RESUMO
Genetic factors coordinate with environmental factors to drive the pathogenesis of prostate adenocarcinoma (PRAD). SPOP is one of the most mutated genes and LRP5 mediates lipid metabolism that is abnormally altered in PRAD. Here, we investigated the potential cross-talk between SPOP and LRP5 in PRAD. We find a negative correlation between SPOP and LRP5 proteins in PRAD. SPOP knockdown increased LRP5 protein while SPOP overexpression resulted in LRP5 reduction that was fully rescued by proteasome inhibitors. LRP5 intracellular tail has SPOP binding site and the direct interaction between LRP5 and SPOP was confirmed by Co-IP and GST-pulldown. Moreover, LRP5 competed with Daxx for SPOP-mediated degradation, establishing a dynamic balance among SPOP, LRP5 and Daxx. Overexpression of LRP5 tail could shift this balance to enhance Daxx-mediated transcriptional inhibition, and inhibit T cell activity in a co-culture system. Further, we generated human and mouse prostate cancer cell lines expressing SPOP variants (F133V, A227V, R368H). SPOP-F133V and SPOP-A227V have specific effects in up-regulating the protein levels of PD-1 and PD-L1. Consistently, SPOP-F133V and SPOP-A227V show robust inhibitory effects on T cells compared to WT SPOP in co-culture. This is further supported by the mouse syngeneic model showing that SPOP-F133V and SPOP-A227V enhance tumorigenesis of prostate cancer in in-vivo condition. Taken together, our study provides evidence that SPOP-LRP5 crosstalk plays an essential role, and the genetic variants of SPOP differentially modulate the expression and activity of immune checkpoints in prostate cancer.
Assuntos
Neoplasias da Próstata , Proteínas Repressoras , Masculino , Animais , Camundongos , Humanos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Antígeno B7-H1/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/patologia , Carcinogênese/genética , Transformação Celular Neoplásica , Mutação , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Chaperonas Moleculares/genética , Proteínas Correpressoras/genéticaRESUMO
Background: Pyroptosis is a programmed death mode of inflammatory cells, which is closely related to tumor progression and tumor immunity. Clear cell renal cell carcinoma (ccRCC) is the major pathological type of renal cell carcinoma (RCC) with poor prognosis. Many theories have tried to clarify the mechanism in the development of ccRCC, but the role of pyroptosis in ccRCC has not been well described. The main purpose of this study is to explore the role of pyroptosis in ccRCC and establish a novel prognosis prediction model of pyroptosis-related molecular signatures for ccRCC. Methods: In the present study, we made a systematical analysis of the association between ccRCC RNA transcriptome sequencing data from The Cancer Genome Atlas (TCGA) database [which included 529 ccRCC patients who were randomized in a training cohort (n=265) and an internal validation cohort (n=264)] and 40 pyroptosis-related genes (PRGs), from which four genes (CASP9, GSDME, IL1B and TIRAP) were selected to construct a molecular prediction model of PRGs for ccRCC. In addition, a cohort of 114 ccRCC patients from Shanghai Eastern Hepatobiliary Surgery Hospital (EHSH) was used as external data to verify the effectiveness of the model by immunohistochemistry. Moreover, the biological functions of the four PRGs were also verified in ccRCC 786-O and 769-P cells by Western blot (WB), CCK-8 cell proliferation, and Transwell invasion assays. Results: The model was able to differentiate high-risk patients from low-risk patients, and this differentiation was consistent with their clinical survival outcomes. In addition, the four PRGs also affected the ability of cell proliferation and invasion in ccRCC. Conclusion: The prediction model of pyroptosis-related molecular markers developed in this study may prove to be a novel understanding for ccRCC.
Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Piroptose/genética , China , Prognóstico , Neoplasias Renais/genéticaRESUMO
BACKGROUND: Renal cell carcinoma (RCC) is a hypermetabolic disease. Abnormal up-regulation of glycolytic signaling promotes tumor growth, and glycolytic metabolism is closely related to immunotherapy of renal cancer. The aim of the present study was to determine whether and how the glycolysis-related biomarker TCIRG1 affects aerobic glycolysis, the tumor microenvironment (TME) and malignant progression of clear cell renal cell carcinoma (ccRCC). METHODS: Based on The Cancer Genome Atlas (TCGA, n = 533) and the glycolysis-related gene set from MSigDB, we identified the glycolysis-related gene TCIRG1 by bioinformatics analysis, analyzed its immunological properties in ccRCC and observed how it affected the biological function and glycolytic metabolism using online databases such as TIMER 2.0, UALCAN, LinkedOmics and in vitro experiments. RESULTS: It was found that the expression of TCIRG1, was significantly increased in ccRCC tissue, and that high TCIRG1 expression was associated with poor overall survival (OS) and short progression-free interval (PFI). In addition, TCIRG1 expression was highly correlated with the infiltration immune cells, especially CD4+T cell Th1, CD8+T cell, NK cell, and M1 macrophage, and positively correlated with PDCD1, CTLA4 and other immunoinhibitors, CCL5, CXCR3 and other chemokines and chemokine receptors. More importantly, TCIRG1 may regulate aerobic glycolysis in ccRCC via the AKT/mTOR signaling pathway, thereby affecting the malignant progression of ccRCC cell lines. CONCLUSIONS: Our results demonstrate that the glycolysis-related biomarker TCIRG1 is a tumor-promoting factor by affecting aerobic glycolysis and tumor immune microenvironment in ccRCC, and this finding may provide a new idea for the treatment of ccRCC by combination of metabolic intervention and immunotherapy.
RESUMO
BACKGROUND: Tumor-associated macrophages (TAMs) are closely related to unfavorable prognosis of patients with clear cell renal cell carcinoma (ccRCC). However, the important molecules in the interaction between ccRCC and TAMs are unclear. METHODS: TCGA-KIRC gene expression data of tumor tissues and normal tissues adjacent to tumor were compared to identify differentially expressed genes in ccRCC. TAMs related genes were discovered by analyzing the correlation between these differentially expressed genes and common macrophage biomarkers. Gene set enrichment analysis was performed to predict functions of TAMs related gene. The findings were further validated using RNA sequencing data obtained from the CheckMate 025 study and immunohistochemical analysis of samples from 350 patients with ccRCC. Kaplan-Meier survival curve, Cox regression analysis and Harrell's concordance index analysis were used to determine the prognostic significance. RESULTS: In this study, we applied bioinformatic analysis to explore TAMs related differentially expressed genes in ccRCC and identified 5 genes strongly correlated with all selected macrophage biomarkers: STAC3, LGALS9, TREM2, FCER1G, and PILRA. Among them, FCER1G was abundantly expressed in tumor tissues and showed prognostic importance in patients with ccRCC who received treatment with Nivolumab; however, it did not exhibit prognostic value in those treated with Everolimus. We also discovered that high expression levels of FCER1G are related to T cell suppression. Moreover, combination of FCER1G and macrophage biomarker CD68 can improve the prognostic stratification of patients with ccRCC from TCGA-KIRC. Based on the immunohistochemical analysis of samples from patients with ccRCC, we further validated that FCER1G and CD68 are both highly expressed in tumor tissue and correlate with each other. Higher expression of CD68 or FCER1G in ccRCC tissue indicates shorter overall survival and progression-free survival; patients with high expression of both CD68 and FCER1G have the worst outcome. Combining CD68 and FCER1G facilitates the screening of patients with a worse prognosis from the same TNM stage group. CONCLUSIONS: High expression of FCER1G in ccRCC is closely related to TAMs infiltration and suppression of T cell activation and proliferation. Combining the expression levels of FCER1G and macrophage biomarker CD68 may be a promising postoperative prognostic index for patients with ccRCC.
Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Receptores Fc/imunologia , Macrófagos Associados a Tumor/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Proliferação de Células/genética , Galectinas/imunologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Ativação Linfocitária/genética , Glicoproteínas de Membrana/imunologia , Prognóstico , Modelos de Riscos Proporcionais , Receptores Imunológicos/imunologia , Análise de Sequência de RNARESUMO
OBJECTIVES: To share our centre's experience dealing with ureteric obstruction, in particular malignant obstructions, by investigating the deformation and flow velocity of three commonly used, readily accessible ureteric stents under at different compression levels and surface change at three time points (new, 1 month and 3 months after implantation). SUBJECTS AND METHODS: Scanning electron microscope (SEM) analysis was conducted on ureteric JJ stents, including the Cook Universa Soft, the Kang Yi Bo (KYB) antireflux and the Urovision Visiostar ESWL JJ stents. Deformation caused by compression was measured using a digital force gauge. Intraluminal flow velocity was tested with the stents subject to different compression levels. RESULTS: The Urovision Visiostar JJ stent demonstrated significantly better anti-compression capability. The Cook Universa Soft and KYB antireflux JJ stents showed favourable draining velocity without compression, but the velocity dropped substantially on compression. The velocity of the KYB antireflux JJ stent reduced substantially after 3 months of implantation, while the Urovision Visiostar achieved the best draining effect when under compression at all three time points. CONCLUSION: The Urovision Visiostar JJ stent demonstrated significantly greater resistance to compression than the other two JJ stents, as well as better drainage under compression. Patients with benign or malignant ureteric compression might benefit from use of the Urovision Visiostar stent. Large prospective clinical trials are needed to confirm these findings.
Assuntos
Ureter , Obstrução Ureteral , Drenagem , Humanos , Estudos Prospectivos , Stents/efeitos adversos , Obstrução Ureteral/etiologia , Obstrução Ureteral/cirurgiaRESUMO
BACKGROUND: The benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. New treatments demand prompt exploration for clinical therapies. Ubiquitin-specific peptidase 39 (USP39) serves as the pro-tumor factor in several previous studies of other malignant tumors. To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC. METHODS: We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. USP39 knockdown or overexpression plasmids were transfected into 786-O and ACHN cells. The HUVEC received cell supernatants of 786-O and ACHN cells with knockdown or overexpression USP39.The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by affinity purification and mass spectrometry, co-immunoprecipitation and Western blot assays. RESULTS: The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P < 0.001), and negatively correlated with the survival rate of RCC patients (P < 0.01). Silencing of USP39 in 786-O and ACHN cells inhibited cell proliferation and colony formation, and induced S phase arrest. USP39 overexpression significantly increased the number of tubules (P < 0.05) and branches (P < 0.01) formed by HUVEC cells, and USP39 knockdown produced an opposite effect (P < 0.05). The USP39 (101-565) fragment directly mediated its binding to SRSF1 and SRPK1, and promoted the phosphorylation of SRSF1 to regulate VEGF-A alternative splicing. USP39 knockdown upregulated the expression of VEGF-A165b, and USP39 overexpression downregulated the expression of VEGF-A165b significantly (both P < 0.05). CONCLUSION: USP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through inhibiting VEGF-A165b alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC.
RESUMO
BACKGROUND: Renal cell carcinoma (RCC) is one of the most common malignant tumors originating from the renal parenchymal urinary epithelial system. Tripartite motif 47 (TRIM47) is a member of the TRIM family proteins, which has E3 ligase activity and has been demonstrated to be involved in the occurrence and prognosis of many tumors. The main purpose of this study is to explore the role and potential mechanism of TRIM47 in promoting malignant biological behavior of RCC. MATERIALS AND METHODS: TRIM47 mRNA and protein levels in human renal cancer and paired normal adjacent tissues were detected by qRT-PCR and Western blot. The effects of TRIM47 knockdown and overexpression in renal cell carcinoma cells on cell proliferation, invasion and xenograft tumor growth in nude mice were analyzed. The molecular mechanism was explored by mass spectrometric exploration,Western blot and immunoprecipitation assays. RESULTS: TRIM47 promoted RCC cell proliferation in vitro and in vivo as an oncogene. Mechanistically, TRIM47 exerted an E3 ligase activity by interacting with P53 protein to increase its ubiquitination and degradation, which further promoted the malignant biological behavior of RCC. CONCLUSIONS: Our study demonstrated that the TRIM47-P53 axis played a functional role in RCC progression and suggested a potential therapeutic target for RCC.
