RESUMEN
Cisplatin (CDDP) chemoresistance is one of the predominant factors in oral squamous cell carcinoma (OSCC) treatment failure. Uncovering the mechanisms underlying CDDP resistance is of great importance in OSCC therapy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs, which are reported to participate in the progression of various diseases, including cancer. However, the function of circRNAs in CDDP resistance in OSCC remains unclear. Quantitative reverse transcription PCR was used to search for different circRNAs between OSCC cell lines and CDDP-resistant cell lines. The results showed that circ-ILF2 expression was higher in CDDP-resistant OSCC cell lines. The stability of circ-ILF2 was also confirmed using RNase R and actinomycin D assays. Functional experiments, including cytotoxicity, apoptosis and growth rate assays, showed that upregulation of circ-ILF2 contributes to CDDP resistance. Luciferase reporter-gene, RNA pull-down and quantitative real-time PCR (RT-qPCR) assays showed that circ-ILF2 functions as a microRNA sponge for miR-1252. Luciferase reporter assays, RNA pull-down, RT-qPCR and Western blotting showed that miR-1252 directly targeted and regulated the expression of KLF8. Circ-ILF2 plays an important role in CDDP resistance in OSCC. Circ-ILF2 exerts its function through the miR-1252/KLF8 pathway. In addition, tumour-associated macrophages (TAM) play important roles in cancer progressions, our results showed that circ-ILF2 in OSCC cells induced the M2 polarization of macrophages which provided new thoughts on immunotherapy. Our results suggest that circ-ILF2 may represent a potential therapeutic target in CDDP-resistant OSCC.
Asunto(s)
Cisplatino , Resistencia a Antineoplásicos , ARN Circular , Carcinoma de Células Escamosas de Cabeza y Cuello , ARN Circular/genética , ARN Circular/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Macrófagos/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Polaridad Celular/genética , HumanosRESUMEN
Aberrant N7 -methylguanosine (m7G) levels closely correlate with tumor genesis and progression. NCBP2 and EIF4E3 are two important m7G-related cap-binding genes. This study aimed to identify the relationship between the EIF4E3/NCBP2 function and immunological characteristics of head and neck squamous cell carcinoma (HNSCC). Hierarchical clustering was employed in classifying HNSCC patients into two groups based on the expressions of NCBP2 and EIF4E3. The differentially expressed genes were identified between the two groups, and GO functional enrichment was subsequently performed. Weighted gene co-expression network analysis was conducted to identify the hub genes related to EIF4E3/NCBP2 expression and immunity. The differential infiltration of immune cells and the response to immunotherapy were compared between the two groups. Single-cell sequence and trajectory analyses were performed to predict cell differentiation and display the expression of EIF4E3/NCBP2 in each state. In addition, quantitative real-time PCR, spatial transcriptome analysis, transwell assay, and western blotting were conducted to verify the biological function of EIF4E3/NCBP2. Here, group A showed a higher EIF4E3 expression and a lower NCBP2 expression, which had higher immune scores, proportion of most immune cells, immune activities, expression of immunomodulatory targets, and a better response to cancer immunotherapy. Besides, 56 hub molecules with notable immune regulation significance were identified. A risk model containing 17 hub genes and a prognostic nomogram was successfully established. Moreover, HNSCC tissues had a lower EIF4E3 expression and a higher NCBP2 expression than normal tissues. NCBP2 and EIF4E3 played a vital role in the differentiation of monocytes. Furthermore, the expression of CCL4/CCL5 can be regulated via EIF4E3 overexpression and NCBP2 knockdown. Collectively, NCBP2 and EIF4E3 can affect downstream gene expression, as well as immune contexture and response to immunotherapy, which could induce "cold-to-hot" tumor transformation in HNSCC patients.
