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1.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208775

RESUMO

Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of N-desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Renais/genética , Inibidores de Proteínas Quinases/farmacologia , Sunitinibe/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Imunofluorescência , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Modelos Biológicos , Inibidores de Proteínas Quinases/uso terapêutico , Sunitinibe/uso terapêutico
2.
Zhonghua Zhong Liu Za Zhi ; 43(7): 769-774, 2021 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-34289571

RESUMO

Objective: To investigate the effect of long non-coding RNA HOTAIR (LncRNA HOTAIR) on the proliferation, apoptosis and drug resistance of Wilms tumor cells and its molecular mechanism. Methods: Collected nephroblastoma tissues and normal tumor side tissues in 32 children with renal syblastoma surgical treatment at Zhengzhou University Children's Hospital from 2015 to 2019. Real-time quantitative reverse transcription polymerase chain reaction, (qRT-PCR)was used to detect the expression of HOTAIR in Wilms tumor tissues and adjacent tissues. Small interfering RNA technology was used to delete the expression of HOTAIR in Wilms tumor cell SK-NEP-1. Cell counting kit-8 (CCK-8)was used to detect cell proliferation after transfection. Flow cytometry and terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) staining to detect the apoptosis. Western blot was used to detect the expression of Wnt/ß-catenin signaling pathway related proteins.CCK-8 was used to detect the proliferation inhibition of cells treated with different concentrations of cisplatin after transfection. Results: Compared with adjacent tissues, HOTAIR was highly expressed in Wilms tumor tissues (P<0.05). The expression levels of Wnt, ß-catenin, Cyclin D1, c-myc in the control group were (0.89±0.08), (0.94±0.10), (0.72±0.06), (1.10±0.11), and (1.06±0.11), (0.92±0.08), (0.66±0.07), (1.25±0.11) of the si-RNA group, while (0.54±0.05), (0.41±0.05), (0.25±0.03), (0.56±0.06) of the si-HOTAIR group. The expression levels of these protein were significantly down-regulated in the si-HOTAIR group when compared with the control group and the si-RNA group (P<0.05). The absorbance (A) values of SK-NEP-1 cells in the si-HOTAIR group at 24, 48 and 72 hours after transfection were (0.31±0.02), (0.37±0.04), (0.69±0.07), significantly lower than (0.49±0.05), (0.78±0.08), (1.22±0.14) in the control group and (0.57±0.06), (0.68±0.07), (0.94±0.09) in the si-RNA group (P<0.05). The apoptosis rate in the si-HOTAIR group was (13.81±1.25)%, significantly higher than (6.54±0.72)% in the control group and (4.35±0.40)% in the si-RNA group (P<0.05). The cell positive rate of TUNEL cells in the si-HOTAIR group was (35.14±3.50)%, significantly higher than (20.16±2.18)% in the control group and (21.09±2.35)% in the si-RNA group (P<0.05). The median inhibitory concentration (IC(50)) of the si-HOTAIR group was (62.48±5.97) µmol/L, significantly lower than (88.27±9.05) µmol/L of the control group and (92.50±9.11) µmol/L of the si-RNA group (P<0.05). Conclusions: Suppression of LncRNA HOTAIR can inhibit the proliferation of Wilms tumor cells, promote cell apoptosis, decrease cell resistance to cisplatin. The mechanism may be related to the inhibition of Wnt/ß-catenin signaling pathway activation.


Assuntos
Neoplasias Renais , RNA Longo não Codificante , Tumor de Wilms , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Criança , Resistência a Medicamentos , Humanos , Neoplasias Renais/genética , RNA Longo não Codificante/genética , Tumor de Wilms/genética , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(7): 652-655, 2021 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-34247370

