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1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1061-1067, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051419

RESUMO

OBJECTIVES: To evaluate the expression of myeloid ecotropic viral integration site 1 (Meis1) and vascular endothelial growth factor receptor 2 (VEGFR-2) in early-stage kidney cancers and the clinical significance. METHODS: The cancer tissues and the matched adjacent normal tissues in patients with kidney cancer, who received surgical treatment from April 2005 to September 2018 in the Haikou Hospital Affiliated to Xiangya School of Medicine, Central South University, were collected. The samples included 80 pairs of paraffin specimen, 15 pairs of fresh cancer and the matched adjacent normal tissues from these patients. Real-time PCR and immunohistochemical method were used to detect the expression levels of Meis1 and VEGFR-2 mRNA and protein in kidney tissues and adjacent normal tissues, and the correlation of clinical pathology parameters and the prognosis were analyzed in the patients. RESULTS: The expression levels of Meis1 and VEGFR-2 mRNA and protein in the renal carcinoma tissues were lower than those in the matched adjacent normal tissues (both P<0.01), and the expression levels of Meis1 were positively correlated with that of VEGFR-2 (r=0.681, P<0.01). The analysis of relevant clinical-pathological parameters in the patients showed that: the expression positive rate of Meis1 was significantly related with the pathological type of renal cancer (P<0.01), while the positive rate of Meis1 and VEGFR-2 expression was not related with the gender, age, T stage of patients (all P>0.05), but it was significantly related with the prognosis in the patients (P<0.05). Cox regression analysis showed that: Meis1 was an independent factor for the prognosis of patients (P<0.05). CONCLUSIONS: The mRNA and protein expression levels of Meis1 and VEGFR-2 in the early-stage kidney cancer tissues are significantly decreased compared with those in the adjacent normal tissues. Meis1 may be served as a tumor suppressor to affect the occurrence and development of kidney cancer. Therefore, Meis1 may be used as a biomarker to predict the prognosis of patients with kidney cancer.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteína Meis1 , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Neoplasias Renais/genética , Proteína Meis1/metabolismo , Prognóstico , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Anticancer Res ; 40(10): 5445-5456, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988866

RESUMO

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.


Assuntos
Jejum , Neoplasias Renais/tratamento farmacológico , Obesidade/tratamento farmacológico , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos , Obesidade/complicações , Obesidade/genética
3.
Adv Exp Med Biol ; 1255: 153-164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949398

RESUMO

Single-cell sequencing (SCS) is a powerful new tool that applies Next Generation Sequencing at the cellular level. SCS has revolutionized our understanding of tumor heterogeneity and the tumor microenvironment, immune infiltration, cancer stem cells (CSCs), circulating tumor cells (CTCs), and clonal evolution. The following chapter highlights the current literature on SCS in genitourinary (GU) malignancies and discusses future applications of SCS technology. The renal cell carcinoma (RCC) section highlights the use of SCS in characterizing the initial cells driving tumorigenesis, the intercellular mutational landscape of RCC, intratumoral heterogeneity (ITH) between primary and metastatic lesions, and genes driving RCC cancer stem cells (CSCs). The bladder cancer section will also illustrate molecular drivers of bladder cancer stem cells (BCSCs), SCS use in reconstructing tumor developmental history and underlying subclones, and understanding the effect of cisplatin on intratumoral heterogeneity in vitro and potential mechanisms behind platinum resistance. The final section featuring prostate cancer will discuss how SCS can be used to identify the cellular origins of benign prostatic hyperplasia and prostate cancer, the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, and the use of SCS in CTCs to understand chemotherapy resistance and gene expression changes after androgen deprivation therapy (ADT). The studies listed in this chapter illustrate many translational applications of SCS in GU malignancies, including diagnostic, prognostic, and treatment-related approaches. The ability of SCS to resolve intratumor heterogeneity and better define the genomic landscape of tumors and CTCs will be fundamental in the new era of precision-based care.


