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1.
Biol Direct ; 19(1): 72, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39175035

RESUMO

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 Nervoso
2.
Cell Death Dis ; 15(7): 533, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39068164

RESUMO

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 , Animais , Feminino , Humanos , Masculino , Camundongos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Glicólise/efeitos dos fármacos , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
3.
J Immunother Cancer ; 12(6)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38908856

RESUMO

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 , Idoso
4.
Cancer Lett ; 593: 216963, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38768682

RESUMO

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 Doença
5.
Cancer Lett ; 587: 216725, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38364963

RESUMO

Next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide (Enza) and darolutamide (Daro), are initially effective for the treatment of advanced prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). However, patients often relapse and develop cross-resistance, which consequently makes drug resistance an inevitable cause of CRPC-related mortality. By conducting a comprehensive analysis of GEO datasets, CRISPR genome-wide screening results, ATAC-seq data, and RNA-seq data, we systemically identified PAK1 as a significant contributor to ARSI cross-resistance due to the activation of the PAK1/RELA/hnRNPA1/AR-V7 axis. Inhibition of PAK1 followed by suppression of NF-κB pathways and AR-V7 expression effectively overcomes ARSI cross-resistance. Our findings indicate that PAK1 represents a promising therapeutic target gene for the treatment of ARSI cross-resistant PCa patients in the clinic. STATEMENT OF SIGNIFICANCE: PAK1 drives ARSI cross-resistance in prostate cancer progression.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Detecção Precoce de Câncer , Recidiva Local de Neoplasia/genética , Nitrilas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
6.
Int J Med Sci ; 21(3): 496-507, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250606

RESUMO

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/genética
8.
iScience ; 26(12): 108370, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38034348

RESUMO

Previous bulk RNA sequencing or whole genome sequencing on clear cell renal cell carcinoma (ccRCC) subtyping mainly focused on ccRCC cell origin or the complex tumor microenvironment (TME). Based on the single-cell RNA sequencing (scRNA-seq) data of 11 primary ccRCC specimens, cancer stem-cell-like subsets could be differentiated into five trajectories, whereby we further classified ccRCC cells into three groups with diverse molecular features. These three ccRCC subgroups showed significantly different outcomes and potential targets to tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). Tumor cells in three differentiation directions exhibited distinct interactions with other subsets in the ccRCC niches. The subtyping model was examined through immunohistochemistry staining in our ccRCC cohort and validated the same classification effect as the public patients. All these findings help gain a deeper understanding about the pathogenesis of ccRCC and provide useful clues for optimizing therapeutic schemes based on the molecular subtype analysis.

9.
Cancer Cell Int ; 23(1): 186, 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37649034

RESUMO

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.

10.
Oncoimmunology ; 12(1): 2173422, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36776524

RESUMO

Increasing evidence reveals that the interaction between tumor cells and tumor-associated macrophages (TAMs) facilitates the progression of prostate cancer, but the related mechanisms remained unclear. This study determined how gankyrin, a component of the 19S regulatory complex of the 26S proteasome, regulates the progression and androgen deprivation therapy (ADT) resistance of prostate cancer through tumor cell-TAM interactions. In vitro functional experiments and in vivo subcutaneous tumor models were used to explore the biological role and molecular mechanisms of gankyrin in prostate cancer cell-TAM interactions. 234 prostate cancer patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin through immunohistochemistry (IHC) and statistical analyses, and high gankyrin expression was correlated with poor prognosis. In addition, gankyrin facilitated the progression and ADT resistance of prostate cancer. Mechanistically, gankyrin recruited and upregulated non-POU-domain-containing octamer-binding protein (NONO) expression, resulting in increased androgen receptor (AR) expression. AR then bound to the high-mobility group box 1 (HMGB1) promoter to trigger HMGB1 transcription, expression, and secretion. Moreover, HMGB1 was found to promote the recruitment and activation of TAMs, which secrete IL-6 to reciprocally promote prostate cancer progression, ADT resistance and gankyrin expression via STAT3, resulting in formation of a gankyrin/NONO/AR/HMGB1/IL-6/STAT3 positive feedback loop. Furthermore, targeting the interaction between tumor cells and TAMs by blocking this loop inhibited ADT resistance in a tumor xenograft model. Taken together, the data show that gankyrin serves as a reliable prognostic indicator and therapeutic target for prostate cancer patients.