RESUMO

OBJECTIVE: To analyze the expression of microRNA-106a(miR-106a) in renal cell carcinoma (RCC) and its correlation with clinicopathological characteristics and prognosis of patients. METHODS: Serum samples of 64 patients with newly diagnosed RCC were collected as the study group, and serum samples of 40 healthy individuals were used as the control group. Real-time fluorescence quantitative PCR was used to determine the expression level of miR-106a in each group. The correlation between miR-106a expression and clinicopathological characteristics of the patients was studied with single factor analysis and multiple Logistic regression model. Kaplan-Meier survival curve was used to analyze its correlation with the prognosis of patients. RESULTS: Before surgery, compared with the control group (1.17± 0.58), RCC patients with high- (9.15± 0.96) and low-expression(3.45± 0.37) had increased expression of miR-106a. Postoperatively, the expression level of miR-106a in both groups of patients decreased to 1.53± 0.18 and 1.75± 0.21, respectively. The area under the curve (AUC) of the diagnostic value of serum miR-106a for RCC was 0.782 (95% CI: 0.661-0.902). With an optimal cutoff value of 0.531, the sensitivity was 78.10% and the specificity was 75.00%. Serum miR-106a level of RCC patients with TNM stage T3 or T4, clinical stage II or III, lymph node metastasis, and recurrence were significantly increased. The high expression of serum miR-106a in RCC patients has an independent relationship with the tumor TNM stage and lymph node metastasis. Of the 64 follow-up patients, 4 were lost and 30 had died. Among them, the median survival time of patients in the miR-106a high expression group was 30 months, which was significantly shorter than that of the low expression group (52 months). CONCLUSION: The serum level of miR-106a is elevated in RCC patients, and may be used as a molecular marker for the diagnosis of RCC. High serum expression of miR-106a is an independent predictor for tumor TNM stage and lymph node metastasis, as well as an independent predictor for poor prognosis of RCC patients.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , MicroRNAs , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , MicroRNAs/genética , Recidiva Local de Neoplasia , Prognóstico
4.
BMJ Case Rep ; 14(6)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172479

RESUMO

Xp11.2 translocation renal cell carcinoma (TRCC) is a rare and aggressive variant of renal cell carcinoma (RCC) when presenting in adults. We report a case of a man in his early 40s who was diagnosed with stage III Xp11.2 TRCC and underwent radical nephrectomy. Seven months following the surgery, an adrenal nodule and bilateral pulmonary nodules were discovered. He underwent cryoablation of the adrenal nodule and systemic treatment with daily pazopanib. He displayed stable disease for approximately 6 years. Following this period, multiple hospitalisations interrupted daily pazopanib therapy resulting in progression of disease. His regimen was then changed to ipilimumab and nivolumab, followed by current daily therapy with axitinib. The patient now shows stable disease in his 10th year after diagnosis. This case study demonstrates the efficacy of pazopanib for metastatic Xp11.2 TRCC and warrants further investigation to supplement the guidelines regarding the use of targeted therapy for TRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Adulto , Carcinoma de Células Renais/genética , Cromossomos Humanos X , Humanos , Indazóis , Neoplasias Renais/genética , Masculino , Pirimidinas , Sulfonamidas , Translocação Genética
5.
Nat Commun ; 12(1): 3896, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162837

RESUMO

Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference "cellular signals" in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of "fetalness" with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.


Assuntos
Neoplasias Renais/genética , Rim/metabolismo , RNA Mensageiro/genética , RNA-Seq/métodos , Análise de Célula Única/métodos , Transcriptoma , Adulto , Algoritmos , Criança , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Rim/embriologia , Neoplasias Renais/embriologia , Neoplasias Renais/metabolismo , Modelos Genéticos , Transdução de Sinais/genética
6.
Nat Commun ; 12(1): 3969, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172722

RESUMO

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1+ tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Resultado do Tratamento , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Sequenciamento Completo do Genoma
7.
BMC Bioinformatics ; 22(Suppl 10): 270, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34058987

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinoma and patients at advanced stage showed poor survival rate. Despite microRNAs (miRNAs) are used as potential biomarkers in many cancers, miRNA biomarkers for predicting the tumor stage of ccRCC are still limitedly identified. Therefore, we proposed a new integrated machine learning (ML) strategy to identify a novel miRNA signature related to tumor stage and prognosis of ccRCC patients using miRNA expression profiles. A multivariate Cox regression model with three hybrid penalties including Least absolute shrinkage and selection operator (Lasso), Adaptive lasso and Elastic net algorithms was used to screen relevant prognostic related miRNAs. The best subset regression (BSR) model was used to identify optimal prognostic model. Five ML algorithms were used to develop stage classification models. The biological significance of the miRNA signature was analyzed by utilizing DIANA-mirPath. RESULTS: A four-miRNA signature associated with survival was identified and the expression of this signature was strongly correlated with high risk patients. The high risk patients had unfavorable overall survival compared with the low risk group (HR = 4.523, P-value = 2.86e-08). Univariate and multivariate analyses confirmed independent and translational value of this predictive model. A combined ML algorithm identified six miRNA signatures for cancer staging prediction. After using the data balancing algorithm SMOTE, the Support Vector Machine (SVM) algorithm achieved the best classification performance (accuracy = 0.923, sensitivity = 0.927, specificity = 0.919, MCC = 0.843) when compared with other classifiers. Furthermore, enrichment analysis indicated that the identified miRNA signature involved in cancer-associated pathways. CONCLUSIONS: A novel miRNA classification model using the identified prognostic and tumor stage associated miRNA signature will be useful for risk and stage stratification for clinical practice, and the identified miRNA signature can provide promising insight to understand the progression mechanism of ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , MicroRNAs , Carcinoma de Células Renais/genética , Humanos , Neoplasias Renais/genética , MicroRNAs/genética , Estadiamento de Neoplasias , Taxa de Sobrevida
8.
Adv Exp Med Biol ; 1311: 117-126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014538

