrospectives , Espagne , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Sérine-thréonine kinases TOR/métabolisme , Facteurs temps , Échec thérapeutique , Jeune adulteRÉSUMÉ
Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.
Sujet(s)
Antinéoplasiques/pharmacologie , Néphrocarcinome/traitement médicamenteux , DNA (Cytosine-5-)-methyltransferase 1/génétique , Tumeurs du rein/traitement médicamenteux , Complexe-1 cible mécanistique de la rapamycine/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/pharmacologie , Sirolimus/analogues et dérivés , Animaux , Néphrocarcinome/enzymologie , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , DNA (Cytosine-5-)-methyltransferase 1/métabolisme , Méthylation de l'ADN , Résistance aux médicaments antinéoplasiques/génétique , Femelle , Humains , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Complexe-1 cible mécanistique de la rapamycine/métabolisme , Souris de lignée BALB C , Souris SCID , Mutation , Transplantation tumorale , Transduction du signal , Sirolimus/pharmacologie , Charge tumorale/effets des médicaments et des substances chimiques , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Renal cell carcinoma (RCC) includes diverse tumour types characterised by various genetic abnormalities. The genetic changes, like mutations, deletions and epigenetic alterations, play a crucial role in the modification of signalling networks, tumour pathogenesis and prognosis. The most prevalent RCC type, clear cell RCC (ccRCC), is asymptomatic in the early stages and has a poorer prognosis compared with the papillary and the chromophobe types RCCs. Generally, ccRCC is refractory to chemotherapy and radiation therapy. Loss of von Hippel-Lindau (VHL) gene and upregulation of hypoxia-inducible factors (HIF), the signature of most sporadic ccRCC, promote multiple growth factors. Hence, VHL/HIF and a variety of pathways, including phosphatase and TEnsin homolog on chromosome 10/phosphatidylinositol-3-kinase (PI3K)/AKT, are closely connected and contribute to the ontogeny of ccRCC. In the recent decade, multiple targeting agents have been developed based on blocking major signalling pathways directly or indirectly involved in ccRCC tumour progression, metastasis, angiogenesis and survival. However, most of these drugs have limitations; either metastatic ccRCC develops resistance to these agents, or despite blocking receptors, tumour cells use alternate signalling pathways. This review compiles the state of knowledge about the PI3K/AKT signalling pathway confined to ccRCC and its cross-talks with VHL/HIF pathway.
Sujet(s)
Facteurs de transcription à motif basique hélice-boucle-hélice/génétique , Marqueurs biologiques tumoraux , Néphrocarcinome/enzymologie , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Tumeurs du rein/enzymologie , Phosphatidylinositol 3-kinase/métabolisme , Protéine Von Hippel-Lindau supresseur de tumeur/génétique , Animaux , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Néphrocarcinome/traitement médicamenteux , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Humains , Tumeurs du rein/traitement médicamenteux , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Thérapie moléculaire ciblée , Phosphohydrolase PTEN/métabolisme , Inhibiteurs des phosphoinositide-3 kinases/usage thérapeutique , Protéines proto-oncogènes c-akt/métabolisme , Transduction du signal , Sérine-thréonine kinases TOR/métabolisme , Résultat thérapeutique , Hypoxie tumorale , Microenvironnement tumoralRÉSUMÉ
Metabolism reprograming is a hallmark of cancer and plays an important role in tumor progression. The aberrant metabolism in renal cell carcinoma (RCC) leads to accumulation of the oncometabolite L-2-hydroxyglurate (L-2HG). L-2HG has been reported to inhibit the activity of some α-ketoglutarate-dependent dioxygenases such as TET enzymes, which mediate epigenetic alteration, including DNA and histone demethylation. However, the detailed functions of L-2HG in renal cell carcinoma have not been investigated thoroughly. In our study, we found that L-2HG was significantly elevated in tumor tissues compared to adjacent tissues. Furthermore, we demonstrated that L-2HG promoted vasculogenic mimicry (VM) in renal cancer cell lines through reducing the expression of PHLDB2. A mechanism study revealed that activation of the ERK1/2 pathway was involved in L-2HG-induced VM formation. In conclusion, these findings highlighted the pathogenic link between L-2HG and VM and suggested a novel therapeutic target for RCC.