Assuntos
Proteína HMGB1 , Neoplasias da Próstata , Complexo de Endopeptidases do Proteassoma , Humanos , Masculino , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/uso terapêutico , Proteína HMGB1/genética , Interleucina-6/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo
11.
Cell Death Dis ; 14(1): 30, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36646679

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.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/metabolismo , Serpina E2/genética , Multiômica , Análise da Expressão Gênica de Célula Única , Linhagem Celular Tumoral , Neoplasias Renais/metabolismo , Proliferação de Células/genética , RNA , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Microambiente Tumoral/genética
12.
Oncol Rep ; 49(2)2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36562383

RESUMO

Clear cell renal cell carcinoma (ccRCC) is a frequent malignant tumor of the kidney which has a dismal prognosis. At present, targeted therapies and immunotherapy have achieved significant results; however, the overall survival rate of patients with ccRCC remains unacceptably poor. It is therefore necessary to find novel therapeutic and diagnostic targets for ccRCC. It has been reported that enolase 2 (ENO2) is an oncogene, although its function in the immune microenvironment and in the growth of ccRCC has yet to be fully elucidated. The present study analyzed the data of patients with ccRCC both from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, and from clinical samples obtained from Third Affiliated Hospital of the Second Military Medical University to investigate the role of ENO2 in the progression of ccRCC and the correlation between ENO2 and certain clinical features. It was found that the expression of ENO2 was elevated both in patients with ccRCC retrieved from the GEO and TCGA databases and in clinical ccRCC samples obtained from Third Affiliated Hospital of the Second Military Medical University. In addition, the prognosis of patients was poorer when ENO2 was highly expressed. Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) confirmed that ENO2 participated in the regulation of various pathways in ccRCC. In vitro experiments including Cell Counting Kit­8 cell proliferation assay, Transwell and Matrigel assays confirmed that ENO2 could promote the proliferation and migration of ccRCC cells. Furthermore, a number of immunosuppressive indicators were identified that positively correlated with ENO2 expression. In conclusion, the present study revealed that ENO2 expression promotes the proliferation, invasion and migration of ccRCC cells, and may serve as a novel predictor to evaluate prognosis and the efficacy of immune checkpoint blockade treatment for patients with ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Fosfopiruvato Hidratase , Microambiente Tumoral , Humanos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Prognóstico , Microambiente Tumoral/imunologia , Invasividade Neoplásica
13.
BMC Cancer ; 22(1): 140, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35120484

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 RNA
14.
Medicine (Baltimore) ; 100(39): e27101, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596111

RESUMO

ABSTRACT: Rhabdomyosarcoma (RMS) is a common malignant soft tissue sarcoma, which is the third most common soft tissue sarcoma after malignant fibrohistoma and liposarcoma. The discovery of potential postbiomarkers could lead to early and more effective treatment measures to reduce the mortality of RMS. The discovery of biomarker is expected to be the direction of targeted therapy, providing a new direction for the precise treatment of RMS.Gene Expression Omnibus database was used to download the tow gene profiles, GSE28511 and GSE135517. GEO2R was applied to identify differently expressed genes (DEGs) between RMS and normal group. Database for Annotation, Visualization and Integrated Discovery and Metascape can perform the enrichment analysis for the DEGs. Protein-protein interaction network was constructed, and the hub genes was identified by the Cytoscape. Expression and overall survival analysis of hub genes were performed.A total of 15 common DEGs were screened between RMS and normal tissues. The enrichment analysis here showed that the DEGs mainly enriched in the muscle filament sliding, myofibril, protein complex, sarcomere, myosin complex, nuclear chromosome, and tight junction. The 6 hub genes (DNA Topoisomerase II Alpha, Insulin Like Growth Factor 2, HIST1H4C, Cardiomyopathy Associated 5, Myosin Light Chain 2 [MYL2], Myosin Heavy Chain 2) were identified. Compared with the normal tissues, MYL2 were down-regulated in the RMS tissues. RMS patients with low expression level of MYL2 had poorer overall survival times than those with high expression levels (P < .05).In summary, lower expression of MYL2 was 1 prediction for poor prognosis of RMS. MYL2 is hope to be the target of therapy, which leads to more effective treatment and reduces the mortality rate of RMS.