Asunto(s)
Quimiocina CCL4 , Quimiocina CCL5 , Factor 4E Eucariótico de Iniciación , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/fisiopatología , Neoplasias de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Quimiocina CCL4/genética , Quimiocina CCL4/metabolismo , Complejo Proteico Nuclear de Unión a la Caperuza/metabolismo , Factor 4E Eucariótico de Iniciación/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Línea Celular Tumoral , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inmunoterapia , Modelos Estadísticos , Mutación/genéticaRESUMEN
Oral squamous cell carcinoma (OSCC) is particularly prevalent in Taiwan. The goal of this study was to determine the clinicopathological role of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) proteins as an indicator of clinical outcomes in OSCC patients. In this study, immunohistochemical (IHC) analysis was used to examine IGF2BP2 protein expression in 244 OSCC patients. We investigated the relationships among IGF2BP2 expression, clinicopathological variables, and patient survival. Our results showed that IGF2BP2 cytoplasmic protein expression was significantly correlated with lymph node metastasis, cancer stage, and patient survival. Kaplan-Meier survival curves revealed that elevated cytoplasmic IGF2BP2 expression levels in OSCC patients were associated with poor overall survival. Moreover, multivariate cox proportional hazard models revealed that cytoplasmic IGF2BP2 expression, T status, and lymph node metastasis were independent prognostic factors for survival. In conclusion, IGF2BP2 protein was found to be a helpful predictive marker for OSCC patients, as well as a possible therapeutic target for OSCC treatment.
Asunto(s)
Neoplasias de Cabeza y Cuello , Proteínas de Unión al ARN/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello , Biomarcadores de Tumor/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/fisiopatología , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatologíaRESUMEN
For a number of years, oral cancer has remained in the top ten most common types of cancer, with an incidence rate that is steadily increasing. In total, ~75% oral cancer cases are associated with lifestyle factors, including uncontrolled alcohol consumption, betel and tobacco chewing, and the excessive use of tobacco. Notably, betel chewing is highly associated with oral cancer in Southeast Asia. Arsenic is a key environmental toxicant; however, arsenic trioxide has been used as a medicine for the treatment of acute promyelocytic leukemia, highlighting its anticancer properties. The present study aimed to investigate the role of arsenic compounds in the treatment of cancer, using FaDu oral squamous carcinoma cells treated with sodium arsenite (NaAsO2) and dimethyl arsenic acid (DMA). The results demonstrated that FaDu cells exhibited membrane blebbing phenomena and high levels of apoptosis following treatment with 10 µM NaAsO2 and 1 mM DMA for 24 h. The results of cell viability assay demonstrated that the rate of FaDu cell survival was markedly reduced as the concentration of arsenic compounds increased from 10 to 100 µM NaAsO2, and 1 to 100 mM DMA. Moreover, flow cytometry was carried out to further examine the effects of arsenic compounds on FaDu cell cycle regulation; the results revealed that treatment with NaAsO2 and DMA led to a significant increase in the percentage of FaDu cells in the subG1 and G2/M phases of the cell cycle. An Annexin V/PI double staining assay was subsequently performed to verify the levels of FaDu cell apoptosis following treatment with arsenic compounds. Furthermore, the results of the western blot analyses revealed that the expression levels of caspase8, 9 and 3, and poly ADPribose polymerase, as well the levels of phosphorylated JNK and ERK1/2 were increased following treatment with NaAsO2 and DMA in the FaDu cells. On the whole, the results of the present study revealed that treatment with NaAsO2 and DMA promoted the apoptosis of FaDu oral cancer cells, by activating MAPK pathways, as well as the extrinsic and intrinsic apoptotic pathways.
Asunto(s)
Apoptosis/efectos de los fármacos , Arsénico/farmacología , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Arsénico/metabolismo , Caspasas/metabolismo , Caspasas/farmacología , Supervivencia Celular/efectos de los fármacos , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatologíaRESUMEN
The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.
Asunto(s)
Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Ciclo Celular , Regulación Neoplásica de la Expresión Génica , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Humanos , Transporte de Proteínas , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatologíaRESUMEN
CASE PRESENTATION: A 31-year-old woman (gravida 3 and para 1-0-1-1 at 20 weeks gestation) was admitted to the hospital for a presumed acute asthma exacerbation. She had a history of severe persistent asthma since childhood. She described her symptoms as progressively worsening since the beginning of her pregnancy. In addition to her dyspnea and wheeze, both of which occurred at rest and with exertion, she complained of worsening hoarseness and mild dysphagia of solid foods over the week before admission. Her primary care provider treated her with a combined corticosteroid and long-acting beta-agonist inhaler, albuterol inhaler and nebulizer, azithromycin, and two courses of prednisone without improvement. Her allergist performed a handheld spirometry 2 months before admission that was repeated 3 weeks later in the office. She had a social history of alcohol dependence but had been sober for 9 months. She was a former one-pack-per-day smoker but quit 20 weeks before admission and used marijuana occasionally. She had no known occupational or inhalation exposures.