Sujet(s)
Néphrocarcinome/métabolisme , Protéines de transport/métabolisme , Tumeurs du rein/métabolisme , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Alcohol oxidoreductases , Néphrocarcinome/enzymologie , Néphrocarcinome/génétique , Néphrocarcinome/mortalité , Protéines de transport/génétique , Lignée cellulaire tumorale , Évolution de la maladie , Régulation négative , Femelle , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes tumoraux/génétique , Humains , Tumeurs du rein/enzymologie , Tumeurs du rein/génétique , Tumeurs du rein/mortalité , Système de signalisation des MAP kinases/génétique , Mâle , Adulte d'âge moyen , Mixed function oxygenases/métabolisme , Protéines proto-oncogènes/métabolisme , Petit ARN interférent , RNA-Seq , Réaction de polymérisation en chaine en temps réelRÉSUMÉ
BACKGROUND Protein kinase membrane-associated tyrosine/threonine (PKMYT1) has been found in many tumors, but its association with clear cell renal cell carcinoma (ccRCC) remains unclear. MATERIAL AND METHODS PKMYT1 expression in ccRCC was examined in the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Tumor Immune Estimation Resource databases. The correlation between PKMYT1 expression and clinicopathological parameters was explored via the chi-square test. Receiver operating characteristic curves were used to estimate the diagnostic performance of PKMYT1. Kaplan-Meier curves, a Cox model, nomogram, time-dependent receiver operating characteristic curves, and decision curve analysis (DCA) were used to evaluate the prognostic value and clinical utility of PKMYT1. Genes coexpressed with PKMYT1 in ccRCC were identified based on TCGA, the gene expression profiling interactive, and cBioPortal. Gene Set Enrichment Analysis revealed biological pathways associated with PKMYT1 in ccRCC. RESULTS Weighted gene coexpression network analysis identified PKMYT1 as one of the genes most significantly correlated with progression of histological grade. PKMYT1 was significantly upregulated in ccRCC compared with normal tissue (P<0.001), with a trend toward differentiating between individuals with ccRCC and those who were healthy (area under the curve=0.942). High PKMYT1 expression was correlated with unsatisfactory survival (hazard ratio=1.67, P=0.001), indicating that it is a risk factor for ccRCC. A nomogram incorporating PKMYT1 level was created and showed a clinical net benefit. PKMYT1 was strongly positively correlated with the anti-silencing function of 1B histone chaperone (ASF1B) gene in ccRCC. CONCLUSIONS PKMYT1 is upregulated in ccRCC and its presence indicates poor prognosis, making it a potential therapeutic target for ccRCC.
Sujet(s)
Néphrocarcinome , Bases de données d'acides nucléiques , Régulation de l'expression des gènes codant pour des enzymes , Régulation de l'expression des gènes tumoraux , Tumeurs du rein , Protéines membranaires/biosynthèse , Protéines tumorales/biosynthèse , Protein-Serine-Threonine Kinases/biosynthèse , Protein-tyrosine kinases/biosynthèse , Néphrocarcinome/diagnostic , Néphrocarcinome/enzymologie , Femelle , Humains , Tumeurs du rein/diagnostic , Tumeurs du rein/enzymologie , Mâle , Adulte d'âge moyen , PronosticRÉSUMÉ
Fatty acid synthase (FASN), a key enzyme essential for fatty acid (FA) synthesis, was reportedly implicated in the initiation and progression of various cancers. However, the clinical significance of FASN in renal cell carcinoma (RCC) has not been fully elucidated yet. Here we compare the expression profile and evaluate the prognostic significance of FASN in clear cell RCC (ccRCC) patients. FASN expression was examined in 3 pairs ccRCC and their adjacent nontumor tissues by western blotting (WB) analysis, and its expression was assessed in 145 ccRCC and 13 nontumor tissues by immunohistochemistry (IHC) analysis with tissue microarrays (TMAs). The prognosis of FASN was further investigated in large-scale database using LinkedOmics (n = 537) and The Cancer Protein Atlas (TCPA, n = 445), respectively. WB detected higher FASN expression in ccRCC than normal tissues, then IHC analysis revealed that FASN expression was positively associated with histological grade, pathological stage, tumor size and metastasis status, and negatively associated with cancer-specific survival (CSS). Univariate survival analysis demonstrated that high grade, advanced stage, large tumor, metastasis, and high FASN expression were significantly associated with a shorter CSS, and multivariate analysis revealed tumor grade, stage, metastasis and FASN were identified as independent predictors for CSS in patients with ccRCC. Further LinkedOmics and TCPA analyses confirmed that high FASN expression was correlated with a poorer overall survival (OS) of ccRCC. Collectively, these findings demonstrated FASN could be a poor prognostic factor in ccRCC patients, which indicated that FA synthesis might be implicated in the tumorigenesis and progression of ccRCC.