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Bisphenol A (BPA) and its substitute fluorene-9-bisphenol (BHPF) are used in consumer products; however, their toxic effects on intestinal epithelium remain largely unknown. In this study, we combined intestinal organoids and single-cell RNA sequencing to investigate the impact of BPA and BHPF exposure on intestinal cell composition, differentiation, and function. Both compounds inhibited the growth of small intestinal organoids, with BHPF exhibiting a more potent inhibitory effect. BPA and BHPF did not significantly alter the overall cell type composition; however, they led to different alterations in cell-cell communications. Gene Ontology enrichment analysis showed that BPA and BHPF exposures affected various biological processes, such as glutathione transferase activity, antioxidant activity, and lipid metabolism, in cell type-specific and compound-dependent manners. Trajectory analysis demonstrated that BPA and BHPF altered the differentiation trajectory of the intestinal cells. To further connect the cellular mechanism to the phenotypic impact in vivo, we constructed a mouse model exposed to BPA or BHPF and observed significant alterations in intestinal morphology, including reduced crypt depth and villus length and impaired stem cell proliferation and self-renewal. These results provide novel insights into the cell type-specific effects of BPA and BHPF on the intestinal epithelium and highlight the potential risks of exposure to these compounds. Our findings underscore the importance of evaluating the safety of BPA substitutes and contribute to a better understanding of the effects of environmental chemicals on gut health.
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BACKGROUND: The cellular origin of hypopharyngeal diseases is crucial for further diagnosis and treatment, and the microenvironment in tissues may also be associated with specific cell types at the same time. Normal adjacent tissues (NATs) of hypopharyngeal carcinoma differ from non-tumor-bearing tissues, and can influenced by the tumor. However, the heterogeneity in kinds of disease samples remains little known, and the transcriptomic profile about biological information associated with disease occurrence and clinical outcome contained in it has yet to be fully evaluated. For these reasons, we should quickly investigate the taxonomic and transcriptomic information of NATs in human hypopharynx. RESULTS: Single-cell suspensions of normal adjacent tissues (NATs) of hypopharyngeal carcinoma were obtained and single-cell RNA sequencing (scRNA-seq) was performed. We present scRNA-seq data from 39,315 high-quality cells in the hypopharyngeal from five human donors, nine clusters of normal adjacent human hypopharyngeal cells were presented, including epithelial cells, endothelial cells (ECs), mononuclear phagocyte system cells (MPs), fibroblasts, T cells, plasma cells, B cells, mural cells and mast cells. Nonimmune components in the microenvironment, including epithelial cells, endothelial cells, fibroblasts and the subpopulations of them were performed. CONCLUSIONS: Our data provide a solid basis for the study of single-cell landscape in human normal adjacent hypopharyngeal tissues biology and related diseases.
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Neoplasias Hipofaríngeas , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/patologia , Microambiente Tumoral/genética , Hipofaringe/patologia , Hipofaringe/metabolismo , Perfilação da Expressão Gênica , Masculino , Análise de Sequência de RNARESUMO
BACKGROUND: The malignant characteristics of cancer depend not only on intrinsic properties of cancer cells but also on the functions of infiltrating immune cells. In this study, we aimed to investigate the functional landscape of immune cells in head and neck squamous cell carcinoma (HNSCC). METHODS: We employed single-sample gene set enrichment analysis to examine the immunophenotypes of HNSCC based on 29 immune cell functions (ICFs) in TCGA and GSE65858 datasets. We analyzed the clinical features, immune microenvironment, molecular profiles, and biological processes. Additionally, we developed and validated an ICF-based risk score for personalized prognosis prediction. We confirmed the value of the ICF score in our cohort using qRT-PCR and immunohistochemistry. Molecular docking was used to predict potential compounds for immunotherapy. RESULTS: Three immunophenotypes (Immune-L, Immune-M, and Immune-H) were identified in 769 HNSCC samples. The characteristics of Immune-H were consistent with a "Hot" tumor, Immune-L was similar to a "Cold" tumor, and Immune-M exhibited intermediate features. The ICF risk score was associated with immune checkpoints, infiltrating immune cells, tumor mutation burden, and sensitivities to targeted/chemotherapeutic agents. Gene set variation analysis implicated the involvement of metabolic reprogramming pathways in the high-risk group. The combination of "Tumor Immune Dysfunction and Exclusion" and "Immunophenoscore" algorithms indicated that the low-risk group had a higher likelihood of benefiting from immunotherapy. Finally, we identified Eltrombopag and other compounds that may be beneficial for HNSCC immunotherapy. CONCLUSION: Our study provides a novel perspective on the tumor microenvironment of HNSCC, aiding in the understanding of HNSCC heterogeneity and the development of personalized/precision medicine.