RESUMO

According to data from the American Cancer Society, cancer is one of the deadliest health problems globally. Annually, renal cell carcinoma (RCC) causes more than 100,000 deaths worldwide [1-4], posing an urgent need to develop effective treatments to increase patient survival outcomes. New therapies are expected to address a major factor contributing to cancer's resistance to standard therapies: oncogenic heterogeneity. Gene expression can vary tremendously among different types of cancers, different patients of the same tumor type, and even within individual tumors; various metabolic phenotypes can emerge, making singletherapy approaches insufficient. Novel strategies targeting the diverse metabolism of cancers aim to overcome this obstacle. Though some have yielded positive results, it remains a challenge to uncover all of the distinct metabolic profiles of RCC. In the quest to overcome this obstacle, the metabolic oriented research focusing on these cancers has offered freshly new perspectives, which are expected to contribute heavily to the development of new treatments.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Fenótipo
9.
Oxid Med Cell Longev ; 2021: 6617969, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953831

RESUMO

Deleterious effects of SNPs found in genes encoding transcriptional factors, as well as antioxidant and detoxification enzymes, are disputable; however, their functional significance seems to modify the risk for clear cell renal cell carcinoma (ccRCC) development and progression. We investigated the effect of specific Nrf2, SOD2, GPX1 gene variants and GSTP1ABCD haplotype on ccRCC risk and prognosis and evaluated the association between GSTP1 and regulatory (JNK1/2) and executor (caspase-3) apoptotic molecule expression in ccRCC tissue samples and the presence of GSTP1 : JNK1/2 protein : protein interactions. Genotyping was performed in 223 ccRCC patients and 336 matched controls by PCR-CTTP and qPCR. Protein expression was analyzed using immunoblot, while the existence of GSTP1 : JNK1 protein : protein interactions was investigated by immunoprecipitation experiments. An increased risk of ccRCC development was found among carriers of variant genotypes of both SOD2 rs4880 and GSTP1 rs1695 polymorphisms. Nrf2 rs6721961 genetic polymorphism in combination with both rs4880 and rs1695 showed higher ccRCC risk as well. Haplotype analysis revealed significant risk of ccRCC development in carriers of the GSTP1C haplotype. Furthermore, GSTP1 variant forms seem to affect the overall survival in ccRCC patients, and the proposed molecular mechanism underlying the GSTP1 prognostic role might be the presence of GSTP1 : JNK1/2 protein : protein interactions.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Fator 2 Relacionado a NF-E2/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Progressão da Doença , Predisposição Genética para Doença , Genótipo , Homeostase , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Polimorfismo de Nucleotídeo Único , Prognóstico
10.
Med Sci Monit ; 27: e930639, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33963171

RESUMO

Renal cell carcinoma (RCC) is a most common type of urologic neoplasms; it accounts for 3% of malignant tumors, with high rates of relapse and mortality. The most common types of renal cancer are clear cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal carcinoma (chRCC), which account for 90%, 6-15%, and 2-5%, respectively, of all renal malignancies. Although surgical resection, chemotherapy, and radiotherapy are the most common treatment method for those diseases, their effects remain dissatisfactory. Furthermore, recent research shows that the treatment efficacy of checkpoint inhibitors in advanced RCC patients is widely variable. Hence, patients urgently need a new molecular biomarker for early diagnosis and evaluating the prognosis of RCC. MicroRNAs (miRNAs) belong to a family of short, non-coding RNAs that are highly conserved, have long half-life evolution, and post-transcriptionally regulate gene expression; they have been predicted to play crucial roles in tumor metastasis, invasion, angiogenesis, proliferation, apoptosis, epithelial-mesenchymal transition, differentiation, metabolism, cancer occurrence, and treatment resistance. Although some previous papers demonstrated that miRNAs play vital roles in renal cancer, such as pathogenesis, diagnosis, and prognosis, the roles of miRNAs in kidney cancer are still unclear. Therefore, we reviewed studies indexed in PubMed from 2017 to 2020, and found several studies suggesting that there are more than 82 miRNAs involved in renal cancers. The present review describes the current status of miRNAs in RCC and their roles in progression, diagnosis, therapy targeting, and prognosis of RCC.