Asunto(s)
Asma/diagnóstico , Carboplatino/administración & dosificación , Neoplasias Laríngeas , Paclitaxel/administración & dosificación , Infecciones por Papillomavirus/complicaciones , Complicaciones Neoplásicas del Embarazo , Radioterapia/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello , Adulto , Antineoplásicos/administración & dosificación , Cesárea/métodos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Diagnóstico Diferencial , Femenino , Ronquera/diagnóstico , Ronquera/etiología , Humanos , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/fisiopatología , Laringoscopía/métodos , Embarazo , Complicaciones Neoplásicas del Embarazo/patología , Complicaciones Neoplásicas del Embarazo/fisiopatología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Oral cavity squamous cell carcinoma (OSCC) is a common head and neck cancer characterized by a poor prognosis associated with locoregional or distant failure. Among the predictors of prognosis, a dense infiltration of adaptive immune cells is protective and associated with improved clinical outcomes. However, few tools are available to integrate immune contexture variables into clinical settings. By using digital microscopy analysis of a large retrospective OSCC cohort (n = 182), we explored the clinical significance of tumor-infiltrating CD8+ T-cells. To this end, CD8+ T-cells counts were combined with well-established clinical variables and peripheral blood immune cell parameters. Through variable clustering, five metavariables (MV) were obtained and included descriptors of nodal (NODALMV) and primary tumor (TUMORMV) involvement, the frequency of myeloid (MYELOIDMV) or lymphoid (LYMPHOIDMV) peripheral blood immune cell populations, and the density of tumor-infiltrating CD8+ T-cells (TI-CD8MV). The clinical relevance of the MV was evaluated in the multivariable survival models. The NODALMV was significantly associated with all tested outcomes (p < 0.001), the LYMPHOIDMV showed a significant association with the overall, disease-specific and distant recurrence-free survival (p < 0.05) and the MYELOIDMV with the locoregional control only (p < 0.001). Finally, TI-CD8MV was associated with distant recurrence-free survival (p = 0.029). Notably, the performance in terms of survival prediction of the combined effect of NODALMV and immune metavariables (LYMPHOIDMV, MYELOIDMV and TI-CD8MV) was superior to the TNM stage for most of the outcomes analyzed. These findings indicate that the analysis of the baseline host immune features are promising tools to complement clinical features, in stratifying the risk of recurrences.
Asunto(s)
Biomarcadores de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Inmunidad Adaptativa/inmunología , Inmunidad Adaptativa/fisiología , Anciano , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Femenino , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Humanos , Italia/epidemiología , Linfocitos Infiltrantes de Tumor/fisiología , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Resultado del TratamientoRESUMEN
Few prospective cohort trials have evaluated the difference in treatment-interval total body composition (TBC) changes assessed by dual-energy X-ray absorptiometry (DXA) between two patient subgroups with locally advanced head and neck squamous cell carcinoma (LAHNSCC) receiving concurrent chemoradiotherapy (CCRT): oral cavity cancer with adjuvant CCRT (OCC) and non-oral cavity with primary CCRT (NOCC). This study prospectively recruited patients with LAHNSCC. Clinicopathological variables, blood nutritional/inflammatory markers, CCRT-related factors, and TBC data assessed by DXA before and after treatment were collected. Multivariate linear regression analysis identified the factors associated with treatment-interval changes in body composition parameters, including lean body mass (LBM), total fat mass (TFM), and bone mineral content (BMC). A total of 127 patients (OCC (n = 69) and NOCC (n = 58)) were eligible. Body composition parameters were progressively lost during CCRT in both subgroups. Extremities lost more muscle mass than the trunk for LBM, whereas the trunk lost more fat mass than the extremities for TFM. BMC loss preferentially occurred in the trunk region. Different factors were independently correlated with the interval changes of each body composition parameter for both OCC and NOCC subgroups, particularly mean daily calorie intake for LBM and TFM loss, and total lymphocyte count for BMC loss. In conclusion, treatment-interval TBC changes and related contributing factors differ between the OCC and NOCC subgroups.