Assuntos
Neoplasias Renais/genética , Neoplasias da Próstata/genética , Análise de Sequência , Análise de Célula Única , Androgênios , Humanos , Neoplasias Renais/patologia , Masculino , Neoplasias da Próstata/patologia
4.
Nat Commun ; 11(1): 4168, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820162

RESUMO

There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.


Assuntos
Carcinoma de Células Renais/terapia , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Imunoterapia/métodos , Neoplasias Renais/terapia , Mutação , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/patologia , Pessoa de Meia-Idade
5.
Nat Commun ; 11(1): 4111, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807776

RESUMO

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Células 3T3 , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Inflamação/genética , Inflamação/metabolismo , Neoplasias Renais/genética , Espectrometria de Massas , Camundongos , Proteômica/métodos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
6.
J Comput Assist Tomogr ; 44(5): 737-743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32842065

RESUMO

PURPOSE: The aim of the study was to investigate associations between computed tomography (CT) imaging characteristics, DNA methylation subtyping, and overall survival in renal cell carcinomas. METHODS: Survival curves were calculated using the Kaplan-Meier analysis. The CT data from 212 patients generated with The Cancer Imaging Archive (TCIA) were reviewed. Identified were 70 (33.0%) M1 subtype, 17 (8.0%) M2 subtype, and 125 (59.0%) M3 subtype. Univariate and multivariate analyses were performed using the logistic regression model. RESULTS: Patients with M1 subtype had the shortest median overall survival (P < 0.001). On univariate analysis, long axis of 70 mm, intratumoral calcifications, enhancement, long axis > median, short axis > median, and intratumoral vascularity were associated with a significantly higher incidence of M1 subtype (P < 0.05). Short axis ≤ median, absence of necrosis, absence of intratumoral vascularity, and nodular enhancement were associated with M2 subtype (P < 0.05). Short axis ≤ median, long axis ≤ median, long axis of less than 70 mm, and necrosis were associated with a significantly higher incidence of M3 subtype (P < 0.05). On multivariate logistic regression analysis, long axis of greater than 70 mm (odds ratio [OR] = 2.452, P = 0.004; 95% confidence interval [CI] = 1.332-4.514) and necrosis (OR = 4.758, P = 0.041, 95% CI = 1.065-21.250) were associated with M1 subtype (area under the curve [AUC] = 0. 664). Necrosis (OR = 0.047, P < 0.001, 95% CI = 0.012-0.178) and enhancement (OR = 0.083, P = 0.024, 95% CI = 0.010-0.716) were associated with M2 subtype (AUC = 0.909). Long axis > median (OR = 0.303, P < 0.001, 95% CI = 0.164-0.561) and necrosis (OR = 3.256, P = 0.003, 95% CI = 1.617-10.303) were associated with M3 subtype (AUC = 0. 664). CONCLUSIONS: The shortest survival was observed in patients with M1 subtype. This preliminary radiogenomics analysis of renal cell carcinoma demonstrated associations between CT imaging characteristic and DNA methylation subtyping.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/genética , Metilação de DNA , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/genética , Carcinoma de Células Renais/mortalidade , Estudos de Coortes , Feminino , Genômica , Humanos , Neoplasias Renais/mortalidade , Modelos Logísticos , Masculino , Tomografia Computadorizada por Raios X
7.
Bull Cancer ; 107(5S): S24-S34, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32620204

RESUMO

The standard of care for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the past decades thanks to the increasing number of treatments: anti-VEGFR tyrosine kinase inhibitors (TKI), mTOR inhibitors and immune checkpoint inhibitors (ICI): anti PD(L)-1 used as monotherapy or in combination with anti CTLA-4 or anti angiogenic therapies. In the face of rising therapeutic options, the question of the therapeutic sequences arises: which treatment for which patient? Actually, there is a lack of predictive biomarkers. A greater understanding of the cancer biology and its interaction with the microenvironment has allowed the development of genomic signatures which could perhaps be used as predictive biomarker. This review will give an insight on some robust genomic signatures assessed in mccRCC and will have a closer look at BIONIKK phase II trial, which is the first trial to adapt treatments according to the molecular characteristics of the tumor in the context of mccRCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Carcinoma de Células Renais/secundário , Tomada de Decisão Clínica , Humanos , Neoplasias Renais/patologia , Guias de Prática Clínica como Assunto
8.
Zhonghua Bing Li Xue Za Zhi ; 49(7): 693-698, 2020 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-32610380