Assuntos
Neoplasias Renais/genética , Neoplasias Renais/patologia , MicroRNAs/genética , Animais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Transição Epitelial-Mesenquimal/genética , Humanos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Prognóstico
11.
Aging (Albany NY) ; 13(10): 14015-14038, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030133

RESUMO

BACKGROUND: Sorafenib can improve the survival of metastatic clear cell renal cell carcinoma (ccRCC) patients. However, its benefits are modest, as patients eventually become resistant, and the mechanisms remain elusive. NUPR1, a stress-induced protein, has been reported in malignancies and functions as an oncogene by modulating the stress response, facilitating survival in harsh environments and conferring drug resistance. However, its role in ccRCC has not been explored. METHODS: The expression and clinical significance of NUPR1 were analyzed in ccRCC patients in in-house patients and The Cancer Genome Atlas (TCGA) cohorts. The biological functions of NUPR1 were investigated. Xenografts were performed to confirm the effects of NUPR1 on tumorigenesis. The molecular mechanism of NUPR1 was investigated in vitro and in vivo. RESULTS: NUPR1 expression was upregulated in tumor tissue. Further analysis showed that NUPR1 overexpression was associated with an aggressive phenotype and predicted a poor prognosis. Depletion of NUPR1 suppressed tumorigenesis and sensitized cells to sorafenib treatment. Finally, mechanistic investigations indicated that NUPR1 promoted tumorigenesis in ccRCC by increasing stemness and activating the PTEN/AKT/mTOR signaling pathway. CONCLUSIONS: Collectively, our results suggest that NUPR1 may serve as a predictor of ccRCC. Notably, NUPR1 silencing reversed sorafenib resistance in ccRCC. These findings provide a novel potential therapeutic target in the clinical management of ccRCC.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Sorafenibe/farmacologia , Idoso , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
J Transl Med ; 19(1): 209, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33985542

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal malignancy. Methyltransferase like 13 (METTL13) functions as an oncogene in most of human cancers, but its function and mechanism in ccRCC remains unreported. METHODS: qRT-PCR, western blotting and immunohistochemistry were used to detect METTL13's expression in tissues. The effects of METTL13 on ccRCC cells' growth and metastasis were determined by both functional experiments and animal experiments. Weighted gene co-expression network analysis (WGCNA) was performed to annotate METTL13's functions and co-immunoprecipitation (co-IP) was used to determine the interaction between METTL13 and c-Myc. RESULTS: METTL13 was underexpressed in ccRCC tissues compared to normal kidney tissues and its low expression predicted poor prognosis for ccRCC patients. The in vitro studies showed that knockdown and overexpression of METTL13 respectively led to increase and decrease in ccRCC cells' proliferation, viability, migratory ability and invasiveness as well as epithelial-mesenchymal transition (EMT). The in vivo experiment demonstrated the inhibitory effect that METTL13 had on ccRCC cells' growth and metastasis. Bioinformatic analyses showed various biological functions and pathways METTL13 was involved in. In ccRCC cells, we observed that METTL13 could negatively regulate PI3K/AKT/mTOR/HIF-1α pathway and that it combined to c-Myc and inhibited c-Myc protein expression. CONCLUSIONS: In general, our finding suggests that high expression of METTL13 is associated with favorable prognosis of ccRCC patients. Meanwhile, METTL13 can inhibit growth and metastasis of ccRCC cells with participation in multiple potential molecular mechanisms. Therefore, we suggest METTL13 can be a new diagnostic and therapeutic target for ccRCC in the future.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Metiltransferases , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
13.
Adv Anat Pathol ; 28(4): 251-257, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009776