Asunto(s)
Composición Corporal/fisiología , Quimioradioterapia/métodos , Neoplasias de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Densidad Ósea/fisiología , Estudios de Cohortes , Femenino , Neoplasias de Cabeza y Cuello/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/fisiopatología , Neoplasias de la Boca/terapia , Estudios Prospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatologíaRESUMEN
OBJECTIVE: This study aimed to investigate the effects of quercetin on the proliferation and invasion in oral squamous cell carcinoma (OSCC) and examine its effect on the activation of the miR-1254/CD36 signaling pathway. METHODS: Proliferation and invasion experiments were performed in the OSCC cell line CAL-27 in which miR-1254 was overexpressed or inhibited. The levels of miR-1254 and CD36 were determined using quantitative real-time polymerase chain reaction and Western blotting assays. RESULTS: Quercetin significantly suppressed the proliferation and invasion of CAL-27 cells in a dose-dependent manner, while up-regulating miR-1254 and down-regulating CD36. The overexpression of miR-1254 also considerably down-regulated CD36 and enhanced the ability of quercetin to inhibit CAL-27 cell survival and invasion. Conversely, the inhibition of miR-1254 significantly up-regulated CD36 and antagonized the inhibitory effects of quercetin. CONCLUSION: Our study suggests that quercetin might suppress the progression of OSCC by activating the miR-1254/CD36 signaling pathway, indicating its potential as a treatment against OSCC.
Asunto(s)
Antineoplásicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , MicroARNs/efectos de los fármacos , Neoplasias de la Boca/tratamiento farmacológico , Quercetina/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Células Cultivadas/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias de la Boca/fisiopatología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatologíaRESUMEN
OBJECTIVES: In this study, a meta-analysis was conducted to evaluate the occult lymph node metastasis rate in patients with early-stage (T1-T2) oral tongue squamous cell carcinoma. Also, the correlation between occult lymph node metastasis rate and T2 ratio among T1-T2 or the reported year of each study was analyzed to adjust other confound variables. STUDY DESIGN: Literature search. METHODS: A systematic computerized search of the electronic databases was carried out for articles published between January 1, 1980, and December 31, 2018, which reported occult nodal metastasis rate in T1 and T2 (separately) tongue cancer patients. Statistical analysis was performed using Comprehensive Meta Analysis version 3.3.070. Publication bias was assessed by the Egger test and Begg funnel plot method. The correlation between occult nodal metastasis rate and T2 ratio or reported year, respectively, was assessed by meta-regression analysis. RESULTS: From 19 studies, a total of 1567 cases were included in the meta-analysis. By random effects model, the mean occult cervical lymph node metastasis was 24.4% (95% confidence interval; 0.205-0.248). The meta-regression revealed that the T2 ratio and the reported year of the studies did not have a significant effect on the occult metastasis rate (correlation coefficientâ=â0.531 and 0.002, respectively, and Pâ=â.426 and 0.921, respectively). CONCLUSION: The meta-analysis revealed that the early-stage oral tongue squamous cell carcinoma had a rate of 24.4% for occult nodal metastasis. The occult nodal metastasis rate was not significantly affected by neither T2 ratio among T1-T2 nor reported year of the studies.
Asunto(s)
Protocolos Clínicos , Metástasis de la Neoplasia/fisiopatología , Carcinoma de Células Escamosas de Cabeza y Cuello/complicaciones , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Humanos , Metaanálisis como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
Social isolation has affected a large number of people and may lead to impairment of physical and mental health. Although stress resulting from social isolation may increase cancer progression, its interference on tumorigenesis is poorly known. In this study, we used a preclinical model to evaluate the effects of social isolation stress on chemically induced oral carcinogenesis. Sixty-two 21-day-old male Wistar rats were divided into isolated and grouped groups. After 90 days of age, the rats from both groups underwent oral carcinogenesis with 4-nitroquinoline 1-oxide (4NQO) for 20 weeks. All rats were assessed for depressive-like behavior and euthanized for oral squamous cell carcinoma (OSCC) diagnosis and measurement of inflammatory mediators in the tumor microenvironment. Social isolation stress increased the OSCC occurrence by 20.4% when compared to control. Isolated rats also showed higher tumor volume and cachexia than the grouped rats. Social isolation did not induce changes in the depressive-like behavior after carcinogenic induction. Tumors from stressed rats had increased levels of the inflammatory mediators, TNF-alpha, IL1-beta and MCP-1. The concentrations of TNF-alpha and MCP-1 were significantly increased in the large tumors from isolated animals. Higher tumor levels of TNF-alpha, IL-6, IL1-beta and MCP-1 were positively correlated with OSCC growth. This study provides the first evidence that social isolation stress may facilitate OSCC occurrence and tumor progression, an event accompanied by increased local levels of inflammatory mediators.
