RESUMEN
Tumor progression is a complex process involving extracellular matrix (ECM) remodeling and stiffening. However, the mechanisms that govern these processes and their roles in tumor progression are still poorly understood. In this study, we performed bioinformatics, immunohistochemical, and biochemical analyses to examine if collagen cross-linking is associated with tumor stage and regional lymph node metastasis (RLNM) in oral squamous cell carcinoma (OSCC). We found that the genes encoding key enzymes for cross-linking are frequently overexpressed in oral, head, and neck cancers. Specifically, the enzymes lysyl hydroxylase 2 (LH2) or lysyl oxidase (LOX) and LOX-like 2 (LOXL2) were significantly upregulated in late-stage tumors and associated with poor patient prognosis. The protein levels of these enzymes in the primary human OSCC were also significantly increased in late-stage tumors and markedly elevated in the RLNM-positive tumors. Notably, while overall LOX/LOXL2-catalyzed collagen cross-links were enriched in late-stage and RLNM-positive tumors, LH2-mediated stable cross-links were significantly increased. To our knowledge, this is the first study to investigate the association of collagen cross-linking and expression of key enzymes regulating this process with OSCC stage. The data indicate a critical role for collagen cross-linking in OSCC tumor progression and metastasis, which may provide insights into development of novel therapeutic strategies to prevent OSCC progression.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de la Boca , Aminoácido Oxidorreductasas , Colágeno , Matriz Extracelular , Humanos , Proteína-Lisina 6-OxidasaRESUMEN
BACKGROUND: MicroRNAs (miRNAs) are involved in essential biological activities, and have been reported to exhibit differential expression profiles in various cancers. Our previous study demonstrated that intercellular adhesion molecule-2 (ICAM2) inhibition induces radiosensitisation in oral squamous cell carcinoma (OSCC) cells. Thus, we hypothesised that certain miRNAs play crucial roles in radioresistance in OSCC by regulating ICAM2 expression. METHODS: Because predicted target gene analyses revealed that microRNA-125b (miR-125b) potentially regulates ICAM2 mRNA expression, we examined the association between miR-125b and radioresistance. The expression of miR-125b was investigated by real-time quantitative reverse transcriptase-PCR. For a functional analysis, miR-125b was transfected to OSCC-derived cells. RESULTS: A downregulated expression of miR-125b was found in OSCC-derived cell lines and OSCC samples. The miR-125b-transfected cells showed a decreased proliferation rate, enhanced radiosensitivity to X-ray irradiation and diminished ICAM2 mRNA expression. Moreover, miR-125b expression correlated with OSCC tumour staging and survival. CONCLUSION: These findings suggested that the downregulated miR-125b expression was associated with proliferation and radioresistance mechanisms, probably through ICAM2 signalling. Thus, controlling the expression or activity of miR-125b might contribute to suppressing proliferation and overcoming radioresistance in OSCC.
Asunto(s)
Antígenos CD/metabolismo , Carcinoma de Células Escamosas/radioterapia , Moléculas de Adhesión Celular/metabolismo , MicroARNs/metabolismo , Neoplasias de la Boca/radioterapia , Tolerancia a Radiación/genética , Antígenos CD/biosíntesis , Carcinoma de Células Escamosas/genética , Moléculas de Adhesión Celular/biosíntesis , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Neoplasias de la Boca/genética , Pronóstico , ARN Mensajero/biosíntesis , Transducción de Señal , Transfección , Rayos XRESUMEN
Conventional therapies including radiation therapy cannot cure squamous cell carcinoma (SCC), and new treatments are clearly required. Our recent studies have shown that SCC cell lines exhibiting radioresistance show significant upregulation of the fibroblast growth factor receptor 3 (FGFR3) gene. We hypothesized that inhibiting FGFR3 would suppress tumor cell radioresistance and provide a new treatment approach for human SCCs. In the present study, we found that RNA interference-mediated FGFR3 depletion in HSC-2 cells, a radioresistant cell line, induced radiosensitivity and inhibited tumor growth. Use of an FGFR3 inhibitor (PD173074) obtained similar results with suppression of the autophosphorylation extracellular signal-regulated kinase pathway in HSC-2 cells and lung cancer cell lines. Moreover, the antitumor growth effect of the combination of PD173074 and radiation in vivo was also greater than that with either drug alone or radiation alone. Our results provided novel information on which to base further mechanistic study of radiosensitization by inhibiting FGFR3 in human SCC cells and for developing strategies to improve outcomes with concurrent radiotherapy.