RESUMO

Recent advances in molecular genetics have expanded our knowledge of renal tumors and enabled a better classification. These studies have revealed that renal tumors with predominantly "eosinophilic/oncocytic" cytoplasm include several novel biological subtypes beyond the traditionally well-recognized renal oncocytoma and an eosinophilic variant of chromophobe renal cell carcinoma. Herein, we present a comprehensive review of the eosinophilic vacuolated tumor (EVT) building upon a case report including radiology, histopathology, electron microscopy, and next-generation sequencing. EVTs are characterized by mTORC1 activation. We speculate that loss of chromosome 1 in EVT with MTOR mutation may be driven in part by an advantage conferred by loss of the remaining MTOR wild-type allele. mTORC1 is best known for its role in promoting protein translation and it is interesting that dilated cisterns of rough endoplasmic reticulum (ER) likely account for the cytoplasmic vacuoles seen by light microscopy. We present an integrated view of EVT as well as cues that can assist in the differential diagnosis.


Assuntos
Carcinoma de Células Renais/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 1/genética , Neoplasias Renais/patologia , Mutação , Serina-Treonina Quinases TOR/genética , Biomarcadores Tumorais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Cromossomos Humanos Par 1/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Serina-Treonina Quinases TOR/metabolismo
14.
Comput Methods Programs Biomed ; 206: 106132, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34010800

RESUMO

Kidney cancer is a dangerous disease affecting many patients all over the world. Early-stage diagnosis and correct identification of kidney cancer subtypes play an essential role in the patient's survival; therefore, its subtypes diagnosis and classification are the main challenges in kidney cancer treatment. Medical studies have proved that miRNA dysregulation can increase the risk of cancer. Thus, in this paper, we propose a new machine learning approach for significant miRNAs identification and kidney cancer subtype classification to design an automatic diagnostic tool. The proposed method contains two main steps: feature selection and classification. First, we apply the feature selection algorithm to choose the candidate miRNAs for each subtype. The feature selection algorithm utilizes the AMGM measure to select significant miRNAs with high discriminant power. Next, the candidate miRNAs are fed to a classifier to evaluate the candidate features. In the classification step, the proposed self-organizing deep neuro-fuzzy system is employed to classify kidney cancer subgroups. The new deep neuro-fuzzy system consists of a deep structure in the rule layer and novel architecture in the fuzzifier layer. The proposed self-organizing deep neuro-fuzzy system can help us to overcome the main obstacles in the field of neuro-fuzzy system applications, such as the curse of dimensionality. The goal of this paper is to illustrate that the neuro-fuzzy system can very useful in high dimensional data, such as genomics data, using the proposed deep neuro-fuzzy system. The obtained results illustrated that our proposed method has succeeded in classifying kidney cancer subtypes with high accuracy based on the selected miRNAs.


Assuntos
Neoplasias Renais , MicroRNAs , Algoritmos , Lógica Fuzzy , Genômica , Humanos , Neoplasias Renais/genética , MicroRNAs/genética , Redes Neurais de Computação
15.
Niger J Clin Pract ; 24(4): 614-620, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33851686

RESUMO

Aim: To assess the VHL gene expression as a prognostic marker in Renal Cell Carcinoma (RCC) and compare it with clinicopathologic features. Materials and Methods: This retrospective observational study was conducted in the department of Urology and Renal Transplantation in Sri Ramachandra Institute of Higher Education and Research, Chennai from August 2016 to August 2018. Thirty patients who have undergone a radical/partial nephrectomy with biopsy proven histological diagnosis of RCC during the study period were included in the study. Data was analyzed using Statistical package for Social Sciences version 17. Results: A complete loss and retained VHL expression were noted in 60% and 40% of the RCC specimens. Association between smoking and VHL expression was found to be statistically significant. There was no statistical significance found between age group, sex, chief complaints, BMI. ECOG score, hypertension, family history, location of tumor, calcification, venous system or lymphnode involvement. However, rT staging, nature of lesion and cut surface, HPE type, pT staging, HPE grade, necrosis and lympho-vascular invasion were also found to be statistically significant. Conclusion: Complete loss of VHL expression was noted in majority of the specimens that leads to the development of RCC. Smoking has been found to be statistically significant in tumors that retain VHL expression which may contributes to more aggressive form of tumor. Association between rT staging, nature of lesion and cut surface, HPE type, pT staging, HPE grade, necrosis and lympho-vascular invasion were also found to be statistically significant.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Humanos , Índia , Neoplasias Renais/genética , Prognóstico , Proteína Supressora de Tumor Von Hippel-Lindau
16.
Zhonghua Yi Xue Za Zhi ; 101(14): 1020-1025, 2021 Apr 13.
Artigo em Chinês | MEDLINE | ID: mdl-33845541