Asunto(s)
4-Nitroquinolina-1-Óxido/toxicidad , Conducta Animal , Depresión , Neoplasias de Cabeza y Cuello , Aislamiento Social , Carcinoma de Células Escamosas de Cabeza y Cuello , Estrés Psicológico , Animales , Citocinas/metabolismo , Depresión/metabolismo , Depresión/patología , Depresión/fisiopatología , Neoplasias de Cabeza y Cuello/inducido químicamente , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/fisiopatología , Mediadores de Inflamación/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Ratas , Ratas Wistar , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Estrés Psicológico/fisiopatologíaRESUMEN
BACKGROUND: p53 and DIRAS3 are tumor suppressors that are frequently silenced in tumors. In this study, we sought to determine whether the concurrent re-expression of p53 and DIRAS3 could effectively induce head and neck squamous cell carcinoma (HNSCC) cell death. METHODS: CAL-27 and SCC-25 cells were treated with Ad-DIRAS3 and rAd-p53 to induce re-expression of DIRAS3 and p53 respectively. The effects of DIRAS3 and p53 re-expression on the growth and apoptosis of HNSCC cells were examined by TUNEL assay, flow cytometric analysis and MTT. The effects of DIRAS3 and p53 re-expression on Akt phosphorylation, oncogene expression, and the interaction of 4E-BP1 with eIF4E were determined by real-time PCR, Western blotting and immunoprecipitation analysis. The ability of DIRAS3 and p53 re-expression to induce autophagy was evaluated by transmission electron microscopy, LC3 fluorescence microscopy and Western blotting. The effects of DIRAS3 and p53 re-expression on HNSCC growth were evaluated by using an orthotopic xenograft mouse model. RESULTS: TUNEL assay and flow cytometric analysis showed that the concurrent re-expression of DIRAS3 and p53 significantly induced apoptosis (P < 0.001). MTT and flow cytometric analysis revealed that DIRAS3 and p53 re-expression significantly inhibited proliferation and induced cell cycle arrest (P < 0.001). Mechanistically, the concurrent re-expression of DIRAS3 and p53 down-regulated signal transducer and activation of transcription 3 (STAT3) and up-regulated p21WAF1/CIP1 and Bax (P < 0.001). DIRAS3 and p53 re-expression also inhibited Akt phosphorylation, increased the interaction of eIF4E with 4E-BP1, and reduced the expression of c-Myc, cyclin D1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), epidermal growth factor receptor (EGFR) and Bcl-2 (P < 0.001). Moreover, the concurrent re-expression of DIRAS3 and p53 increased the percentage of cells with GFP-LC3 puncta compared with that in cells treated with control adenovirus (50.00% ± 4.55% vs. 4.67% ± 1.25%, P < 0.001). LC3 fluorescence microscopy and Western blotting further showed that DIRAS3 and p53 re-expression significantly promoted autophagic activity but also inhibited autophagic flux, resulting in overall impaired autophagy. Finally, the concurrent re-expression of DIRAS3 and p53 significantly decreased the tumor volume compared with the control group in a HNSCC xenograft mouse model [(3.12 ± 0.75) mm3 vs. (189.02 ± 17.54) mm3, P < 0.001]. CONCLUSIONS: The concurrent re-expression of DIRAS3 and p53 is a more effective approach to HNSCC treatment than current treatment strategies.