RESUMO

Objective: To study clinical pathological characteristics, immunohistochemical, molecular genetical changes and prognosis in pediatric eosinophilic solid and cystic renal cell carcinoma (ESC RCC) with TSC2 gene mutations. Methods: The tissue samples were collected from two pediatric ESC RCC patients between 2017 and 2018. The tissues were subjected to histological examination and immunohistochemistry using EnVision system. The TFE3, TFEB gene rearrangements were tested using FISH and molecular genetic study. The paraffin sections were used for DNA extraction, PCR amplification and NGS sequencing. Results: The two patients with ESC RCC were both male, aged at 9 years and 8 months, and 13 years, respectively. The tumors were from the right kidney, 5 cm and 7 cm in size, respectively, with solid and cystic changes in cross section, and grey-reddish or grey-whitish fish meat appearance. Microscopic observation revealed the tumors had fibrous capsules, which were infiltrated by the tumor cells. The tumor cells were diffusely distributed, round-shaped, or polygon-shaped, and had voluminous cytoplasm, eosinophilic cytoplasm, various sizes of vacuoles and clear cell-like appearance. There were papillary structures in some areas, with visible fiber septa. The nuclei were round and vesicular, with multi-nucleated cells and megakaryocytes. The mitoses were not seen. A few cystic structures were visible in different sizes, and capsule walls were covered with a single layer of spike-like tumor cells. Thick-walled blood vessels were seen in the stroma, with focal lymphocytic infiltration, eosinophilic necrosis, calcifications and cholesterol crystals. Immunohistochemistry of the tumor cells was positive for PAX8 (diffuse), CK20 (focal), CKpan (focal), CK10 (1 focal, 1 diffuse), INI1, vimentin, CD68, and Ki-67 (5%~10%); the tumor cells were negative for HMB45, S-100, Melan A, p53, desmin, TFE3, CK7, CK19, EMA, CD56, CgA, Syn, CD30, CD117, WT1 and SMA. Molecular genetic study showed that TFE3 and TFEB gene rearrangements were not detected by FISH. NGS sequencing showed TSC2 p.Lys574Ter (0.198) was found in patient one and TSC2 p.Arg406Ter (0.355) in patient two. Conclusions: ESC RCC in children is a rare disease, and can be misdiagnosed easily. It has unique pathological characteristics, and immunohistochemical, molecular and genetic changes. The prognosis is relatively good.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteína 2 do Complexo Esclerose Tuberosa/genética , Adolescente , Biomarcadores Tumorais , Carcinoma de Células Renais/genética , Criança , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Masculino , Mutação
9.
Gene ; 754: 144839, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504654

RESUMO

Wilms tumor is the most frequently occurring pediatric renal malignancy. Wilms tumor suppressor-1-associated protein (WTAP) is a vital component of N6-methyltransferase complex involved in tumorigenesis. However, the roles of WTAP gene single nucleotide polymorphisms (SNPs) in Wilms tumor risk have not been clarified to date. We successfully genotyped three WTAP gene SNPs using TaqMan assay in 405 Wilms tumor patients and 1197 cancer-free controls of Chinese children. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to determine the effects of WTAP gene SNPs on Wilms tumor risk. Carriers of the rs1853259 G variant are less susceptible to developing Wilms tumor, with an adjusted OR of 0.78 (AG vs. AA: 95% CI = 0.61-0.995, P = 0.046). Single locus analysis of rs9457712 G > A and rs7766006 G > T, as well as the combined analysis of risk genotypes, failed to unveil an association with Wilms tumor risk, respectively. Stratified analysis of the three SNPs and their combined risk effects showed more significant relationships with Wilms tumor risk under certain subgroups. In all, we found weak evidence of the association between WTAP gene SNPs and the risk of Wilms tumor. Further replication studies with greater sample size and different ethnicities are necessary to verify our findings.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Fatores de Processamento de RNA/genética , Tumor de Wilms/genética , Estudos de Casos e Controles , Transformação Celular Neoplásica/patologia , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Prognóstico , Tumor de Wilms/epidemiologia , Tumor de Wilms/patologia
10.
BMC Bioinformatics ; 21(1): 232, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513106