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Neoplasias de Cabeça e Pescoço , Imunoterapia , Humanos , Simulação de Acoplamento Molecular , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Prognóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Microambiente Tumoral/genéticaRESUMO
Head neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors which ranks the sixth incidence in the world. Although treatments for HNSCC have improved significantly in recent years, its recurrence rate and mortality rate remain high. Myosin genes have been studied in a variety of tumors, however its role in HNSCC has not been elucidated. GSE58911 and GSE30784 gene expression profile analysis were performed to detect significantly dys-regulated myosin genes in HNSCC. The Cancer Genome Atlas (TCGA) HNSCC database was used to verify the dys-regulated myosin genes and study the relationship between these genes and prognosis in HNSCC. The results showed that MYL1, MYL2, MYL3, MYH2, and MYH7 were down-regulated, while MYH10 was up-regulated in patients with HNSCC. Interestingly, MYL1, MYL2, MYH1, MYH2, and MYH7 were shown to be unfavorable prognostic markers in HNSCC. It is also worth noting that MYL1 was a specific unfavorable prognostic biomarker in HNSCC. MYL1, MYL2, MYL3, MYH2, MYH7, and MYH10 promoted CD4 + T cells activation in HNSCC. MYL1 was proved to be down-regulated in HNSCC tissues compared to normal tissues at protein levels. MYL1 overexpression had no effect on proliferation, but significantly promoted migration of Fadu cells. MYL1 increased EGF and EGFR protein expression levels. Moreover, there is a positive correlation between MYL1 expression and Tcm CD8 cells, Tcm CD4 + cells, NK cells, Mast cells, NKT cells, Tfh cells and Treg cells in HNSCC. Overall, MYL1 facilitates tumor metastasis and correlates with tumor immune infiltration in HNSCC and these effects may be associated with the EGF/EGFR pathway.
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Neoplasias de Cabeça e Pescoço , Segunda Neoplasia Primária , Humanos , Biomarcadores , Fator de Crescimento Epidérmico , Receptores ErbB , Neoplasias de Cabeça e Pescoço/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genéticaRESUMO
Background: Human hypopharygeal squamous cell carcinoma (HSCC) is a common head and neck cancer with a poor prognosis in advanced stages. The occurrence and development of tumor is the result of mutual influence and co-evolution between tumor cells and tumor microenvironment (TME). Tumor immune microenvironment (TIME) refers to the immune microenvironment surrounding tumor cells. Studying TIME in HSCC could provide new targets and therapeutic strategies for HSCC. Methods: We performed single-cell RNA sequencing (scRNA-seq) and analysis of hypopharyngeal carcinoma, paracancerous, and lymphoid tissues from five HSCC patients. Subdivide of B cells, T cells, macrophages cells, and monocytes and their distribution in three kinds of tissues as well as marker genes were analyzed. Different genes of IGHG1 plasma cells and SPP1+ macrophages between HSCC tissues, adjacent normal tissues and lymphatic tissues were analyzed. Additionally, we studied proliferating lymphocytes, T cells exhaustion, and T cell receptor (TCR) repertoire in three kinds of tissues. Results: Transcriptome profiles of 132,869 single cells were obtained and grouped into seven cell clusters, including epithelial cells, lymphocytes, mononuclear phagocytics system (MPs), fibroblasts, endothelial cells (ECs), plasmacytoid dendritic cells (pDCs), and mast cells. Tumor metastasis occurred in three lymphoid tissues. Four distinct populations were identified from lymphocytes, including B cells, plasma cells, T cells and proliferating lymphocytes. We found IGHA1 and IGHG1 specific plasma cells significantly overexpressed in HSCC tissues compared with normal hypopharygeal tissues and lymphatic tissues. Five distinct populations from MPs were identified, including macrophages, monocytes, mature dendritic cells (DCs), Type 1 conventional dendritic cells (cDC1) and Type 2 conventional dendritic cells (cDC2). SPP1+ macrophages were significantly overexpressed in HSCC tissues and lymphatic tissues compared with normal hypopharygeal tissues, which are thought to be M2-type macrophages. Exhaustion of CD8+ Teff cells occurred in HSCC tissues. At last, we verified that IgA and IgG1 protein expression levels were significantly up-regulated in HSCC tissues compared to adjacent normal tissues. Conclusion: Overall, this study revealed TIME in HSCC and lymphatic metastasis, and provided potential therapeutic targets for HSCC.