Asunto(s)
Autofagia/genética , Fragmentos de Péptidos/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/complicaciones , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Proteína p53 Supresora de Tumor/farmacología , Proteínas de Unión al GTP rho/farmacología , Animales , Apoptosis/genética , Células Cultivadas , Expresión Génica/genética , Ratones , Ratones Endogámicos BALB C , Fragmentos de Péptidos/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Proteína p53 Supresora de Tumor/uso terapéutico , Proteínas de Unión al GTP rho/uso terapéuticoRESUMEN
Overexpression of epithelial cell adhesion molecule (EpCAM) has been associated with chemotherapeutic resistance, leads to aggressive tumor behavior, and results in an adverse clinical outcome. The molecular mechanism by which EpCAM enrichment is linked to therapeutic resistance via Nrf2, a key regulator of antioxidant genes is unknown. We have investigated the link between EpCAM and the Nrf2 pathway in light of therapeutic resistance using head and neck squamous cell carcinoma (HNSCC) patient tumor samples and cell lines. We report that EpCAM was highly expressed in Nrf2-positive and HPV-negative HNSCC cells. In addition, cisplatin-resistant tumor cells consisted of a higher proportion of EpCAMhigh cells compared to the cisplatin sensitive counterpart. EpCAMhigh populations exhibited resistance to cisplatin, a higher efficiency in colony formation, sphere growth and invasion capacity, and demonstrated reduced reactive oxygen species (ROS) activity. Furthermore, Nrf2 expression was significantly higher in EpCAMhigh populations. Mechanistically, expression of Nrf2 and its target genes were most prominently observed in EpCAMhigh populations. Silencing of EpCAM expression resulted in the attenuation of expressions of Nrf2 and SOD1 concomitant with a reduction of Sox2 expression. On the other hand, silencing of Nrf2 expression rendered EpCAMhigh populations sensitive to cisplatin treatment accompanied by the inhibition of colony formation, sphere formation, and invasion efficiency and increased ROS activity. The molecular mechanistic link between EpCAM expression and activation of Nrf2 was found to be a concerted interaction of interleukin-6 (IL-6) and p62. Silencing of p62 expression in EpCAMhigh populations resulted in the attenuation of Nrf2 pathway activation suggesting that Nrf2 pathway activation promoted resistance to cisplatin in EpCAMhigh populations. We propose that therapeutic targeting the Nrf2-EpCAM axis might be an excellent approach to modulate stress resistance and thereby survival of HNSCC patients enriched in EpCAMhigh populations.
Asunto(s)
Resistencia a Antineoplásicos/fisiología , Molécula de Adhesión Celular Epitelial/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Molécula de Adhesión Celular Epitelial/fisiología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Interleucina-6/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/fisiología , Proteínas de Unión al ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción SOXB1 , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatologíaRESUMEN
Cardiac metastasis from head and neck cancer is an extremely rare and devastating condition with an abysmal prognosis. Most of our knowledge about this condition is from case reports and series. We present a case of squamous cell carcinoma of the tonsils that was complicated by embolic stroke and critical limb ischemia that were found to be secondary to intracardiac metastasis. We believe that this condition is under-reported; hence, we conducted a thorough review of the literature to highlight the characteristics and previous therapeutic experiences with various presentations of cardiac metastasis from head and neck carcinoma. Clinicians are encouraged to report their experience with evaluating and managing this type of metastasis.
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Accidente Cerebrovascular Embólico , Neoplasias Cardíacas , Disección del Cuello/métodos , Nivolumab/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello , Tonsilectomía/métodos , Quimioradioterapia Adyuvante/métodos , Diagnóstico Diferencial , Accidente Cerebrovascular Embólico/diagnóstico , Accidente Cerebrovascular Embólico/etiología , Accidente Cerebrovascular Embólico/fisiopatología , Resultado Fatal , Neoplasias Cardíacas/patología , Neoplasias Cardíacas/fisiopatología , Neoplasias Cardíacas/secundario , Neoplasias Cardíacas/cirugía , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Tonsila Palatina/diagnóstico por imagen , Tonsila Palatina/patología , Tonsila Palatina/cirugía , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugíaRESUMEN
Oral Mucositis (OM) is a common adverse effect of head and neck squamous cell carcinoma (HNSCC) treatment. The purpose of this study was to investigate the significance of early changes in tissue electrical parameters (TEPs) in predicting the development of OM in HNSCC patients receiving radiation therapy (RT). The current study combined two study designs. The first was a case-control study. The control group comprised of RT patients who did not receive head and neck RT, and patients with HNSCC who received RT comprised the case group. In the second part of the study, the case group was included in a parallel cohort. A total of 320 patients were assessed for eligibility, and 135 patients were enrolled. Double blinding was performed, and neither the patients nor the care providers knew the measured parameters. The primary outcome was the detection of between-group changes in local TEPs over the follow-up period. The secondary outcome was the appearance of OM grades II, III, or IV and the predictive value of local TEPs in determining the incidence of OM after RT. The variables, impedance module, resistance, reactance, phase angle, and capacitance, were analyzed by the receiver operator curves (ROC). The case and control groups did not differ in demographic and clinical characteristics. Radiation therapy increased the local impedance module, resistance, reactance, and phase angle and reduced the local tissue capacitance in both groups. Evaluation of TEPs in the first week of RT correlated with the development of OM lesions during cancer therapy. ROC analysis showed that local impedance module and resistance presented higher specificity than did other parameters in predicting OM. In conclusion, local tissue electrical parameters measured at the first RT week can be useful tools to predict oral mucositis.