Asunto(s)
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Tolerancia a Radiación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos , Pirimidinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidoresRESUMEN
BACKGROUND: Sindbis virus (SIN) infection causes no or only mild symptoms (fever, rash, and arthralgia) in humans. However, SIN has a strong cytopathic effect (CPE) on various cancer cells. This study focuses on the oncolytic activity of SIN AR399 on oral cancer cells compared with reovirus, a well-known oncolytic virus that targets cancer cells. METHODS: We analysed the cytotoxicity and growth of SIN in 13 oral squamous cell carcinoma (OSCC) cell lines (HSC-2, HSC-3, HSC-4, Ca9-22, H-1, Sa-3, KON, KOSC-2, OK-92, HO-1-N1, SCC-4, SAT, SKN-3) and normal human oral keratinocytes (NHOKs). RESULTS: Sindbis virus infection induced CPE in 12 OSCC cell lines at a low multiplicity of infection (MOI) of 0.01, but not in the OSCC cell line, HSC-4 or NHOKs. Sindbis viral growth was not observed in NHOKs, whereas high SIN growth was observed in all OSCC cell lines, including HCS-4. The cytotoxicity and growth of SIN was the same as reovirus at an MOI of 20 in 12 OSCC cell lines. The CPE was shown, by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labelling assays, to be apoptotic cell death. Furthermore, quantitative RT-PCR of mRNA in HSC-3 and HSC-4 cells after SIN infection showed that activation of caspases, cytochrome c, and IkappaBalpha was associated with SIN-induced apoptosis. CONCLUSION: As a replication-competent oncolytic virus, SIN may be a useful therapeutic modality for oral cancers.
Asunto(s)
Carcinoma de Células Escamosas/virología , Neoplasias de la Boca/virología , Viroterapia Oncolítica/métodos , Virus Oncolíticos/fisiología , Virus Sindbis/fisiología , Infecciones por Alphavirus , Apoptosis/fisiología , Línea Celular Tumoral , Expresión Génica , Humanos , Etiquetado Corte-Fin in Situ , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Virales/biosíntesisRESUMEN
The aim of the present study was to clarify the clinical characteristics of postoperative delirium and to determine appropriate postoperative management for its prevention. The authors analysed 132 cases of primary surgery for oral carcinoma and observed 24 (18%) cases of postoperative delirium. Univariate analysis revealed that significant risk factors for postoperative delirium were older age, male gender, extensive surgery and morphine pain control. Logistic regression analysis showed that older age and male gender were significant risk factors for postoperative delirium, while patient-controlled analgesia with fentanyl was effective for prevention of postoperative delirium. There was a trend for postoperative delirium to be associated with extensive surgery. In those who had delirium, blood tests revealed that alkaline phosphatase, total protein, sodium, chlorine, red blood cell count, haemoglobin and haematocrit were significantly diminished after surgery. These results indicate that general condition is closely related to the onset of postoperative delirium, and suggest that appropriate postoperative management can reduce the incidence of this complication.
Asunto(s)
Carcinoma de Células Escamosas/cirugía , Delirio/etiología , Delirio/prevención & control , Neoplasias de la Boca/cirugía , Procedimientos Quirúrgicos Orales/efectos adversos , Factores de Edad , Analgesia Controlada por el Paciente , Analgésicos Opioides/administración & dosificación , Delirio/sangre , Femenino , Fentanilo/administración & dosificación , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Morfina/administración & dosificación , Cuidados Posoperatorios , Estudios Retrospectivos , Factores de Riesgo , Factores SexualesRESUMEN
To characterise Ca(2+) -binding protein gene expression changes in oral squamous cell carcinomas (OSCCs), we compared the gene expression profiles in OSCC-derived cell lines with normal oral tissues. One hundred Ca(2+) -binding protein genes differentially expressed in OSCCs were identified, and genetic pathways associated with expression changes were generated. Among genes mapped to the network with the highest significance, glucose-regulated protein 94 kDa (Grp94) was evaluated further for mRNA and protein expression in the OSCC cell lines, primary OSCCs, and oral premalignant lesions (OPLs). A significant (P<0.001) overexpression of Grp94 protein was observed in all cell lines compared to normal oral epithelium. Immunohistochemical analysis showed highly expressed Grp94 in primary OSCCs and OPLs, whereas most of the corresponding normal tissues had no protein immunoreaction. Real-time quantitative reverse transcriptase-PCR data agreed with the protein expression status. Moreover, overexpression of Grp94 in primary tumours was significantly (P<0.001) correlated with poor disease-free survival. The results suggested that Grp94 may have potential clinical application as a novel diagnosis and prognostic biomarker for human OSCCs.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas de Unión al Calcio/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Glicoproteínas de Membrana/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/genética , Biomarcadores de Tumor/genética , Western Blotting , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Supervivencia sin Enfermedad , Técnica del Anticuerpo Fluorescente Directa , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Glicoproteínas de Membrana/genética , Neoplasias de la Boca/patología , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
Synovial sarcoma is a mesenchymal spindle-cell tumour that occurs infrequently in the head and neck. It originates from unknown stem cells differentiating into mesenchymal and/or epithelial structures. Most synovial sarcomas are biphasic in character, consisting of epithelial and spindle-cell elements. Here is reported a case of monophasic epithelial synovial sarcoma arising in the temporomandibular joint. The tumour was of a predominantly epithelial pattern, although a minute area of sarcomatous cells was found. The primary mode of treatment was wide en-bloc excision. Two years after surgery, the patient died of hepatocellular carcinoma, but there was no evidence of synovial sarcoma recurrence.