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and accounts for cancer-related deaths. Survival rates are very low when the tumor is discovered in the late-stage. Thus, developing an efficient strategy to stratify patients by the stage of the cancer and inner mechanisms that drive the development and progression of cancers is critical in early prevention and treatment. RESULTS: In this study, we developed new strategies to extract important gene features and trained machine learning-based classifiers to predict stages of ccRCC samples. The novelty of our approach is that (i) We improved the feature preprocessing procedure by binning and coding, and increased the stability of data and robustness of the classification model. (ii) We proposed a joint gene selection algorithm by combining the Fast-Correlation-Based Filter (FCBF) search with the information value, the linear correlation coefficient, and variance inflation factor, and removed irrelevant/redundant features. Then the logistic regression-based feature selection method was used to determine influencing factors. (iii) Classification models were developed using machine learning algorithms. This method is evaluated on RNA expression value of clear cell renal cell carcinoma derived from The Cancer Genome Atlas (TCGA). The results showed that the result on the testing set (accuracy of 81.15% and AUC 0.86) outperformed state-of-the-art models (accuracy of 72.64% and AUC 0.81) and a gene set FJL-set was developed, which contained 23 genes, far less than 64. Furthermore, a gene function analysis was used to explore molecular mechanisms that might affect cancer development. CONCLUSIONS: The results suggested that our model can extract more prognostic information, and is worthy of further investigation and validation in order to understand the progression mechanism.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Aprendizado de Máquina , Área Sob a Curva , Carcinoma de Células Renais/genética , Feminino , Humanos , Neoplasias Renais/genética , Modelos Logísticos , Estadiamento de Neoplasias , RNA/metabolismo , Curva ROC
11.
Int J Exp Pathol ; 101(3-4): 87-95, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32496656

RESUMO

There are many unknown aspects of the pathogenesis of renal cell carcinoma (RCC). The aim of the current study was to define new RCC-related genes and measure their associations with RCC and clinical parameters, especially platelet/lymphocyte ratio which may be an independent predictor of prognosis in patients with RCC and other forms of cancer. Via in silico analysis upon RCC-specific deleted genes in chromosome 3, four possible ceRNAs (ATXN3, ABI2, GOLGB1 and SMAD2) were identified. Then, the expression levels of these genes in tumour and adjacent healthy kidney tissues of 19 RCC patients were determined by real-time PCR. ATXN3 and GOLGB1 gene expression levels increased but ABI2 gene expression level decreased in tumour kidney tissues when compared to normal ones. ATXN3, ABI2 and GOLGB1 gene expression levels were significantly higher in Fuhrman grade 4 than other grades (P < .001). ABI2 gene expression levels were significantly associated with higher platelet/lymphocyte ratio of the patients with RCC (P < .05). ATXN3, ABI2 and GOLGB1 may predict higher RCC grades. Also, ABI2 may regulate platelet/lymphocyte ratio which may be an independent predictor of RCC and other forms of cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Plaquetas , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Linfócitos , MicroRNAs/genética , Idoso , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Projetos Piloto , Contagem de Plaquetas
12.
Anticancer Res ; 40(6): 3119-3128, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487606