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Fenómenos Electrofisiológicos/efectos de la radiación , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Estomatitis/diagnóstico , Estomatitis/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatologíaRESUMEN
OBJECTIVES: To investigate MRI features in discriminating chronic invasive fungal rhinosinusitis (CIFRS) from sinonasal squamous cell carcinomas (SNSCC). METHODS: MRI findings of 33 patients with CIFRS and 47 patients with SNSCC were retrospectively reviewed and compared. Multivariate logistic regression analysis was performed to identify significant imaging features in distinguishing between CIFRS and SNSCC. The ROC curves and the AUC were used to evaluate diagnostic performance. RESULTS: There were significant differences in cavernous sinus involvement (p < 0.001), sphenoid sinus involvement (p < 0.001), meningeal involvement (p = 0.024), T2 signal intensity (p = 0.006), and enhancement pattern (p < 0.001) between CIFRS and SNSCC. Multivariate logistic regression analysis identified cavernous sinus involvement (odds ratio [OR] = 0.06, 95% confidence interval [95% CI] = 0.02-0.20) and sphenoid sinus involvement (OR = 0.14, 95% CI = 0.05-0.45) as significant indicators for CIFRS and T2 isointensity to gray matter (OR = 4.44, 95% CI = 1.22-16.22) was a significant indicator for SNSCC. ROC curve analysis showed the AUC from a combination of three imaging features was 0.95 in differentiating CIFRS and SNSCC. CONCLUSIONS: MRI showed significant differences between CIFRS and SNSCC features. In immunocompromised patients, a sinonasal hypointense mass on T2WI with septal enhancement or loss of contrast enhancement, and involvement of cavernous sinus, sphenoid sinus, and meninges strongly suggest CIFRS. KEY POINTS: ⢠Chronic invasive fungal rhinosinusitis (CIFRS) is often difficult to distinguish from sinonasal squamous cell carcinomas (SNSCC) in clinical practice. ⢠Cavernous sinus and sphenoid sinus involvement appear to be significant indicators for CIFRS. T2 isointensity to gray matter appears to be a significant indicator for SNSCC. ⢠Loss of contrast enhancement and septal enhancement can be used to distinguish CIFRS from SNSCC with a high degree of specificity.