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Carcinoma de Células Escamosas , Células Endoteliais , Humanos , Metástase Linfática , Células Endoteliais/metabolismo , Microambiente Tumoral/genética , Prognóstico , Carcinoma de Células Escamosas/metabolismo , Análise de Sequência de RNARESUMO
Background: Hypopharyngeal squamous cell cancer (HSCC) is one of the most malignant tumors of the head and neck. It is not easy to detect in the early stage due to its hidden location; thus, lymph node metastasis is highly likely at diagnosis, leading to a poor prognosis. It is believed that epigenetic modification is related to cancer invasion and metastasis. However, the role of m6A-related lncRNA in the tumor microenvironment (TME) of HSCC remains unclear. Methods: The whole transcriptome and methylation sequencing of 5 pairs of HSCC tissues and adjacent tissues were performed to identify the methylation and transcriptome profiles of lncRNAs. The biological significance of lncRNAs differentially expressing the m6A peak was analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. By constructing an m6A lncRNA-microRNA network, the mechanism of m6A lncRNAs in HSCC was analyzed. The relative expression levels of selected lncRNAs were examined by quantitative polymerase chain reaction. The CIBERSORT algorithm was used to evaluate the relative proportion of immune cell infiltration in HSCC and paracancerous tissues. Results: Based on an in-depth analysis of the sequencing results, 14413 differentially expressed lncRNAs were revealed, including 7329 up-regulated and 7084 down-regulated lncRNAs. Additionally, 4542 up-methylated and 2253 down-methylated lncRNAs were detected. We demonstrated methylation patterns and gene expression profiles of lncRNAs of HSCC transcriptome. In the intersection analysis of lncRNAs and methylated lncRNAs, 51 lncRNAs with up-regulated transcriptome and methylation and 40 lncRNAs with down-regulated transcriptome and methylation were screened, and significantly differentiated lncRNAs were further studied. In the immune cell infiltration analysis, B cell memory was significantly elevated in cancer tissue, while γδT cell amount was significantly decreased. Conclusion: m6A modification of lncRNAs might be involved in HSCC pathogenesis. Infiltration of immune cells in HSCC might provide a new direction for its treatment. This study provides new insights for exploring the possible HSCC pathogenesis and searching for new potential therapeutic targets.
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The peroxisome is a ubiquitous organelle in rodent cells and plays important roles in a variety of cell types and tissues. It is previously indicated that peroxisomes are associated with auditory function, and patients with peroxisome biogenesis disorders (PBDs) are found to have hearing dysfunction, but the specific role of peroxisomes in hearing remains unclear. In this study, two peroxisome-deficient mouse models (Atoh1-Pex5-/- and Pax2-Pex5-/- ) are established and it is found that peroxisomes mainly function in the hair cells of cochleae. Furthermore, peroxisome deficiency-mediated negative effects on hearing do not involve mitochondrial dysfunction and oxidative damage. Although the mammalian target of rapamycin complex 1 (mTORC1) signaling is shown to function through peroxisomes, no changes are observed in the mTORC1 signaling in Atoh1-Pex5-/- mice when compared to wild-type (WT) mice. However, the expression of large-conductance, voltage-, and Ca2+ -activated K+ (BK) channels is less in Atoh1-Pex5-/- mice as compared to the WT mice, and the administration of activators of BK channels (NS-1619 and NS-11021) restores the auditory function in knockout mice. These results suggest that peroxisomes play an essential role in cochlear hair cells by regulating BK channels. Hence, BK channels appear as the probable target for treating peroxisome-related hearing diseases such as PBDs.