Asunto(s)
Neoplasias Mandibulares/patología , Sarcoma Sinovial/patología , Trastornos de la Articulación Temporomandibular/patología , Articulación Temporomandibular/patología , Anciano , Epitelio/patología , Resultado Fatal , Humanos , Masculino , Neoplasias Mandibulares/cirugía , Sarcoma Sinovial/cirugía , Articulación Temporomandibular/cirugía , Trastornos de la Articulación Temporomandibular/cirugíaRESUMEN
In this report, we described an adult case that had a long-term radiculopathy due to an extruded osseous endplate of the lumbar spine at the L5-S1 intervertebral disc level. The osseous material inside the extruded material was not absorbed, and it had continued compressing the nerve root for one year. Endoscopically, the bony fragment was successfully removed. After the surgery, the patient's symptom disappeared, and neurological deficits became normalized. In conclusion, we propose that surgical intervention should be taken into account for the treatment of HNP, when the extruded material contains bony fragment such as osseous endplate.
Asunto(s)
Desplazamiento del Disco Intervertebral/complicaciones , Placa Motora , Neuroendoscopía , Osificación Heterotópica/complicaciones , Osificación Heterotópica/cirugía , Radiculopatía/etiología , Adulto , Femenino , Humanos , Desplazamiento del Disco Intervertebral/cirugíaRESUMEN
Stathmin is an intracellular phosphoprotein that is overexpressed in a number of human malignancies. Our previous study using proteomic profiling showed that significant upregulation of stathmin occurs in oral squamous-cell carcinoma (OSCC)-derived cell lines. In the current study, to determine the potential involvement of stathmin in OSCC, we evaluated the state of stathmin protein and mRNA expression in OSCC-derived cell lines and human primary OSCCs. A significant increase in stathmin expression was observed in all OSCC-derived cell lines examined compared to human normal oral keratinocytes. In immunohistochemistry, 65% of the OSCCs were positive for stathmin, and no immunoreaction was observed in corresponding normal tissues. Real-time quantitative reverse transcriptase-polymerase chain reaction data were consistent with the protein expression status. Moreover, stathmin expression status was correlated with the TNM stage grading. Furthermore, we found a statistical correlation between the protein expression status and disease-free survival (P=0.029). These results suggest that expression of stathmin could contribute to cancer progression/prognosis, and that stathmin may have potential as a biomarker and a therapeutic target for OSCC.
Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias de la Boca/genética , Estatmina/biosíntesis , Anciano , Biomarcadores de Tumor/análisis , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Queratinocitos/fisiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estatmina/genética , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
Frequent allelic imbalances (AIs) including loss of heterozygosity and microsatellite instability on a specific chromosomal region have been identified in a variety of human malignancies. The objective of our study was to assess the possibility of prognostication and monitoring of oral squamous cell carcinoma (SCC) by microsatellite blood assay. DNA from normal and tumorous tissues and serum DNA obtained at three time points (preoperatively, postoperatively, and 4 weeks postoperatively) from 64 patients with oral SCC was examined at nine microsatellite loci. In all, 38 (59%) DNA samples from tumorous tissues and 52% from serum showed AIs in at least one locus. Patterns of AIs in the serum DNA were matched to those detected in tumour DNA. Of them, AIs were frequently detected preoperatively (44%, 28 of 64), and postoperatively (20%, 13 of 64). Moreover, among 12 cases with AIs during the postoperative period, six had no evidence of an AI 4 weeks postoperatively, and they had no recurrence and were disease free. In contrast, six patients with AI-positive DNA 4 weeks postoperatively have died with distant metastasis within 44 weeks. Thus, our results suggest that the assessment of microsatellite status in the serum DNA could be a useful predictive tool to monitor disease prognosis.