RESUMO
Human Ataxin-3 protein was first identified as a transcript from patients with Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3). Recent studies have demonstrated that Ataxin-3 is involved in gastric cancer and lung cancer. However, the role of Ataxin-3 in testicular cancer (TC) remains poorly understood. This study aims to explore the significance of Ataxin-3 expression in TC. Firstly, we investigated 53 paired TC and para-tumor tissues and found that Ataxin-3 was overexpressed in TC tissues, and this overexpression of Ataxin-3 was correlated with tumor stages. Functionally, Ataxin-3 overexpression promoted cell proliferation, and Ataxin-3 knockdown inhibited cell proliferation. In addition, up-regulation of Ataxin-3 inhibited the expression of PTEN and activated the AKT/mTOR pathway. Conversely, inhibition of Ataxin-3 suppressed the expression of p-AKT and p-mTOR, and increased the expression of p-4EBP1. These findings may provide a better understanding about the mechanism of TC and suggest that Ataxin-3 may be a potential prognostic biomarker and therapeutic target for TC.
Assuntos
Ataxina-3/genética , Regulação Neoplásica da Expressão Gênica , PTEN Fosfo-Hidrolase/genética , Proteínas Repressoras/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Ataxina-3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Humanos , Masculino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Testiculares/metabolismo , Testículo/metabolismo , Testículo/patologiaRESUMO
BACKGROUND: Health-related quality-of-life (HRQoL) is an important consideration after radical cystectomy (RC). Lack of effective ways to assess HRQoL after RC and unawareness of disease-specific problems related to ileal conduit (IC) and orthotopic ileal neobladder (OIN) are serious problems. The present study was to evaluate and compare morbidity and HRQoL between IC and OIN after RC, and examine their unmet needs in the two groups. METHODS: A retrospective analysis was made of 294 patients treated with RC in our hospital between 2007 and 2013. Matched pair analysis was used to determine the patients of IC and OIN groups. Patient HRQoL between IC and OIN groups was assessed using the bladder-specific bladder cancer index (BCI) and European Organization for Research and Treatment of Cancer Body Image scale (BIS) questionnaires. Unmet information of patients undergoing these two urinary diversions was recorded through individual interviews. RESULTS: Of the 117 included patients, 39 patients were treated with OIN and the other 78 matched patients with IC as controls for matched pair analysis. There was no significant difference in baseline characteristics between the two groups. OIN patients showed significantly better BIS scores in terms of HRQoL outcomes after RC at a short-term (<1 year) follow-up level, but there was no significant difference at a long-term (>1 year) follow-up level between the two groups. Interestingly, urinary bother (UB) and urinary function (UF) were poor in OIN patients at the one-year follow-up level, but there was no significant difference in UB between the two groups at the long term follow-up level. Unmet needs analysis showed that OIN patients had a more positive attitude towards treatment and participated in physical and social activities more positively, although they may have more urine leakage problems. CONCLUSIONS: The mean BIS score in OIN group patients was significantly better than that in IC group patients at the one-year follow-up level, but there was no significant difference at the long-term follow-up level. Due attention should be paid to some particular unmet needs in individual patients in managing the two UD modalities.
Assuntos
Cistectomia/psicologia , Cistectomia/reabilitação , Íleo/transplante , Avaliação das Necessidades/estatística & dados numéricos , Qualidade de Vida/psicologia , Derivação Urinária/psicologia , Idoso , China/epidemiologia , Terapia Combinada , Cistectomia/estatística & dados numéricos , Feminino , Humanos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Satisfação do Paciente/estatística & dados numéricos , Prevalência , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Derivação Urinária/estatística & dados numéricosRESUMO
Nin one binding-1 protein (NOB1) is a kind of zinc protein involved in ribosome biogenesis and controlled proteolysis. To explore the function of NOB1 in human prostate malignancy, we analyzed the expression of NOB1 in prostate cancer and found that NOB1 was elevated in prostate cancer tissues compared to the adjacent normal tissues. Knockdown of NOB1 by lentivirus-shRNA inhibited the proliferation and colony-formation ability of PC-3 and DU145 prostate cancer cells. Cell cycle analysis showed that silencing of NOB1 caused G0/G1 phase arrest and a slight decrease in S phase (P < 0.05). Furthermore, knockdown of NOB1 significantly suppressed the mobility of PC-3 and DU145 prostate cancer cells (P < 0.05). Collectively, these findings suggested that NOB1 might be involved in tumorigenecity of prostate cancer, and could be a potential molecular target for prostate cancer gene therapy.