RESUMO

BACKGROUND/AIM: Myoferlin (MYOF) has emerged as an oncogenic protein in various human cancer types. This study was conducted to investigate comprehensively the expression and functional properties of MYOF in clear-cell renal-cell carcinoma (ccRCC) with respect to its value as diagnostic biomarker and therapeutic target. MATERIALS AND METHODS: mRNA and protein expression of MYOF were assessed by quantitative polymerase chain reaction and immunohistochemistry. siRNA-mediated knockdown of MYOF was performed in the RCC cell line ACHN followed by proliferation, migration and invasion assays. RESULTS: MYOF mRNA and protein expression were significantly up-regulated in ccRCC. Higher mRNA levels were measured in advanced tumors. MYOF protein expression was increased in tumors with higher histological grades, and those with positive lymph node and surgical margin status. MYOF knockdown led to reduction of migration and invasion in ACHN cells, whereas expression of angiogenesis-associated genes tyrosine-protein kinase receptor-2 (TIE2), angiopoietin 2 (ANG2) and caveolin-1 (CAV1) was up-regulated following knockdown. CONCLUSION: MYOF may serve as a diagnostic biomarker of tumor progression and a potential therapeutic target in ccRCC.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Proteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Carcinoma de Células Renais/patologia , Movimento Celular , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Invasividade Neoplásica
13.
Nat Commun ; 11(1): 3096, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555180

RESUMO

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Variações do Número de Cópias de DNA/genética , Epigenômica , Mutação em Linhagem Germinativa/genética , Humanos , Filogenia
14.
Cell Prolif ; 53(7): e12853, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32537867

RESUMO

BACKGROUND: Hypoxia-inducible factors (HIFs) are thought to play important roles in the carcinogenesis and progression of VHL-deficient clear cell renal cell carcinoma (ccRCC). METHODS: The roles of HIF-1/2α in VHL-deficient clear cell renal cell carcinoma were evaluated by bioinformatics analysis, immunohistochemistry staining and Kaplan-Meier survival analysis. The downstream genes that counteract the cancer-promoting effect of HIF were analysed by unbiased proteomics and verified by in vitro and in vivo assays. RESULTS: There was no correlation between the high protein level of HIF-1/2α and the poor prognosis of ccRCC patients in our large set of clinical data. Furthermore, NDRG1 was found to be up-regulated by both HIF-1α and -2α at the cellular level and in ccRCC tissues. Intriguingly, the high NDRG1 expression was correlated with lower Furman grade, TNM stage and longer survival for ccRCC patients compared with the low NDRG1 expression. In addition, NDRG1 suppressed the expression of series oncogenes as well as the proliferation, metastasis and invasion of VHL-deficient ccRCC cells in vitro and vivo. CONCLUSIONS: Our study demonstrated that HIF downstream gene of NDRG1 may counteract the cancer-promoting effect of HIF. These results provided evidence that NDRG1 may be a potential prognostic biomarker as well as a therapeutic target in ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Proteínas de Ciclo Celular/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Renais/genética , Regulação para Cima/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Gravidez , Ativação Transcricional/genética , Adulto Jovem
15.
Mol Biol Rep ; 47(6): 4383-4392, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-260333

RESUMO

The ACE2 gene is a receptor of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) for COVID-19 (coronavirus disease 2019). To analyze the expression profiles and clinical significances for this gene in humans, RNA-seq data representing 27 different tissues were analyzed using NCBI; total RNA was extracted from different tissues of mouse and semi-quantitative reverse transcriptional-polymerase chain reaction (Q-RT-PCR) was carried out. Immunohistochemistry expression profiles in normal tissues and cancer tissues and TCGA survival analysis in renal and liver cancer were conducted. ACE2 was highly conserved in different species. In normal tissues, ACE2 expression distributions were organ-specific, mainly in the kidney, male testis and female breast, and cardiovascular and gastrointestinal systems. High level of expression in testis, cardiovascular and gastrointestinal system indicated that SARS-CoV-2 might not only attack the lungs, but also affect other organs, particularly the testes, thus it may severely damage male sexual development for younger male and lead to infertility in an adult male, if he contracted COVID-19. On the other side, high expression of ACE2 was correlated with increased survival rate in renal and liver cancer, indicating that ACE2 is a prognostic marker in both renal cancer and liver cancers. Thus, the ACE2 is a functional receptor for SARS-CoV-2 and has a potential anti-tumor role in cancer. Taken together, this study may not only provide potential clues for further medical pathogenesis of COVID-19 and male fertility, but also indicate the clinical significance of the role of the ACE2 gene in cancer.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Neoplasias Renais/genética , Neoplasias Hepáticas/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Receptores Virais/genética , Glicoproteína da Espícula de Coronavírus/genética , Adulto , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Bases de Dados Genéticas , Feminino , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Rim/metabolismo , Rim/patologia , Rim/virologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/virologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Glândulas Mamárias Humanas/virologia , Camundongos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Ligação Proteica , Receptores Virais/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/metabolismo , Análise de Sobrevida , Testículo/metabolismo , Testículo/patologia , Testículo/virologia
16.
Gene ; 754: 144811, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32464246