RESUMO

Objective: To investigate the role of miR-186 in renal cell carcinoma (RCC) and its molecular mechanism of miR-186 targeting E-cadherin to inhibit cell proliferation and metastasis of RCC. Methods: A total of 40 RCC samples which were collected in Shanxi Provincial People's Hospital from January 2015 to January 2019 and four RCC cell lines were measured the expression of miR-186 by real-time quantitative polymerase chain reaction (qPCR). The effect of miR-186 overexpression on the proliferation, invasion, migration and apoptosis of 786-O cells were detected by cell counting kit-8(CCK-8), colony formation, wound healing and Transwell assay and flow cytometric analysis. The effect of miR-186 on the expression of epithelial-to-mesenchymal transition (EMT) related markers (E-cadherin, N-cadherin and Vimentin) was analyzed by Western blot, and the dual luciferase reporter was used to verify the miR-186 targeting E-cadherin. Results: There were 26 males and 14 females with an age of (58.4±9.2) years. miR-186 expression levels decreased significantly in RCC tissues and cells (tissues: 0.005 2±0.000 4 vs 0.015 5±0.001 5, P<0.001; cells: 0.334 3±0.025 1, 0.457 0±0.026 6, 0.229 8±0.011 0, 0.741 1±0.091 0 vs 1.000 0±0.085 2, all P<0.001). The expression of miR-186 had a negative correlation with tumor size (≥4 cm: 0.003 2±0.003 4 vs<4 cm: 0.008 4±0.007 2, P<0.001), TNM staging (≤Ⅱ: 0.007 8±0.005 8 vs>Ⅱ: 0.002 7±0.002 3, P=0.021) and Fuhrman grade (<Ⅱ: 0.008 8±0.006 3 vs ≥Ⅱ: 0.004 6±0.003 0, P<0.001). The overexpression of miR-186 significantly inhibited cell proliferation and metastasis, and induced cell apoptosis. delivered.miR-186 overexpression can retard tumor growth in nude mice. Luciferase assay showed that E-cadherin was a direct target gene of miR-186. Conclusion: miR-186 may affect EMT of RCC and inhibit the proliferation and metastasis of RCC by directly regulating E-cadherin.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , MicroRNAs , Animais , Caderinas/genética , Caderinas/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética
17.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(3): 447-452, 2021 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-33849838

RESUMO

OBJECTIVE: To investigate the effect of speckle-type POZ protein (SPOP) on proliferation, apoptosis, migration and invasion of renal cell carcinoma (RCC) and explore the potential mechanisms. OBJECTIVE: Renal carcinoma cell lines (786-O, A704, and Caki-2) cultured in vitro were transfected with a SPOP-overexpressing plasmid, and the changes in proliferation of the cells were detected using colony formation and MTT assay; TUNEL assay was used to assess apoptosis of the cells. The changes in migration and invasion abilities of the cells were examined using wound healing assay and Transwell assay. The mRNA and protein levels of SPOP and c-Jun in the transfected cells were measured using real-time PCR and Western blotting. OBJECTIVE: SPOP over-expression obviously promoted the proliferation, migration and invasion of 786-O, A704 and Caki-2 cells (P < 0.05). Compared with the control cells, 786-o and Caki-2 cells over-expressing SPOP exhibited significantly lowered apoptosis rates (P < 0.05). The results of real-time PCR demonstrated that the transfected cells did not show obvious changes in the mRNA level of c-Jun, but the protein expressions of SPOP and c-jun increased significantly as shown by Western blotting (P < 0.05). OBJECTIVE: SPOP can promote proliferation, migration, and invasion and suppress apoptosis of renal carcinoma cells possibly by promoting the expression of c-Jun.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Apoptose , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Invasividade Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-jun , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
18.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799514