Assuntos
Proteínas Nucleares/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas de Ligação a RNA/genética , Androgênios/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos Nus , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/metabolismo , RNA Interferente Pequeno , Proteínas de Ligação a RNA/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Prostate cancer (PCa) is one of the most threatening health problems for the elderly males. However, our understanding of the disease has been limited by the research technology for a long time. Recently, the maturity of sequencing technology and omics studies has been accelerating the studies of PCa, establishing themselves as an essential impetus in this field. Methods: We assessed Web of Science (WoS) database for publications of sequencing and omics studies in PCa on July 3rd, 2023. Bibliometrix was used to conduct ulterior bibliometric analysis of countries/affiliations, authors, sources, publications, and keywords. Subsequently, purposeful large amounts of literature reading were proceeded to analyze research hotspots in this field. Results: 3325 publications were included in the study. Research associated with sequencing and omics studies in PCa had shown an obvious increase recently. The USA and China were the most productive countries, and harbored close collaboration. CHINNAIYAN AM was identified as the most influential author, and CANCER RESEARCH exhibited huge impact in this field. Highly cited publications and their co-citation relationships were used to filtrate literatures for subsequent literature reading. Based on keyword analysis and large amounts of literature reading, 'the molecular pathogenesis of PCa' and 'the clinical application of sequencing and omics studies in PCa' were summarized as two research hotspots in the field. Conclusion: Sequencing technology had a deep impact on the studies of PCa. Sequencing and omics studies in PCa helped researchers reveal the molecular pathogenesis, and provided new possibilities for the clinical practice of PCa.
RESUMO
BACKGROUND: Kidney renal papillary cell carcinoma (KIRP) is the second most prevalent malignant cancer originating from the renal epithelium. Nowadays, cancer stem cells and stemness-related genes (SRGs) are revealed to play important roles in the carcinogenesis and metastasis of various tumors. Consequently, we aim to investigate the underlying mechanisms of SRGs in KIRP. METHODS: RNA-seq profiles of 141 KIRP samples were downloaded from the TCGA database, based on which we calculated the mRNA expression-based stemness index (mRNAsi). Next, we selected the differentially expressed genes (DEGs) between low- and high-mRNAsi groups. Then, we utilized weighted gene correlation network analysis (WGCNA) and univariate Cox analysis to identify prognostic SRGs. Afterwards, SRGs were included in the multivariate Cox regression analysis to establish a prognostic model. In addition, a regulatory network was constructed by Pearson correlation analysis, incorporating key genes, upstream transcription factors (TFs), and downstream signaling pathways. Finally, we used Connectivity map analysis to identify the potential inhibitors. RESULTS: In total, 1124 genes were characterized as DEGs between low- and high-RNAsi groups. Based on six prognostic SRGs (CCKBR, GPR50, GDNF, SPOCK3, KC877982.1, and MYO15A), a prediction model was established with an area under curve of 0.861. Furthermore, among the TFs, genes, and signaling pathways that had significant correlations, the CBX2-ASPH-Notch signaling pathway was the most significantly correlated. Finally, resveratrol might be a potential inhibitor for KIRP. CONCLUSIONS: We suggested that CBX2 could regulate ASPH through activation of the Notch signaling pathway, which might be correlated with the carcinogenesis, development, and unfavorable prognosis of KIRP.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Células-Tronco Neoplásicas , Humanos , Prognóstico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Biomarcadores Tumorais/genética , Feminino , Perfilação da Expressão Gênica , Pessoa de Meia-Idade , Transdução de Sinais/genéticaRESUMO