RESUMO

Renal cell carcinoma (RCC) is one of the most common tumors of the urinary system, seriously impacting public health. CircRNAs have been indicated as potentially critical mediators in tumorigenesis and cancer progression. However, their specific role in the metastasis of RCC remains unclear. In present study, we identified that miR-130a-3p presented aberrantly low-level in RCC cells. Furthermore, it was demonstrated that upregulated miR-130a-3p suppressed the proliferation and migration of cell and promoted cell apoptosis in RCC. Then we predicted the underlyingly upstream modulator of miR-130a-3p was a novel circRNA hsa_circ_0054537, which exhibited dysregulated in RCC cells. Subsequently, we confirmed the direct interaction between hsa_circ_0054537 and miR-130a-3p by RNA pulldown assay. Additionally, luciferase assay confirmed the correlation between hsa_circ_0054537 and miR-130a-3p at the transcriptional level. We also found hsa_circ_0054537 could affect the tumorigenesis through binding to miR-130a-3p competitively. In addition, we identified the target of miR-130a-3p was oncogene cMet, which could be co-controlled by hsa_circ_0054537 and miR-130a-3p. In conclusion, we demonstrated that circRNA hsa_circ_0054537 functioned as a competitive endogenous RNA to regulate cMet expression via sponging miR-130a-3p in renal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Circular/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinogênese , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Proliferação de Células , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Proteínas Proto-Oncogênicas c-met/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Med ; 26(6): 909-918, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32472114

RESUMO

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Apresentação do Antígeno/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Deleção Cromossômica , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Deleção de Genes , Genômica , Antígenos de Histocompatibilidade Classe II/genética , Histona Desmetilases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Prognóstico , Complexo de Endopeptidases do Proteassoma/genética , Análise de Sequência de RNA , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Sequenciamento Completo do Exoma
18.
Medicine (Baltimore) ; 99(19): e20071, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384474

RESUMO

Renal cell carcinoma (RCC) is known to be more prevalent in autosomal dominant polycystic kidney disease (ADPKD) patients than in the general population. However, little is known about genetic alterations or changes in signaling pathways in RCC in patients with ADPKD.In the current report, whole-exome and transcriptome sequencing was performed for paired samples of tumor tissue, cyst tissue, and peripheral blood (triple set) from a patient diagnosed with ADPKD and RCC.A 68-year-old man with ADPKD underwent left partial nephrectomy and was diagnosed with RCC. DNA and RNA were extracted from the triple set of the patient. A nonsense mutation in PKD2 (p.Arg742X), which is well known as a pathogenic variant in ADPKD, was identified in the paired triple set. In the tumor sample, a somatic missense mutation of VHL (p.S65L) was found, which is known as a pathogenic mutation in Von Hippel-Lindau syndrome and RCC. Furthermore, loss of chromosome 3p, where VHL is located, was detected. Upregulated VEGFA was found in the analysis of RCC mRNA, which might be caused by the loss of VHL and accelerate angiogenesis in RCC.Proliferation was also expected to be activated by the MAPK signaling pathway, including NRAS and MAPK1 expression.