RESUMO

Treatment of patients with urothelial carcinoma (UC) of the bladder or renal cancer has changed significantly during recent years and efforts towards biomarker-directed therapy are being investigated. Immune checkpoint inhibition (ICI) or fibroblast growth factor receptor (FGFR) directed therapy are being evaluated for non-muscle invasive bladder cancer (NMIBC) patients, as well as muscle-invasive bladder cancer (MIBC) patients. Meanwhile, efforts to predict tumor response to neoadjuvant chemotherapy (NAC) are still ongoing, and genomic biomarkers are being evaluated in prospective clinical trials. Currently, patients with metastatic UC (mUC) are usually treated with second-line ICI, while cisplatin-ineligible patients with programmed death-ligand 1 (PD-L1) positive tumors can benefit from first-line ICI. Platinum-relapsed UC patients harboring FGFR2/3 mutations can be treated with erdafitinib, while enfortumab vedotin has emerged as a novel third-line treatment option for mUC. In metastatic (clear cell) renal cell carcinoma (RCC), ICI was first introduced as second-line treatment after vascular endothelial growth factor receptor-tyrosine kinase inhibition (VEGFR-TKI). Currently, ICIs have also been introduced as first-line treatment in metastatic RCC. Although there is no evidence up to now for beneficial adjuvant treatment after surgery with VEGFR-TKIs in high-risk non-metastatic RCC, several trials are underway investigating the potential beneficial effect of ICIs in this setting.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Cisplatino/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Metástase Linfática , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/imunologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/imunologia , Recidiva , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
19.
Biomed Res Int ; 2021: 6682758, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33834072

RESUMO

It was initially found that neural-restrictive silencer factor/repressor 1-silencing transcription factor (REST) is a transcriptional repressor of neuronal genes in nonneuronal cells. However, it is reported to be abundantly expressed in various types of aggressive cancer cells. In this study, we evaluated the expression patterns of REST in renal cell carcinoma and found that its expression is lower in tumor tissues compared to normal tissues. The chi-square test showed that the low REST expression was closely related to patients' clinicopathologic parameters, including the pathologic stage and survival status. ROC curve showed that REST had excellent clinical diagnostic prospect. In addition, patients with low REST expression had poor over survival (OS) and relapse-free survival (RFS). Univariate and multivariate Cox regression analysis confirmed that the low REST expression was an independent predictor of poor prognosis in renal cell carcinoma. Gene set enrichment analysis identified P53 pathway, reactive oxygen species pathway, glycolysis, DNA repair, cholesterol homeostasis, and MYC targets V2 enriched with low REST expression phenotype. These results suggested that REST may be a novel biomarker for the diagnosis and prognosis of renal cell carcinoma in clinical applications.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/diagnóstico , Neoplasias Renais/metabolismo , Proteínas Repressoras/metabolismo , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Prognóstico , Curva ROC , Proteínas Repressoras/genética , Transdução de Sinais
20.
Biomed Res Int ; 2021: 6627562, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791367

RESUMO

Background: The optimal tool for predicting the survival of renal cell carcinoma (RCC) patients with lung metastases remains controversial. Methods: We selected patients diagnosed with RCC and lung metastases, from 2010 to 2015, from the Surveillance, Epidemiology, and End Results (SEER) database. After the selection of inclusion criteria and exclusion criterion, the rest of the patients were incorporated into model analysis. Least absolute shrinkage and selection operator (LASSO) regression was used to select the most important features for construction of a nomogram predicting cancer-specific survival. A calibration plot and the concordance index (C-index) were used to estimate nomogram efficacy in a validation cohort. The association between important factors selected by LASSO regression, and prognosis was assessed by the Kaplan-Meier (KM) survival curve. The receiver operating characteristic (ROC) curves were drawn to compare sensitivity and specificity between the nomogram we built and the TNM stage-based model. Results: A total of 1,369 patients met the inclusion criteria, but not the exclusion criteria. The LASSO regression model reduced 15 features to seven potential predictors of survival, including tumor grade, the extent of surgery, N and T status, histological profile, and brain and bone metastasis status. Such features had good discrimination in the KM survival curves. The nomogram showed excellent discriminatory power (C-index, 0.71; 95% confidence interval: 0.70 to 0.72) and good calibration in terms of both 1- and 2-year cancer-specific survival. The nomogram showed great discriminatory power (C-index 0.68) and adequate calibration when applied to the validation cohort. The areas under the curve (AUCs) of nomogram were 0.767 and 0.780, respectively, and the AUCs of TNM stage were 0.617 and 0.618 at 1 and 2 years, respectively. Conclusions: Our nomogram might play a major role in predicting the cancer-specific survival of RCC patients with lung metastases.


Assuntos
Carcinoma de Células Renais , Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais , Neoplasias Pulmonares , Nomogramas , Idoso , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Taxa de Sobrevida
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