To compare clinical characteristics and survival outcomes of patients with multiple renal cell carcinoma versus single renal cell carcinoma. Develop a prognostic model for predicting prognosis in patients with multiple tumors and analyze prognostic factors. Patients with primary multiple renal cell carcinoma were selected from the Surveillance, Epidemiology, and End Results database (2004-2015). They were divided into single-tumor and multiple-tumor groups. Survival analysis was conducted using the Kaplan-Meier method and log-rank test. A Cox regression model was used to identify potential prognostic factors. A total of 19,489 renal cell carcinoma cases were included, with 947 in the multiple-tumor group and 18,542 in the single-tumor group. The multiple-tumor group had lower cancer-specific survival (P = 0.03, HR = 1.431). Cox regression identified risk factors for the multiple-tumor group including number of tumors, gender, combined summary stage, T stage, N stage, tumor size, and type of surgery. The predicted probabilities showed acceptable agreement with the actual observations at 3-, 5-, and 8-years area under the curve values in both the training and validation cohorts (0.831 vs. 0.605; 0.775 vs. 0.672; and 0.797 vs. 0.699, respectively). Compared with single renal cell carcinoma, multiple renal cell carcinoma is associated with decreased cancer-specific survival. Additionally, we identified several prognostic factors including the number of tumors, T stage, tumor size, and type of surgery. These findings offer valuable insights for selecting appropriate treatment strategies for patients diagnosed with multiple renal cell carcinomas.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Programa de SEER , Humanos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Idoso , Análise de Sobrevida , Estimativa de Kaplan-Meier , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/mortalidade , Estadiamento de Neoplasias , Adulto , Fatores de Risco , Idoso de 80 Anos ou mais , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: TSPAN7 is an important factor in tumor progression. However, the precise function of TSPAN7 and its role in pan-cancer are not clear. METHODS: Based on Xinhua cohort incorporating 370 patients with kidney neoplasm, we conducted differential expression analysis by immunohistochemistry between tumor and normal tissues, and explored correlations of TSPAN7 with patients' survival. Subsequently, we conducted a pan-cancer study, and successively employed differential expression analysis, competing endogenous RNA (ceRNA) analysis, protein-protein interaction (PPI) analysis, correlation analysis of TSPAN7 with clinical characteristics, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. Last but not least, gene set enrichment analysis was applied to identify enriched pathways of TSPAN7. RESULTS: In Xinhua cohort, TSPAN7 expression was significantly up-regulated (P-value = 0.0019) in tumor tissues of kidney neoplasm patients. High TSPAN7 expression was associated with decreases in overall survival (OS) (P-value = 0.009) and progression-free survival (P-value = 0.009), and it was further revealed as an independent risk factor for OS (P-value = 0.0326, HR = 5.66, 95%CI = 1.155-27.8). In pan-cancer analysis, TSPAN7 expression was down-regulated in most tumors, and it was associated with patients' survival, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. The ceRNA network and PPI network of TSPAN7 were also constructed. Last but not least, the top five enriched pathways of TSPAN7 in various tumors were identified. CONCLUSION: TSPAN7 served as a promising biomarker of various tumors, especially kidney neoplasms, and it was closely associated with tumor purity, tumor genomics, tumor immunology, and drug sensitivity in pan-cancer level.