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Diagnóstico Diferencial , Infecciones Fúngicas Invasoras/diagnóstico por imagen , Neoplasias de los Senos Paranasales/diagnóstico por imagen , Rinitis/diagnóstico por imagen , Sinusitis/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Adulto , Anciano , Aspergilosis/diagnóstico por imagen , Aspergilosis/inmunología , Aspergilosis/fisiopatología , Seno Cavernoso/diagnóstico por imagen , Enfermedad Crónica , Epistaxis/fisiopatología , Dolor Facial/fisiopatología , Femenino , Cefalea/fisiopatología , Humanos , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/inmunología , Infecciones Fúngicas Invasoras/fisiopatología , Modelos Logísticos , Imagen por Resonancia Magnética , Masculino , Meninges/diagnóstico por imagen , Persona de Mediana Edad , Mucormicosis/diagnóstico por imagen , Mucormicosis/inmunología , Mucormicosis/fisiopatología , Análisis Multivariante , Obstrucción Nasal/fisiopatología , Neoplasias Nasales/diagnóstico por imagen , Neoplasias Nasales/fisiopatología , Neoplasias de los Senos Paranasales/fisiopatología , Estudios Retrospectivos , Rinitis/inmunología , Rinitis/fisiopatología , Rinorrea/fisiopatología , Sinusitis/inmunología , Sinusitis/fisiopatología , Seno Esfenoidal/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Trastornos de la Visión/fisiopatologíaRESUMEN
OBJECTIVES: Hypopharyngeal cancer is typically detected at a late stage by ear, nose, and throat (ENT) physicians, when the prognosis is poor. We evaluated how hypopharyngeal cancer (Tis, T1 and T2) were detected by ENT physicians and gastrointestinal endoscopists (GEs) according to the detection reasons. MATERIALS AND METHODS: A total of 109 consecutive patients with hypopharyngeal cancer (Tis, T1 and T2) who received treatment in our institution from January 2014 to February 2018 was enrolled. The detection detail of hypopharyngeal cancer lesions by ENT physicians and GEs, tumor size and location, and the characteristics of the lesions missed by ENT physicians and GEs were reviewed retrospectively. RESULTS: Twenty seven and 82 of 109 (24.8% and 75.2%) patients were detected by ENT physicians and GEs, respectively. The most frequent original reasons for ENT physicians and GEs were both pharyngeal discomfort screening and examination of swollen neck lymph nodes (12 of 27, 44.4% for each) and pre-treatment or follow-up screening for esophageal cancer (25 of 82, 30.5%), respectively. Among the 13 cases of upper gastrointestinal tract screening of the head-and-neck cancer other than pharyngeal cancer detected by GEs, 11 (84.6%) were missed by ENT physicians. In contrast, among the 25 cases of pre-treatment screening of the esophageal cancer detected by GEs, 12 (48%) were missed by other GEs just before the consultation from other institutions. CONCLUSIONS: The percentage of detection of hypopharyngeal cancer (especially, Tis and T1) by ENT physicians is low. A careful examination of the pharynx should be conducted by GEs.
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Endoscopía del Sistema Digestivo , Gastroenterólogos , Neoplasias Hipofaríngeas/diagnóstico , Otorrinolaringólogos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon , Trastornos de Deglución/fisiopatología , Endoscopía , Neoplasias Esofágicas , Femenino , Neoplasias de Cabeza y Cuello , Humanos , Neoplasias Hipofaríngeas/patología , Neoplasias Hipofaríngeas/fisiopatología , Neoplasias Hipofaríngeas/terapia , Neoplasias Pulmonares , Ganglios Linfáticos/patología , Linfadenopatía/fisiopatología , Masculino , Persona de Mediana Edad , Diagnóstico Erróneo , Cuello , Estadificación de Neoplasias , Neoplasias Primarias Múltiples , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Neoplasias GástricasAsunto(s)
Deglución/fisiología , Neoplasias de Cabeza y Cuello/terapia , Cirugía Endoscópica por Orificios Naturales/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Adulto , Anciano , Quimioradioterapia Adyuvante , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Boca , Estadificación de Neoplasias , Radioterapia Adyuvante , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: We aimed to compare frailty status between patients with head and neck cancer (HNC) and other solid malignancies. METHODS: Data collection was prospective, and the following were compared between cohorts at baseline: patient and tumour characteristics, Charlson Comorbidity Index (CCI), Groningen Frailty Indicator (GFI), Mini Mental State Examination (MMSE), Activities of Daily Living (ADLs), Instrumental ADLs (IADLs), Timed Up and Go (TUG) and Quality of Life (QoL). Univariate and multivariate logistic regression analyses were performed, and odds ratios (ORs) with their 95% confidence intervals (95% CIs) were estimated. RESULTS: In total, 242 patients with HNC and 180 with other oncology diagnoses were enrolled, of whom 32.6% and 21.8% were frail according to the GFI respectively. Comorbidity scores were not significantly different between the cohorts (7.4% vs. 13.1%; OR 0.54; 95% CI 0.28-1.02). In the univariate analysis, the GFI was significantly worse in the HNC cohort (OR 1.74; 95% CI 1.11-2.71). However, in the multivariate analysis, the MMSE, TUG and global QoL were significantly worse in the HNC cohort, with ORs of 20.03 (95% CI 2.44-164.31), 11.56 (95% CI 1.86-71.68) and 0.98 (95% CI 0.97-1.00) respectively. CONCLUSION: Patients with HNC appear to be frailer than patients with other solid malignancies despite comparable levels of comorbidity.