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Perda Auditiva , Canais de Potássio Ativados por Cálcio de Condutância Alta , Camundongos , Animais , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Peroxissomos/metabolismo , Células Ciliadas Auditivas/metabolismo , Camundongos Knockout , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mamíferos/metabolismoRESUMO
The inhibition of histone deacetylases (HDACs) has been considered a promising therapeutic strategy for treatment of many diseases, especially cancer. In the current study, a series of 8-substituted quinoline-2-carboxamide derivatives were designed and synthesized as potent HDAC inhibitors. The most potent compound 21 g (IC50 = 0.050 µM) exhibited 3-fold greater HDAC inhibitory activity compared to the known HDAC inhibitor Vorinostat (IC50 = 0.137 µM). Additionally, compound 21g exhibited low toxicity against normal cells(IC50 in HUVEC cell > 50 µM) and showed good liver microsomal stability, therefore, may serve as a new lead compound for further development.
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Antineoplásicos , Hidroxiquinolinas , Quinolinas , Inibidores de Histona Desacetilases/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Histona Desacetilases/metabolismo , Desenho de Fármacos , Simulação de Acoplamento Molecular , Hidroxiquinolinas/farmacologia , Quinolinas/farmacologia , Proliferação de Células , Relação Estrutura-Atividade , Histona Desacetilase 1RESUMO
Hypopharyngeal squamous cell carcinoma (HSCC) is a kind of head and neck squamous cell carcinoma (HNSCC) with poor prognosis. Metabolic reprogramming may regulate the tumor microenvironment (TME) by adapting quickly to cellular stress and regulating immune response, but its role in HSCC has not been reported. We used the nCounter® Metabolic Pathways Panel to investigate metabolic reprogramming, cellular stress, and their relationship in HSCC tissues and adjacent normal tissues. Metabolism-related pathways nucleotide synthesis and glycolysis pathways were significantly upregulated, while amino acid synthesis and fatty acid oxidation pathways were significantly downregulated in HSCC tissues compared to adjacent normal tissues. There is a significant correlation between metabolism-related pathways and cellular stress pathways. Enrichment of immune cell and tumor infiltrating lymphocyte (TIL) analysis showed changes in immune responses between HSCC tissues and adjacent normal tissues. Overall survival analysis showed that upregulated genes CD276, LDHB, SLC3A2, EGFR, SLC7A5, and HPRT1 are potential unfavorable prognostic markers in HNSCC, while downregulated genes EEA1, IDO1, NCOA2, REST, CCL19, and ALDH2 are potential favorable prognostic markers in HNSCC. Moreover, metabolism-related genes IDO1, ALDH2, NCOA2, SLC7A5, SLC3A2, LDHB, and HPRT1 are correlated with immune infiltrates in HNSCC. These results suggest that metabolic reprogramming occurs and correlates with cellular stress and immune response in HSCC, which may help researchers understand mechanisms of metabolic reprogramming and develop effective immunotherapeutic strategies in HNSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Aldeído-Desidrogenase Mitocondrial/metabolismo , Antígenos B7/metabolismo , Carcinoma de Células Escamosas/genética , Cadeia Pesada da Proteína-1 Reguladora de Fusão , Neoplasias de Cabeça e Pescoço/genética , Humanos , Transportador 1 de Aminoácidos Neutros Grandes , Coativador 2 de Receptor Nuclear/metabolismo , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Microambiente Tumoral/genéticaRESUMO
Hypopharyngeal squamous cell carcinoma (HSCC) accounts 95% of hypopharyngeal cancer, which is characterized by high early metastasis rate and poor prognosis. It is reported that circular RNA is involved in the occurrence and development of cancer; however, the role of circRNA in hypopharyngeal cancer has little been investigated. We performed hypopharyngeal carcinoma circRNA microarray and qRT-PCR verification. The results showed circ_0058106 expression level was significantly upregulated in tumor tissues than in corresponding normal tissues. We found that circ_0058106 upregulation promoted proliferation, migration and invasion of HSCC cells, while knockdown of circ_0058106 inhibited proliferation, migration and invasion of HSCC cells both in vitro and in vivo. Bioinformatics predicted circ_0058106 may interact with miR-185-3p. We verified circ_0058106 directly bound miR-185-3p and downregulated miR-185-3p expression by using dual-luciferase reporter assay and qRT-PCR. Moreover, we proved circ_0058106 promoted HSCC cells tumorigenesis and EMT process by regulating Wnt2b/ß-catenin/c-Myc pathway via miR-185-3p. In conclusion, our findings firstly confirmed the carcinogenic effect of circ_0058106 in promoting HSCC cells tumorigenesis, metastasis, invasion and EMT process by regulating Wnt2b/ß-catenin/c-Myc pathway through sponging miR-185-3p, indicating that circ_0058106 may be a new therapeutic target and prognostic marker for HSCC.