Assuntos
Biomarcadores Tumorais/genética , Miosinas Cardíacas/genética , Regulação Neoplásica da Expressão Gênica , Cadeias Leves de Miosina/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma/mortalidade , Humanos , Prognóstico , Taxa de Sobrevida
15.
BMC Cancer ; 21(1): 890, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348693

RESUMO

BACKGROUND: Although many intratumoral biomarkers have been reported to predict clear cell renal cell carcinoma (ccRCC) patient prognosis, combining intratumoral and clinical indicators could predict ccRCC prognosis more accurately than any of these markers alone. This study mainly examined the prognostic value of HECT, C2 and WW domain-containing E3 ubiquitin protein ligase 1 (HECW1) expression in ccRCC patients in combination with established clinical indicators. METHODS: The expression level of HECW1 was screened out by data-independent acquisition mass spectrometry (DIA-MS) and analyzed in ccRCC patients from the The Cancer Genome Atlas (TCGA) database and our cohort. A total of 300 ccRCC patients were stochastically divided into a training cohort and a validation cohort, and real-time PCR, immunohistochemistry (IHC) and statistical analyses were employed to examine the prognostic value of HECW1 in ccRCC patients. RESULTS: The expression level of HECW1 usually decreased in human ccRCC specimens relative to control specimens in TCGA (p < 0.001). DIA-MS, Real-time PCR, and IHC analyses also showed that the majority of ccRCCs harbored decreased HECW1 expression compared with that in normal adjacent tissues (p < 0.001). Additionally, HECW1 expression was reduced in ccRCC cell lines compared with the normal renal cell line HK-2 (p < 0.001). Moreover, lower HECW1 expression was found in ccRCC patients with a higher tumor node metastasis (TNM) stage, bone metastasis, or first-line targeted drug resistance (p < 0.001). Low HECW1 expression indicated higher TNM stage, SSIGN (Stage, Size, Grade, and Necrosis) score and WHO/ISUP grade and poor prognosis in ccRCC patients (p < 0.05). Even after multivariable adjustment, HECW1, TNM stage, and SSIGN score served as independent risk factors. The c-index analysis showed that integrating intratumoral HECW1 expression into TNM stage or SSIGN score resulted in a higher c-index value than these indicators alone for predicting ccRCC patient prognosis. CONCLUSION: HECW1 is a novel prognostic biomarker and therapeutic target in ccRCC, and integrating intratumoral HECW1 expression with established clinical indicators yields higher accuracy in assessing the postoperative prognosis of ccRCC patients.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Expressão Gênica , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Proteínas do Tecido Nervoso/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/diagnóstico , Bases de Dados Genéticas , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , Ubiquitina-Proteína Ligases/metabolismo , Adulto Jovem
16.
Comput Biol Chem ; 92: 107453, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33636636