Asunto(s)
Carcinoma de Células Escamosas/sangre , ADN de Neoplasias/sangre , Neoplasias de la Boca/sangre , Células Neoplásicas Circulantes , Adulto , Anciano , Anciano de 80 o más Años , Desequilibrio Alélico/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Femenino , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Estadificación de Neoplasias , Proyectos Piloto , PronósticoRESUMEN
This study was designed to identify specific gene expression changes in tongue squamous cell carcinomas (TSCCs) compared with normal tissues using in-house cDNA microarray that comprised of 2304 full-length cDNAs from a cDNA library prepared from normal oral tissues, primary oral cancers, and oral cancer cell lines. The genes identified by our microarray system were further analysed at the mRNA or protein expression level in a series of clinical samples by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis and imuunohositochemistry. The microarray analysis identified a total of 16 genes that were significantly upregulated in common among four TSCC specimens. Consistent with the results of the microarray, increased mRNA levels of selected genes with known molecular functions were found in the four TSCCs. Among genes identified, Rab1a, a member of the Ras oncogene family, was further analysed for its protein expression in 54 TSCCs and 13 premalignant lesions. We found a high prevalence of Rab1A-overexpression not only in TSCCs (98%) but also in premalignant lesions (93%). Thus, our results suggest that rapid characterisation of the target gene(s) for TSCCs can be accomplished using our in-house cDNA microarray analysis combined with the qRT-PCR and immunohistochemistry, and that the Rab1A is a potential biomarker of tongue carcinogenesis.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/genética , Perfilación de la Expresión Génica , Neoplasias de la Lengua/genética , Proteínas de Unión al GTP rab1/biosíntesis , Anciano , Carcinoma de Células Escamosas/patología , Transformación Celular Neoplásica , Femenino , Biblioteca de Genes , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Lengua/patologíaRESUMEN
OBJECTIVE: Differential diagnosis of cementifying fibroma, ossifying fibroma and fibrous dysplasia by histological evaluation is often difficult. The aim of this study was to examine the immunoreactivities for keratan sulfate (KS) and chondroitin-4-sulfate (C4S) glycosaminoglycans of the histological samples obtained from mandibles of patients with these diseases. MATERIALS AND METHODS: The samples were collected from three patients with cementifying fibroma, two with ossifying fibroma and three with fibrous dysplasia and were subjected to immunohistochemical analyses. RESULTS: The results demonstrated that a significant immunoreactivity for KS was found in lacunae housing cells in the cementum-particles of cementifying fibromas, while both ossifying fibromas and fibrous dysplasias showed no significant immunoreactivity for KS. For C4S, while the former showed little immunoreactivity, the latter two cases exhibited intensive immunostaining in the pre- and poorly mineralized matrices. CONCLUSIONS: These results suggest that cementifying fibromas could be distinguished from these fibro-osseous tumors by using immunohistochemical analysis for KS and C4S.