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Carcinoma de Células Escamosas/genética , Genes myc/imunologia , Neoplasias Hipofaríngeas/genética , MicroRNAs/metabolismo , beta Catenina/metabolismo , Animais , Carcinogênese , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Hipofaríngeas/patologia , Camundongos , Metástase Neoplásica , TransfecçãoRESUMO
BACKGROUND: Conservative surgery has proven advantageous in controlling hypopharyngeal squamous cell carcinoma (HSCC) and preserving speech and swallowing function in carefully selected patients, typically with early T-stages diseases. A variety of modified surgical procedures or techniques have been proposed. METHODS: In this study, we present a novel surgical approach for hypopharyngeal carcinoma resection utilizing the paraglottic space. RESULTS: The paraglottic space approach can help expose neoplasms under direct vision and save mucosa during surgery while sufficiently preserving laryngeal function, thus benefiting postoperative swallowing and reducing complications. A large cohort of 426 patients with HSCC underwent surgical treatment at our institution using this approach, demonstrating an overall survival (OS) rate of 52.3% and low incidences of postoperative complications. CONCLUSIONS: This surgical approach can be applied in patients with the lesions that do not involve the paraglottic space.
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Carcinoma , Neoplasias Hipofaríngeas , Laringe , Deglutição , Humanos , Neoplasias Hipofaríngeas/cirurgia , LaringectomiaRESUMO
PURPOSE: In the clinical management of hypopharyngeal squamous cell carcinoma (HSCC), preoperative identification of early recurrence (≤2 years) after curative resection is essential. Thus, we aimed to develop a CT-based radiomic signature to predict early recurrence in HSCC patients preoperatively. METHODS: In total, 167 HSCC patients who underwent partial surgery were enrolled in this retrospective study and divided into two groups, i.e., the training cohort (n = 133) and the validation cohort (n = 34). Each individual was followed up for at least for 2 years. Radiomic features were extracted from CT images, and the radiomic signature was built with the least absolute shrinkage and selection operator (LASSO) logistic regression (LR) model. The associations of preoperative clinical factors with early recurrence were evaluated. A radiomic signature-combined model was built, and the area under the curve (AUC) was used to explore their performance in discriminating early recurrence. RESULTS: Among the 1415 features, 335 of them were selected using the variance threshold method. Then, the SelectKBest method was further used for the selection of 31 candidate features. Finally, 11 out of 31 optimal features were identified with the LASSO algorithm. In the LR classifier, the AUCs of the training and validation sets in discriminating early recurrence were 0.83 (95% CI: 0.76-0.90) (sensitivity 0.8 and specificity 0.83) and 0.83 (95% CI: 0.67-0.99) (sensitivity 0.69 and specificity 0.71), respectively. CONCLUSIONS: Using the radiomic signature, we developed a radiomic signature to preoperatively predict early recurrence in patients with HSCC, which may serve as a potential noninvasive tool to guide personalized treatment.