RESUMO

BACKGROUND: It is estimated that there are 338,000 new renal-cell carcinoma releases every year in the world. Renal cell carcinoma (RCC) is a heterogeneous tumor, of which more than 70% is clear cell renal cell carcinoma (ccRCC). It is estimated that about 30% of new renal-cell carcinoma patients have metastases at the time of diagnosis. However, the pathogenesis of renal clear cell carcinoma has not been elucidated. Therefore, it is necessary to further study the pathogenesis of ccRCC. METHODS: Two expression profiling datasets (GSE68417, GSE71963) were downloaded from the GEO database. Differentially expressed genes (DEGs) between ccRCC and normal tissue samples were identified by GEO2R. Functional enrichment analysis was made by the DAVID tool. Protein-protein interaction (PPI) network was constructed. The hub genes were excavated. The clustering analysis of expression level of hub genes was performed by UCSC (University of California Santa Cruz) Xena database. The hub gene on overall survival rate (OS) in patients with ccRCC was performed by Kaplan-Meier Plotter. Finally, we used the ccRCC renal tissue samples to verify the hub genes. RESULTS: 1182 common DEGs between the two datasets were identified. The results of GO and KEGG analysis revealed that variations in were predominantly enriched in intracellular signaling cascade, oxidation reduction, intrinsic to membrane, integral to membrane, nucleoside binding, purine nucleoside binding, pathways in cancer, focal adhesion, cell adhesion molecules. 10 hub genes ITGAX, CD86, LY86, TLR2, TYROBP, FCGR2A, FCGR2B, PTPRC, ITGB2, ITGAM were identified. FCGR2B and TYROBP were negatively correlated with the overall survival rate in patients with ccRCC (P < 0.05). RT-qPCR analysis showed that the relative expression levels of CD86, FCGR2A, FCGR2B, TYROBP, LY86, and TLR2 were significantly higher in ccRCC samples, compared with the adjacent renal tissue groups. CONCLUSIONS: In summary, bioinformatics technology could be a useful tool to predict the progression of ccRCC. In addition, there are DEGs between ccRCC tumor tissue and normal renal tissue, and these DEGs might be considered as biomarkers for ccRCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Biologia Computacional , Neoplasias Renais/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos
17.
Nat Cell Biol ; 23(1): 87-98, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33420488

RESUMO

Prostate cancer shows remarkable clinical heterogeneity, which manifests in spatial and clonal genomic diversity. By contrast, the transcriptomic heterogeneity of prostate tumours is poorly understood. Here we have profiled the transcriptomes of 36,424 single cells from 13 prostate tumours and identified the epithelial cells underlying disease aggressiveness. The tumour microenvironment (TME) showed activation of multiple progression-associated transcriptomic programs. Notably, we observed promiscuous KLK3 expression and validated the ability of cancer cells in altering T-cell transcriptomes. Profiling of a primary tumour and two matched lymph nodes provided evidence that KLK3 ectopic expression is associated with micrometastases. Close cell-cell communication exists among cells. We identified an endothelial subset harbouring active communication (activated endothelial cells, aECs) with tumour cells. Together with sequencing of an additional 11 samples, we showed that aECs are enriched in castration-resistant prostate cancer and promote cancer cell invasion. Finally, we created a user-friendly web interface for users to explore the sequenced data.


Assuntos
Biomarcadores Tumorais/genética , Linhagem da Célula/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/patologia , Análise de Célula Única/métodos , Transcriptoma , Microambiente Tumoral , Sobrevivência Celular , Biologia Computacional , Progressão da Doença , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Neoplasias da Próstata/genética
18.
Med Sci Monit ; 26: e921855, 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32415055

RESUMO

BACKGROUND Esophageal carcinoma (ESCA) is associated with a poor prognosis and high mortality rate. Autophagy plays important roles in promoting or suppressing tumor cell survival at different stages of cancer development. However, the roles of autophagy-related genes (ARGs) during ESCA progression and in patient prognosis remain unclear. Accordingly, in this study, we aimed to identify the relationships of ARGs with ESCA progression and patient prognosis. MATERIAL AND METHODS Clinicopathological information for patients with ESCA was downloaded from The Cancer Genome Atlas (TCGA) database. Transcriptome expression profiles were downloaded from TCGA and GTEx databases, and ARGs were downloaded from the Human Autophagy Database. We investigated the functions of ARGs by bioinformatics analysis. Moreover, statistical analysis of these genes was performed to identify independent prognostic markers. RESULTS Differentially expressed genes between normal and tumor tissues were detected and identified. GO and KEGG analyses of differentially expressed ARGs were performed. Moreover, we derived a risk signature based on the identified independent prognostic markers. The identified genes also could predict the clinicopathological features of ESCA. CONCLUSIONS ARGs were key participants in the tumorigenesis and development of ESCA. Our findings may be useful for developing improved therapeutic approaches for ESCA.


