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BACKGROUND: The molecular mechanism of laryngeal squamous cell carcinoma (LSCC) is not completely clear, which leads to poor prognosis and treatment difficulties for LSCC patients. To date, no study has reported the exact expression level of zinc finger protein 71 (ZNF71) and its molecular mechanism in LSCC. METHODS: In-house immunohistochemistry (IHC) staining (33 LSCC samples and 29 non-LSCC samples) was utilized in analyzing the protein expression level of ZNF71 in LSCC. Gene chips and high-throughput sequencing data collected from multiple public resources (313 LSCC samples and 192 non-LSCC samples) were utilized in analyzing the exact mRNA expression level of ZNF71 in LSCC. Single-cell RNA sequencing (scRNA-seq) data was used to explore the expression status of ZNF71 in different LSCC subpopulations. Enrichment analysis of ZNF71, its positively and differentially co-expressed genes (PDCEGs), and its downstream target genes was employed to detect the potential molecular mechanism of ZNF71 in LSCC. Moreover, we conducted correlation analysis between ZNF71 expression and immune infiltration. RESULTS: ZNF71 was downregulated at the protein level (area under the curve [AUC] = 0.93, p < 0.0001) and the mRNA level (AUC = 0.71, p = 0.023) in LSCC tissues. Patients with nodal metastasis had lower protein expression level of ZNF71 than patients without nodal metastasis (p < 0.05), and male LSCC patients had lower mRNA expression level of ZNF71 than female LSCC patients (p < 0.01). ZNF71 was absent in different LSCC subpopulations, including cancer cells, plasma cells, and tumor-infiltrated immune cells, based on scRNA-seq analysis. Enrichment analysis showed that ZNF71 and its PDCEGs may influence the progression of LSCC by regulating downstream target genes of ZNF71. These downstream target genes of ZNF71 were mainly enriched in tight junctions. Moreover, downregulation of ZNF71 may influence the development and even therapy of LSCC by reducing immune infiltration. CONCLUSION: Downregulation of ZNF71 may promote the progression of LSCC by reducing tight junctions and immune infiltration; this requires further study.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Laríngeas , Humanos , Masculino , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Regulação para Baixo , Imuno-Histoquímica , Carcinoma de Células Escamosas/patologia , RNA Mensageiro/genética , Mineração de Dados , Dedos de Zinco , Coloração e Rotulagem , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , PrognósticoRESUMO
BACKGROUND Immune-related genes (IRGs) are closely related to the incidence and progression of tumors, potentially indicating that IRGs play an important role in laryngeal squamous cell carcinoma (LSCC). MATERIAL AND METHODS An RNA sequencing dataset containing 123 samples was collected from The Cancer Genome Atlas. Based on immune-related differentially expressed genes (IRDEGs), a potential molecular mechanism of LSCC was explored through analysis of information in the Gene Ontology (GO) resource and the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interactions (PPIs). A regulatory network of transcriptional regulators and IRDEGs was constructed to explore the underlying molecular mechanism of LSCC at the upstream level. Candidates from IRDEGs for signature were screened via univariate Cox analysis and using the least absolute shrinkage and selection operator (LASSO) technique. The IRDEG signature of LSCC was constructed by using a multivariate Cox proportional hazards model. RESULTS GO and KEGG analysis showed that IRDEGs may participate in the progression of LSCC through immune-related reactions. PPI analysis demonstrated that, among the IRDEGs in LSCC, the Kininogen 1; C-X-X motif chemokine ligand 10; elastase, neutrophil expressed; and LYZ genes are hub genes in the development of LSCC. At the upstream level, SPI1, SP140, signal transducer and activator of transcription 4, zinc finger E-box binding homeobox, and Ikaros family zinc finger 2 are the hub transcriptional regulators of IRDEGs. The risk score based on the IRDEG signature was able to distinguish prognosis in patients with LSCC and represents an independent prognostic risk factor for LSCC. CONCLUSIONS From the perspective of IRGs, we first constructed an IRDEG signature related to the prognosis of LSCC, which can be used as a novel marker to predict prognosis in patients with LSCC.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/imunologia , Carcinoma de Células Escamosas/diagnóstico , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Neoplasias Laríngeas/diagnóstico , Nomogramas , Prognóstico , Mapas de Interação de Proteínas/genética , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Transcrição/metabolismo , Regulação para Cima/genéticaRESUMO
Laryngeal squamous cell carcinoma (LSCC) is an aggressive type of head and neck squamous cell carcinoma (HNSCC) with a relatively high rate of morbidity and mortality. An altered miR-144-3p level in LSCC with a small number of patients has been previously reported. However, the clinical implication of miR-144-3p and its involved mechanism underlying this disease is not clearly elucidated. In this work, we aimed to confirm the expression of miR-144-3p with larger samples and also to identify target genes for the investigation of the underlying mechanism of miR-144-3p in LSCC. The levels of miR-144-3p were downregulated in 155 samples of LSCC tissues as compared to 26 non-LSCC samples (SMD: -0.78; 95% confidence interval (CI): -1.23, -0.32). The AUC of 0.90 in the summarized ROC curve also indicated a potential ability to differentiate LSCC from non-LSCC tissues, with a sensitivity of 0.78 and a specificity of 0.88. With respect to the molecular mechanism, we predicted the potential targets from online-based prediction, peer-reviewed publications, and RNA-seq and microarray data. In particular, the genes influenced by transfection with miR-144-3p in the LSCC FaDu cell line were collected from the microarray GSE56243. Lastly, 12 novel targets for miR-144-3p in LSCC were obtained by different algorithms. In conclusion, our study confirmed the loss or downregulation of miR-144-3p in LSCC, which might contribute to the LSCC tumorigenesis and progression via regulation of the 12 novel targets, such as IL24, ITGA6, and CEP55. In the future, further investigations are required to validate the present results.