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Neoplasias Hipofaríngeas/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Área Sob a Curva , Feminino , Humanos , Neoplasias Hipofaríngeas/classificação , Neoplasias Hipofaríngeas/diagnóstico por imagem , Neoplasias Hipofaríngeas/patologia , Masculino , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Período Pré-Operatório , Curva ROC , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/classificação , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Tomografia Computadorizada por Raios XRESUMO
Increasing number of circular RNAs (circRNAs) have been reported to play important role in gene regulation, carcinogenesis and pathogenesis in various cancers. However, the biological functions and underlying molecular mechanisms of circRNAs in hypopharyngeal squamous cell carcinoma (HSCC) remain elusive. Thus, secondary circRNA-seq profiling was performed to identify the differentially expressed circRNAs between HSCC tissues and adjacent normal tissues, and the expression level of circMATR3 (derived from human gene matrin3 (MATR3), has_circRNA_0008922) was confirmed by qRT-PCR. Proliferation of HSCC cells was detected by cell counting kit-8 (CCK8) assay, apoptosis and the cell cycle were analysed by flow cytometry, and the migration and invasion of HSCC cells was determined by transwell assay. Bioinformatics analysis was conducted to predict possible pathways and potential miRNA targets of circMATR3. We found that circMATR3 was up-regulated in HSCC tissues, and abundant circMATR3 expression was markedly correlated with late T classification, advanced clinical stage, greater lymph node metastasis, and poor prognosis. Furthermore, knock-down of circMATR3 significantly inhibited proliferation, migration and invasion of HSCC cells, whereas silencing of circMATR3 induced cell apoptosis. Our analysis predicted that circMATR3 may participate in cancer-related pathways by serving as miRNA sponges. In conclusion, our findings first identified the oncogenic roles of circMATR3 in promoting the progression of HSCC and demonstrated that circMATR3 may be a novel prognostic marker and therapeutic target for HSCC.
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Biomarcadores Tumorais/genética , Proteínas Associadas à Matriz Nuclear/genética , RNA Circular/genética , Proteínas de Ligação a RNA/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
BACKGROUND: Hypopharyngeal squamous cell carcinoma (HSCC) is among the most lethal tumors encountered in the head and neck, and currently lacks satisfactory therapeutic targets. Platelet activating factor acetylhydrolase 1B3 (PAFAH1B3), a cancer-relevant metabolic driver, is reported to play a critical role in controlling tumorigenesis and aggressiveness in several types of cancers. However, the role of PAFAH1B3 in HSCC progression has not yet been identified. METHODS: The expression pattern of PAFAH1B3 was examined using immunohistochemistry in 83 HSCC tumor tissues and 44 paired adjacent non-tumor samples. Univariate and multivariate analyses were conducted to explore its association with prognosis of HSCC. In vitro loss-of-function assays were performed to explore the impact of PAFAH1B3 knockdown on the biological phenotype of the human HSCC cell line, ie, FaDu cells. RESULTS: PAFAH1B3 was overly expressed in the HSCC tumor tissues compared with the adjacent non-tumor samples. Moreover, high expression of PAFAH1B3 was positively correlated with cervical lymph node metastasis. PAFAH1B3 overexpression was associated with poor outcome in HSCC, but it was not an independent prognostic indicator. Furthermore, in vitro loss-of function experiments demonstrated that PAFAH1B3 knockdown suppressed cell proliferation by inducing apoptosis and disrupting cell cycle process, and the migratory and invasive capacities were also attenuated in the absence of PAFAH1B3. CONCLUSION: This study for the first time demonstrated the clinical value and the role of PAFAH1B3 in the biological function of HSCC. This work suggested that PAFAH1B3 might serve as a potential therapeutic target for HSCC patients.
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INTRODUCTION: Hypopharyngeal squamous cell carcinoma (HSCC) is among the most lethal tumors encountered in the head and neck and frequently involves regional metastasis. However, the mechanism underlying the aggressiveness of HSCC remains elusive. S100A4 is a well-established metastasis-promoting regulator in a variety of malignancies, but its role in HSCC has not yet been identified. OBJECTIVES: Our objectives were to explore the expression levels of S100A4 in HSCC tumors and its association with clinicopathological parameters and the clinical prognosis of HSCC and to confirm its role in the metastatic process of the HSCC FaDu cell line in vitro. METHODS: We assessed the expression levels of S100A4 with immunohistochemistry (IHC) in HSCC tumors (n = 71) and adjacent normal tissues (n = 44). In vitro experiments were performed to explore the impact of S100A4 knockdown on biological phenotypes of human HSCC FaDu cell line, including migration, invasion, proliferation, apoptosis, and cell cycle. RESULTS: The expression of S100A4 was elevated in HSCC tumors compared with adjacent normal tissues and positively correlated with cervical lymph node metastasis in this HSCC patient cohort. In vitro experiments showed that S100A4 knockdown significantly impaired migration and invasion and increased the proportion of cells in G0/G1 phase with no change in proliferation or apoptosis in FaDu cells. Additionally, nuclear S100A4 expression proved to be an independent prognostic indicator in patients with HSCC. CONCLUSION: This study demonstrated for the first time that S100A4 expression is upregulated in HSCC tumors and that this upregulation is positively correlated with cervical lymph node metastasis of this malignancy. The metastasis-promoting role of S100A4 was further validated in the HSCC FaDu cell line, indicating that S100A4 is a potential therapeutic target for HSCC. Furthermore, this study suggests that nuclear S100A4 expression could be considered a prognostic biomarker for HSCC.