Assuntos
Carcinoma/genética , Neoplasias Esofágicas/genética , Autofagia/genética , Biologia Computacional/métodos , Bases de Dados Factuais , Bases de Dados Genéticas , Progressão da Doença , Neoplasias Esofágicas/patologia , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Humanos , Prognóstico , Transcriptoma/genética
19.
J Comput Biol ; 27(1): 40-54, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424263

RESUMO

The aim of this study was to explore the key genes, microRNA (miRNA), and the pathogenesis of oral squamous cell carcinoma (OSCC) at the molecular level through the analysis of bioinformatics, which could provide a theoretical basis for the screening of drug targets. Data of OSCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified via GEO2R analysis. Next, protein-protein interaction (PPI) network of DEGs was constructed through Search Tool for the Retrieval of Interacting Gene and visualized via Cytoscape, whereas the hub genes were screened out with Cytoscape. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by Database for Annotation, Visualization and Integrated Discovery. The miRNA, which might regulate hub genes, were screened out with TargetScan and GO and KEGG analysis of miRNA was performed by DNA Intelligent Analysis-miRPath. Survival analyses of DEGs were conducted via the Kaplan-Meier plotter. Finally, the relationships between gene products and tumors were analyzed by Comparative Toxicogenomics Database. A total of 121 differential genes were identified. One hundred thirty-five GO terms and 56 pathways were obtained, which were mainly related to PI3K-Akt signals pathway, FoxO signaling pathway, Wnt signaling pathway, cell cycle, p53 signaling pathway, cellular senescence, and other pathways; 10 genes were identified as hub genes through modules analyses in the PPI network. Finally, a survival analysis of 10 hub genes was conducted, which showed that the low expression of matrix metalloproteinase (MMP)1, MMP3, and C-X-C motif chemokine ligand (CXCL)1 and the high expression of CXCL9 and CXCL10 resulted in a significantly poor 5-year overall survival rate in patients with OSCC. In this study, the DEGs of OSCC was analyzed, which assists us in a systematic understanding of the pathogenicity underlying occurrence and development of OSCC. The MMP1, MMP3, CXCL1, CXCL9, and CXCL10 genes might be used as potential targets to improve diagnosis and as immunotherapy biomarkers for OSCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Biologia Computacional/métodos , Redes Reguladoras de Genes , Neoplasias Bucais/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Anotação de Sequência Molecular , Prognóstico , Mapas de Interação de Proteínas , Transdução de Sinais , Análise de Sobrevida
20.
J Comput Biol ; 27(7): 1079-1091, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31638423

RESUMO

Pancreatic cancer (PC) whose mortality is comparable to morbidity is a highly fatal disease. Early approaches of diagnosis and treatment for PC are quite limited, so it is of great urgency to figure out the exact tumorigenesis and development mechanism of PC. To identify the related molecular markers of pancreatic oncogenesis, we downloaded three microarray datasets (GSE63111, GSE101448, and GSE107610) from Gene Expression Omnibus (GEO) database. The common differentially expressed genes (DEGs) among them were identified, and the corresponding function enrichment analyses were accomplished. The protein-protein interaction network was conducted by Search Tool for the Retrieval of Interacting Genes (STRING), and the corresponding module analysis was accomplished by Cytoscape. There were 55 DEGs found in total. The molecular function and biological processes (BP) of these DEGs mainly include cytokinesis, mitotic nuclear division, cell division, cell proliferation, microtubule-based movement, and mineral absorption. Among the 55 DEGs, 14 hub genes were further confirmed and it was concluded that they mainly function in mitotic cytokinesis, microtubule-based movement, mitotic chromosome condensation, and mitotic spindle assembly from the BP analysis. The survival analysis showed that all the 14 hub genes, especially nucleolar and spindle associated protein 1 and abnormal spindle microtubule assembly, may involve in the tumorigenesis and development of PC. And they might be used as new biomarkers for auxiliary diagnosis and potential targets for immunotherapy of PC.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Biologia Computacional , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Proteínas Associadas aos Microtúbulos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas/genética , Análise de Sobrevida
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