Assuntos
Biologia Computacional , Neoplasias Renais , Tetraspaninas , Humanos , Tetraspaninas/genética , Tetraspaninas/metabolismo , Biologia Computacional/métodos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Estudos Retrospectivos , Masculino , Feminino , Neoplasias/genética , Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Prognóstico , Proteínas do Tecido NervosoRESUMO
Neoadjuvant tyrosine kinase inhibitor (TKI) therapy is an important treatment option for advanced renal cell carcinoma (RCC). Many RCC patients may fail to respond or be resistant to TKI therapy. We aimed to explore the key mechanisms of neoadjuvant therapy résistance. We obtained tumor samples from matched pre-treatment biopsy and post-treatment surgical samples and performed single-cell RNA sequencing. Sunitinib-resistant ccRCC cell lines were established. Ferroptosis was detected by ferrous ion and lipid peroxidation levels. Tumor growth and resistance to Sunitinib was validated in vitro and vivo. Immunohistochemistry was used to validate the levels key genes and lipid peroxidation. Multi-center cohorts were included, including TCGA, ICGC, Checkmate-025 and IMmotion151 clinical trial. Survival analysis was performed to identify the associated clinical and genomic variables. Intratumoral heterogeneity was first described in the whole neoadjuvant management. The signature of endothelial cells was correlated with drug sensitivity and progression-free survival. Ferroptosis was shown to be the key biological program in malignant cell resistance. We observed tissue lipid peroxidation was negatively correlated with IL6 and tumor response. TKI-resistant cell line was established. SLC7A11 knockdown promoted cell growth and lipid peroxidation, increased the ferroptosis level, and suppressed the growth of tumor xenografts significantly (P < 0.01). IL6 could reverse the ferroptosis and malignant behavior caused by SLC7A11 (-) via JAK2/STAT3 pathway, which was rescued by the ferroptosis inducer Erastin. Our data indicate that ferroptosis is a novel strategy for advanced RCC treatment, which activated by IL6, providing a new idea for resistance to TKIs.
Assuntos
Sistema y+ de Transporte de Aminoácidos , Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Neoplasias Renais , Terapia Neoadjuvante , Sunitinibe , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Terapia Neoadjuvante/métodos , Sunitinibe/farmacologia , Animais , Linhagem Celular Tumoral , Camundongos , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Proteínas Quinases/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Feminino , Masculino , Terapia de Alvo Molecular , Interleucina-6/metabolismo , Interleucina-6/genética , Progressão da DoençaRESUMO
BACKGROUND: Tertiary lymphoid structures (TLSs) serve as organized lymphoid aggregates that influence immune responses within the tumor microenvironment. This study aims to investigate the characteristics and clinical significance of TLSs and tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC). METHODS: TLSs and TILs were analyzed comprehensively in 754 ccRCC patients from 6 academic centers and 532 patients from The Cancer Genome Atlas. Integrated analysis was performed based on single-cell RNA-sequencing datasets from 21 ccRCC patients to investigate TLS heterogeneity in ccRCC. Immunohistochemistry and multiplex immunofluorescence were applied. Cox regression and Kaplan-Meier analyses were used to reveal the prognostic significance. RESULTS: The study demonstrated the existence of TLSs and TILs heterogeneities in the ccRCC microenvironment. TLSs were identified in 16% of the tumor tissues in 113 patients. High density (>0.6/mm2) and maturation of TLSs predicted good overall survival (OS) (p<0.01) in ccRCC patients. However, high infiltration (>151) of scattered TILs was an independent risk factor of poor ccRCC prognosis (HR=14.818, p<0.001). The presence of TLSs was correlated with improved progression-free survival (p=0.002) and responsiveness to therapy (p<0.001). Interestingly, the combination of age and TLSs abundance had an impact on OS (p<0.001). Higher senescence scores were detected in individuals with immature TLSs (p=0.003). CONCLUSIONS: The study revealed the contradictory features of intratumoral TLSs and TILs in the ccRCC microenvironment and their impact on clinical prognosis, suggesting that abundant and mature intratumoral TLSs were associated with decreased risks of postoperative ccRCC relapse and death as well as favorable therapeutic response. Distinct spatial distributions of immune infiltration could reflect effective antitumor or protumor immunity in ccRCC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Linfócitos do Interstício Tumoral , Estruturas Linfoides Terciárias , Microambiente Tumoral , Humanos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Estruturas Linfoides Terciárias/imunologia , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/genética , Feminino , Masculino , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Prognóstico , Estudos de Coortes , IdosoRESUMO
Renal cell carcinoma (RCC) is considered a "metabolic disease" characterized by elevated glycolysis in patients with advanced RCC. Tyrosine kinase inhibitor (TKI) therapy is currently an important treatment option for advanced RCC, but drug resistance may develop in some patients. Combining TKI with targeted metabolic therapy may provide a more effective approach for patients with advanced RCC. An analysis of 14 RCC patients (including three needle biopsy samples with TKI resistance) revealed by sing-cell RNA sequencing (scRNA-seq) that glycolysis played a crucial role in poor prognosis and drug resistance in RCC. TCGA-KIRC and glycolysis gene set analysis identified DEPDC1 as a target associated with malignant progression and drug resistance in KIRC. Subsequent experiments demonstrated that DEPDC1 promoted malignant progression and glycolysis of RCC, and knockdown DEPDC1 could reverse TKI resistance in RCC cell lines. Bulk RNA sequencing (RNA-seq) and non-targeted metabolomics sequencing suggested that DEPDC1 may regulate RCC glycolysis via AKT/mTOR/HIF1α pathway, a finding supported by protein-level analysis. Clinical tissue samples from 98 RCC patients demonstrated that DEPDC1 was associated with poor prognosis and predicted RCC metastasis. In conclusion, this multi-omics analysis suggests that DEPDC1 could serve as a novel target for TKI combined with targeted metabolic therapy in advanced RCC patients with TKI resistance.