Asunto(s)
Cementoma/química , Sulfatos de Condroitina/análisis , Fibroma Osificante/química , Displasia Fibrosa Ósea/metabolismo , Sulfato de Queratano/análisis , Neoplasias Mandibulares/química , Tumores Odontogénicos/química , Adolescente , Adulto , Cemento Dental/química , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , MasculinoRESUMEN
The interleukin-5 receptor alpha chain (IL-5Ralpha) is known to regulate the development and function of B cells and eosinophils. Although the functions of IL-5Ralpha cytoplasmic domain subregions have been studied extensively using cultured cell lines, this approach has limitations when studying the functions of distinct primary B-cell subpopulations and their responsiveness to IL-5. In the present study, we generated mice on an IL-5Ralpha null background, each expressing a mutant form of an IL-5Ralpha transgene ligated to a mu enhancer and VH promoter, either lacking the cytoplasmic DC3 region or substituting two proline residues for alanine (ApvA) in the membrane-proximal ppvp motif of the cytoplasmic domain. The ppvp motif, which mediates activation of JAK2/STAT5 and Btk, also contributes to c-fos, c-jun and c-myc expression. IL-5Ralpha null mutant mice showed impaired B-1-cell development, reduced serum immunoglobulin G3 (IgG3) and IgM, no IL-5-induced enhancement of B-cell proliferation and IL-5-induced switch recombination from the mu gene to gamma1 gene; these were not recovered following the expression of the ApvA mutant. In contrast, absence of the DC3 region affected the IL-5-induced switch recombination from the mu to the gamma1 gene and B-1-cell development, while IL-5-induced proliferation and IgM production were at levels similar to those of B cells expressing wild-type IL-5Ralpha transgene. The results clearly indicated that the ppvp motif and the DC3 region of IL-5Ralpha played distinct roles in B-cell proliferation and differentiation. Thus, this present approach offers new insights into the functions of the cytoplasmic subregions of IL-5Ralpha, in particular its carboxy-terminal region.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina G/biosíntesis , Receptores de Interleucina/inmunología , Secuencia de Aminoácidos , Animales , Técnicas de Cultivo de Célula , Diferenciación Celular/inmunología , División Celular/inmunología , Citoplasma/inmunología , Inmunoglobulina M/biosíntesis , Interleucina-5/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Mutación , Receptores de Interleucina/genética , Receptores de Interleucina-5 , Relación Estructura-ActividadRESUMEN
BACKGROUND: The role of inflammatory cytokines is still unclear in ischemia-reperfusion injury of the pancreas. We investigated the effect of FR167653 (FR), a newly developed compound that is a potent suppressor of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha on ischemia-reperfusion injury of the isolated pancreatic tail in dogs. METHODS: The tail of the pancreas was subjected to ischemia for 90 minutes. During occlusion of the vascular inflow, the head of the pancreas was removed. A control group (n = 14) and an FR treatment group (n = 11) were evaluated for survival rate, tissue blood flow, arterial oxygen pressure (Pao(2)), serum amylase and lipase levels, glucose and insulin, liver enzymes, creatinine, IL-1beta mRNA in the peripheral blood, and histopathology. RESULTS: Six of the 14 control animals and 2 of the 11 FR-treated animals died. The FR treatment group showed lower amylase (P=.037) and lipase (P =.030) levels, lower IL-1beta mRNA expression (P =.033), and less pancreatic tissue damage (P =.041) than did the control group, but there was no remarkable change in endocrine function (P =.422). Pao(2) during the acute phase in the FR treatment group was maintained (P=.009), but pulmonary tissue was damaged. Results of biochemical and histologic examinations of the liver and kidneys were unremarkable. CONCLUSIONS: FR ameliorates ischemia-reperfusion injury of the pancreas and reduces the production of inflammatory cytokines that may contribute to secondary damage to distant organs.
Asunto(s)
Isquemia/patología , Isquemia/fisiopatología , Páncreas/irrigación sanguínea , Pirazoles/farmacología , Piridinas/farmacología , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Animales , Perros , Femenino , Interleucina-1/sangre , Islotes Pancreáticos/fisiopatología , Masculino , Páncreas/fisiopatologíaRESUMEN
Skeletal unloading induces loss of bone mineral density in weight-bearing bones. The objectives of this study were to characterize the post-translational modifications of collagen of weight-bearing bones subjected to hindlimb unloading for 8 weeks. In unloaded bones, tibiae and femurs, while the overall amino acid composition was essentially identical in the unloaded and control tibiae and femurs, the collagen cross-link profile showed significant differences. Two major reducible cross-links (analyzed as dihydroxylysinonorleucine and hydroxylysinonorleucine) were increased in the unloaded bones. In addition, the ratios of the former to the latter as well as pyridinoline to deoxypyridinoline were significantly decreased in the unloaded bones indicating a difference in the extent of lysine hydroxylation at the cross-linking sites between these two groups. These results indicate that upon skeletal unloading the relative pool of newly synthesized collagen is increased and it is post-translationally altered. The alteration could be associated with impaired osteoblastic differentiation induced by skeletal unloading that results in a mineralization defect.