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Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias Hipofaríngeas/diagnóstico , Neoplasias Hipofaríngeas/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Adulto , Idoso , Apoptose/genética , Biomarcadores Tumorais , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Expressão Gênica , Humanos , Neoplasias Hipofaríngeas/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , PrognósticoRESUMO
BACKGROUND/AIMS: Researchers have shown that long noncoding RNAs are closely associated with the pathogenesis of laryngeal squamous cell carcinoma (LSCC). However, the role of the long noncoding RNA taurine-upregulated gene 1 (TUG1) in the pathogenesis of LSCC remains unclear, although it is recognized as an oncogenic regulator for several types of squamous cell carcinoma. METHODS: qRT-PCR was performed to measure the expression of TUG1 in LSCC tissues and cell lines. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was used to measure the effect of TUG1 on cell proliferation. Transwell assay and flow cytometry were employed to determine the effect of TUG1 on cell migration and invasion. Western-blot were performed to explore the relation of TUG1 and p53 mRNA. RESULTS: Higher TUG1 expression in LSCC than in paired normal tumor-adjacent tissue specimens (N = 64) was observed using quantitative real-time polymerase chain reaction. Also, high TUG1 expression was positively associated with advanced T category, worse lymph node metastasis and late clinical stage. Furthermore, in vitro experiments demonstrated that silencing of TUG1 markedly inhibited proliferation, cell-cycle progression, migration, and invasion of LSCC cells, whereas depletion of TUG1 led to increased apoptosis. CONCLUSION: These findings demonstrated that upregulated TUG1 expression exerted oncogenic effects by promoting proliferation, migration, and invasion, and inhibiting apoptosis in LSCC cells.
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Carcinoma de Células Escamosas/patologia , Proliferação de Células , Neoplasias Laríngeas/patologia , RNA Longo não Codificante/metabolismo , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Neoplasias Laríngeas/genética , Masculino , Pessoa de Meia-Idade , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
PURPOSE: To evaluate clinical features, diagnosis, surgical management, and treatment of parapharyngeal space tumors in a single-center setting due to limited knowledge of diagnosis and treatment of parapharyngeal space. METHODS: Clinical records of 103 patients were included for the analysis of such clinical characteristics. RESULTS: A total of 29 different types of tumors were diagnosed after operation: 20 benign and 9 malignant. With a follow-up of 31-84 months for 90 benign cases, 84 cases had no recurrence and 6 cases were lost to follow-up. In contrast, with an 8- to 51-month follow-up for 13 malignant cases, 11 patients died and 2 were lost to follow-up. Furthermore, for postoperative complications, 3 cases had Horner syndrome, 2 had hoarseness, 2 had facial nerve dysfunction, and each for other types. CONCLUSIONS: Surgery remains the first choice for the treatment of parapharyngeal space tumors, with the transcervical approach used for most tumors. Moreover, CT or MRI may assist in making decisions about operation schemes.