Assuntos
Neoplasias Laríngeas/genética , MicroRNAs/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Integrina alfa6/genética , Integrina alfa6/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Neoplasias Laríngeas/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Tenascina/genética , Tenascina/metabolismoRESUMO
INTRODUCTION: We aimed to explore the downregulation of the coiled-coil domain containing 80 (CCDC80) and its underlying molecular mechanisms in ovarian carcinoma (OVCA). Materials/Methods. Immunohistochemical staining was performed to confirm the expression status of CCDC80 protein. Combining the data from in-house tissue microarrays and high-throughput datasets, we identified the expression level of CCDC80 in OVCA. We utilized cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm and single-sample gene set enrichment analysis (ssGSEA) to explore the relationship between CCDC80 and the tumor microenvironment (TME) landscape in OVCA. Pathway enrichment, function annotation, and transcription factor (TFs) exploration were conducted to study the latent molecular mechanisms. Moreover, the cell line data in the Genomics of Drug Sensitivity in Cancer (GDSC) database was used to discover the relationship between CCDC80 and drug sensitivity. RESULTS: An integrated standard mean difference (SMD) of -0.919 (95% CI: -1.515-0.324, P = 0.002) identified the downregulation of CCDC80 in OVCA based on 1048 samples, and the sROC (AUC = 0.76) showed a moderate discriminatory ability of CCDC80 in OVCA. The fraction of infiltrating naive B cells showed significant differences between the high- and low-CCDC80 expression groups. Also, CCDC80-related genes are enriched in the Ras signaling pathway and metabolic of lipid. Nuclear receptor subfamily three group C member 1 (NR3C1) may be an upstream TF of CCDC80, and CCDC80 may be related to the sensitivity of mitocycin C and nilotinib. CONCLUSION: CCDC80 was downregulated in OVCA and may play a role as a tumor suppressor in OVCA.
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The screening and treatment of laryngeal squamous cell carcinoma (LSCC) still perplexes clinicians, making it necessary to explore new markers. To this end, this research examined the underlying molecular mechanism of LSCC based on high-throughput datasets (n = 249) from multiple databases. It also identified transcription factors (TFs) independently associated with LSCC prognosis. Through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, differential expression genes of LSCC were deemed relevant to the extracellular matrix and its related structures or pathways, suggesting that the extracellular matrix plays an important role in LSCC. At the same time, several hub genes that may also have important roles in LSCC were identified via protein-protein interaction analysis, including CDC45, TPX2, AURKA, KIF2C, NUF, MUC1, MUC7, MUC4, MUC15, and MUC21. Eight unreported LSCC prognostic TFs - BCAT1, CHD4, FOXA2, GATA6, HNF1A, HOXB13, MAFF, and TCF4 - were screened via Kaplan-Meier curves. Cox analysis determined for the first time that HOXB13 expression and gender were independently associated with LSCC prognosis. Compared to control tissues, elevated expression of HOXB13 was found in LSCC tissues (standardized mean difference = 0.44, 95% confidence interval [0.13-0.76]). HOXB13 expression also makes it feasible to screen LSCC from non-LSCC (area under the curve = 0.77), and HOXB13 may play an essential role in LSCC by regulating HOXB7. In conclusion, HOXB13 may be a novel marker for LSCC clinical screening and treatment.