Assuntos
Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/genética , Neoplasias Renais/complicações , Neoplasias Renais/genética , Mutação , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/genética , Idoso , Humanos , Masculino
19.
Oncol Res Treat ; 43(6): 264-275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32403105

RESUMO

OBJECTIVE: Golgi alpha-mannosidase II (GM II) is one of the crucial enzymes in the process of N-glycan processing. The aim of our study was to examine the clinical significance of GM II in patients with clear cell renal cell carcinoma (ccRCC). METHODS: Quantitative reverse transcription polymerase chain reaction analysis and immunohistochemical staining were used to analyze GM II expression in patients with ccRCC. The clinical data of 62 patients with ccRCC were collected to analyze the clinical significance of GM II. The clinical significance among GM II expression, clinicopathological staging, and histological grade of ccRCC was explored. Survival analyses were performed to identify the relevance between the expression of GM II and the overall survival of patients with ccRCC. A uni-/multivariate Cox regression model was used to detect risk factors affecting the prognosis of patients with ccRCC. Subsequently, the proliferation and migration of ccRCC cells were detected after transfecting with GM II-short hairpin RNA (shRNA). RESULTS: The results of these comparisons suggested that GM II expression of ccRCC tissues was dramatically higher than that of para-carcinoma tissues (p < 0.05). GM II expression in the high-differentiation group was lower than that in the median- and low-differentiation groups (p < 0.05). GM II expression in stage I and II tissues was lower than that in stage III and IV tissues (p < 0.05). The expression levels of GM II in the group without lymph node metastasis were lower than those in the group with lymph node metastasis (p < 0.05). Survival analysis indicated that patients with ccRCC with high GM II expression generally had decreased overall survival. Uni-/multivariate Cox model analyses further suggested an association between GM II expression and prognosis of patients with breast cancer. High GM II expression is a potential and independent prognostic biomarker in ccRCC. The inhibition of GM II by transfecting with GM II-shRNA could reduce the proliferation and migration of ccRCC. CONCLUSION: GM II expression in human ccRCC tissues was upregulated compared with that found in normal human renal tissue, and GM II may promote the progression and migration of ccRCC. Furthermore, the GM II gene may be used as a promising tumor marker for the diagnosis and prognosis of ccRCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Manosidases/metabolismo , Idoso , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Masculino , Manosidases/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
20.
Mol Biol Rep ; 47(6): 4383-4392, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32410141

RESUMO

The ACE2 gene is a receptor of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) for COVID-19 (coronavirus disease 2019). To analyze the expression profiles and clinical significances for this gene in humans, RNA-seq data representing 27 different tissues were analyzed using NCBI; total RNA was extracted from different tissues of mouse and semi-quantitative reverse transcriptional-polymerase chain reaction (Q-RT-PCR) was carried out. Immunohistochemistry expression profiles in normal tissues and cancer tissues and TCGA survival analysis in renal and liver cancer were conducted. ACE2 was highly conserved in different species. In normal tissues, ACE2 expression distributions were organ-specific, mainly in the kidney, male testis and female breast, and cardiovascular and gastrointestinal systems. High level of expression in testis, cardiovascular and gastrointestinal system indicated that SARS-CoV-2 might not only attack the lungs, but also affect other organs, particularly the testes, thus it may severely damage male sexual development for younger male and lead to infertility in an adult male, if he contracted COVID-19. On the other side, high expression of ACE2 was correlated with increased survival rate in renal and liver cancer, indicating that ACE2 is a prognostic marker in both renal cancer and liver cancers. Thus, the ACE2 is a functional receptor for SARS-CoV-2 and has a potential anti-tumor role in cancer. Taken together, this study may not only provide potential clues for further medical pathogenesis of COVID-19 and male fertility, but also indicate the clinical significance of the role of the ACE2 gene in cancer.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Neoplasias Renais/genética , Neoplasias Hepáticas/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Receptores Virais/genética , Glicoproteína da Espícula de Coronavírus/genética , Adulto , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Bases de Dados Genéticas , Feminino , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Rim/metabolismo , Rim/patologia , Rim/virologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/virologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Glândulas Mamárias Humanas/virologia , Camundongos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Ligação Proteica , Receptores Virais/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/metabolismo , Análise de Sobrevida , Testículo/metabolismo , Testículo/patologia , Testículo/virologia
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