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Neoplasias Faríngeas/cirurgia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Faríngeas/diagnóstico por imagem , Neoplasias Faríngeas/patologia , Complicações Pós-Operatórias , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
The E26 transformation-specific (ETS) family is one of the largest families of transcription factors. Upon activation by MAPK pathway, ETS participates in cell proliferation, differentiation, migration, apoptosis, and metastasis. However, the mechanism by which ETS is deregulated in cancer is unclear. In this study, the authors investigated the role of ETS factor, ETS2, in hypopharyngeal cancer pathogenesis in hypopharyngeal cancer tissues (N = 20) and corresponding non-neoplastic tissues (N = 20). The results showed that expression of ETS2 was increased in cancer tissues as compared with the expression in corresponding non-neoplastic tissues. Analysis of clinicopathological characteristics showed that increased level of ETS2 is associated with III-IV tumor node metastasis stage and lymph node metastasis. In addition, knockdown of ETS2 by siRNA in pharyngeal cancer cell line, FaDu, significantly decreased cell's vitality and colony-forming ability by inducing caspase-3-dependent apoptosis and cell cycle arrest. Furthermore, inhibition of ETS2 could abrogate the migration, invasion, and transforming growth factor-ß-induced epithelial mesenchymal transition through the upregulation of E-cadherin, zona occludens protein-1, together with downregulation of vimentin and α-sooth muscle actin. These functions of ETS2 could be associated with the activation of MAPK/p38/ERK/JNK signals. Taken together, the authors opined that ETS2 functions as an oncogene and plays a key role in the progression of hypopharyngeal cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Hipofaríngeas/genética , Sistema de Sinalização das MAP Quinases/genética , Proteína Proto-Oncogênica c-ets-2/metabolismo , Apoptose/genética , Carcinogênese/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hipofaríngeas/patologia , Metástase Linfática , Invasividade Neoplásica/genética , Estadiamento de Neoplasias , Proteína Proto-Oncogênica c-ets-2/genética , RNA Interferente Pequeno/metabolismo , Regulação para CimaRESUMO
Circular RNAs (circRNAs), a novel class of endogenous noncoding RNAs, have been shown to have important roles in a number of diseases, including several types of cancers. We hypothesized that circRNAs are involved in the pathogenesis of hypopharyngeal squamous cell carcinoma (HSCC). To test our hypothesis, we initially compared the expression profiles of circRNAs in 4 paired HSCC and adjacent normal tissue samples by using a circRNA microarray. The microarray data showed that 2392 circRNAs, including 1304 upregulated and 1088 downregulated circRNA transcripts, were significantly dysregulated in the HSCC tissues. The 10 most dysregulated circRNAs from the microarray analysis were further validated in another 32 pairs of specimens using quantitative real-time polymerase chain reaction assays. These circRNAs might sponge microRNAs (miRNAs) in predicted circRNA-miRNA-mRNA networks. Bioinformatics analysis was also performed to predict possible pathways in which these networks might be involved. Finally, we analyzed the interaction between validated circRNAs and their potential cancer-related miRNA targets. We are the first to comprehensively delineate the expression profiles of circRNAs in HSCC and to provide potential candidates for future mechanism studies. Our study is potentially of critical significance in uncovering the roles of circRNAs in HSCC.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias Hipofaríngeas/diagnóstico , Neoplasias Hipofaríngeas/genética , RNA , Regiões 3' não Traduzidas , Análise por Conglomerados , Biologia Computacional/métodos , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Biópsia Líquida , MicroRNAs/genética , Prognóstico , Interferência de RNA , RNA Circular , RNA Mensageiro/genética , Reprodutibilidade dos TestesRESUMO
Radioresistance remains a major problem in the treatment of patients with hypopharyngeal squamous cell carcinoma (HSCC). Long noncoding RNAs (lncRNAs) have important roles in the development, invasion, and metastasis of various tumors, including HSCC, but little is known about the role of lncRNAs in cancer radioresistance. The aim of this study was to identify radioresistance-related lncRNAs and mRNAs in radioresistant (RS) hypopharyngeal cancer subclone RS-FaDu cells. In this study, we performed microarray analysis to find the differences in time-course lncRNA and mRNA expression profiles between RS-FaDu and parent FaDu cells after 4 Gy radiation therapy, whose reliability was confirmed by validation experiment. Among these consistently dysregulated lncRNAs, we found that some lncRNAs (e.g., TCONS_00018436) might control resistance of HSCC cells to radiation. Furthermore, our bioinformatics analyses from mRNA/lncRNA microarray data showed that certain lncRNAs or mRNAs potentially are involved in radioresistance of HSCC. Our results from this study laid the foundation for further investigating the roles of these lncRNAs and mRNAs as promising candidates in the occurrence and development of HSCC radioresistance.