Assuntos
Carcinoma de Células Renais , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Renais , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Glicólise/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linhagem Celular Tumoral , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/genética , Transdução de Sinais , Camundongos , Animais , Masculino , Feminino , Camundongos Nus , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão GênicaRESUMO
Wilms tumor, originating from aberrant fetal nephrogenesis, is the most common renal malignancy in childhood. The overall survival of children is approximately 90%. Although existing risk-stratification systems are helpful in identifying patients with poor prognosis, the recurrence rate of Wilms tumors remains as high as 15%. To resolve this clinical problem, diverse studies on the occurrence and progression of the disease have been conducted, and the results are encouraging. A series of molecular biomarkers have been identified with further studies on the mechanism of tumorigenesis. Some of these show prognostic value and have been introduced into clinical practice. Identification of these biomarkers can supplement the existing risk-stratification systems. In the future, more biomarkers will be discovered, and more studies are required to validate their roles in improving the detection rate of occurrence or recurrence of Wilms tumor and to enhance clinical outcomes.
RESUMO
Tumor growth, metastasis and therapeutic response are believed to be regulated by the tumor and its microenvironment (TME) in advanced renal cell carcinoma (RCC). However, the mechanisms underlying genomic, transcriptomic and epigenetic alternations in RCC progression have not been completely defined. In this study, single-cell RNA-sequencing (scRNA-seq) data were obtained from eight tissue samples of RCC patients, including two matched pairs of primary and metastatic sites (lymph nodes), along with Hi-C, transposable accessible chromatin by high-throughput (ATAC-seq) and RNA-sequencing (RNA-seq) between RCC (Caki-1) and human renal tubular epithelial cell line (HK-2). The identified target was verified in clinical tissue samples (microarray of 407 RCC patients, TMA-30 and TMA-2020), whose function was further validated by in vitro and in vivo experiments through knockdown or overexpression. We profiled transcriptomes of 30514 malignant cells, and 14762 non-malignant cells. Comprehensive multi-omics analysis revealed that malignant cells and TME played a key role in RCC. The expression programs of stromal cells and immune cells were consistent among the samples, whereas malignant cells expressed distinct programs associated with hypoxia, cell cycle, epithelial differentiation, and two different metastasis patterns. Comparison of the hierarchical structure showed that SERPINE2 was related to these NNMF expression programs, and at the same time targeted the switched compartment. SERPINE2 was highly expressed in RCC tissues and lowly expressed in para-tumor tissues or HK-2 cell line. SERPINE2 knockdown markedly suppressed RCC cell growth and invasion, while SERPINE2 overexpression dramatically promoted RCC cell metastasis both in vitro and in vivo. In addition, SERPINE2 could activate the epithelial-mesenchymal transition pathway. The above findings demonstrated that the role of distinct expression patterns of malignant cells and TME played a distinct role in RCC progression. SERPINE2 was identified as a potential therapeutic target for inhibiting metastasis in advanced RCC.