Asunto(s)
Matriz Ósea/metabolismo , Huesos/metabolismo , Colágeno/metabolismo , Soporte de Peso , Aminoácidos/análisis , Aminoácidos/metabolismo , Animales , Peso Corporal , Colágeno/química , Suspensión Trasera , Hidroxilación , Lisina/metabolismo , Masculino , Prolina/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Loss of heterozygosity (LOH) on the long arm of chromosome 20 (20q) has been detected in several human cancers. However, little is known about LOH on chromosome 20 in oral squamous cell carcinoma (OSCC). To determine which loci of chromosome 20 were involved in OSCC tumorigenesis, 41 cases of OSCC were examined for LOH state on chromosome 20 at 17 microsatellite loci by PCR-LOH assay. LOH occurred in 41.5% of tumors in at least one locus. Among the 17 loci, D20S48 on 20p11.2 and RPN2 on 20q12-13.1 exhibited higher frequencies of LOH, 27.6% and 31.4%, respectively. The LOH incidence was significantly higher in tumors in which the primary site was on gingiva compared with other oral sites (p=0.012). Our results indicate that allelic deletions on 20q12-13.1 and 20p11.2 may play roles in OSCC carcinogenesis, and suggest that allelic deletions on 20q might have some relation with the primary site of OSCC.
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Carcinoma de Células Escamosas/genética , Deleción Cromosómica , Cromosomas Humanos Par 20/genética , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas/patología , Bandeo Cromosómico , Mapeo Cromosómico , ADN de Neoplasias/genética , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Neoplasias de la Boca/patologíaRESUMEN
Allelic deletions on the short arm of chromosome 8 (8p) are frequent events in many different types of malignant tumors, including head and neck tumors and oropharyngeal cancers. These regions are thought to harbor tumor suppressor genes. However, there has been no detailed analysis of loss of heterozygosity (LOH) on the chromosome arm 8p in oral squamous cell carcinoma (SCC). In order to estimate details of 8p loci involved in oral SCC, 32 patients with oral SCCs were examined for the LOH state 8p by PCR-LOH assay using 14 microsatellite markers. Based on our results a detailed deletion map of 8p showed LOH in at least one of the loci tested in 62.5% (20 of 32) of patients; and microsatellite instability (MI) was observed in 50% (16 of 32). The frequent LOH on this chromosome arm was identified at D8S87 and D8S258, mapped on 8p12 and 8p22, respectively. Fisher's exact test revealed no significant statistical correlation between the incidence of LOH or MI and clinicopathological features. Our observations indicate that the short arm of chromosome 8 may play a role in the pathogenesis of oral SCC; and that the two loci identified in this study may be tumor suppressor gene loci on 8p.
Asunto(s)
Carcinoma de Células Escamosas/genética , Cromosomas Humanos Par 8 , Pérdida de Heterocigocidad , Neoplasias de la Boca/genética , Genes Supresores de Tumor , Humanos , Repeticiones de Microsatélite/genética , Polimorfismo GenéticoRESUMEN
Allelic imbalance or loss of heterozygosity (LOH) studies have been used to identify regions on chromosomes that may contain putative tumor suppressor genes. Deletions of chromosome 9 regions have been observed at high frequency in many other types of sporadic tumor, whereas in oral cancer no decisive information about the allelic loss on chromosome 9 has been reported. To provide detailed understanding of the genetic alterations in oral cancer, 24 highly polymorphic markers mapped on chromosome 9 were used to examine 34 cases of oral squamous cell carcinoma (SCC). LOH was detected in 18 (53%) of 34 informative samples at one or more loci examined. On the basis of our results, three commonly deleted regions were identified and a detailed deletion map was constructed. One of the novel regions was on 9p22, where a tumor suppressor gene, interferon a cluster (IFNA) gene, was identified before. Another region was D9S157 locus at 9p22, telomeric to IFNA locus and p15/16 genes, and the third was located on 9p21 of the D9S104 locus, centromelic to methylthioadenosine phosphorylase (MTAP) gene and p15/16 genes. Thus, our data suggest that, except for p15/16 and MTAP gene, there were at least two candidate tumor suppressor genes located at chromosome 9p, and that the alteration of these genes is associated with the tumorigenesis of oral SCC.
Asunto(s)
Carcinoma de Células Escamosas/genética , Mapeo Cromosómico , Cromosomas Humanos Par 9 , Genes Supresores de Tumor , Neoplasias de la Boca/genética , Humanos , Interferón-alfa/genética , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Purina-Nucleósido Fosforilasa/genéticaRESUMEN
OBJECTIVE: To test the authors' hypothesis of the causal mechanism(s) of postoperative tetany in patients with Graves disease. SUMMARY BACKGROUND DATA: Previous studies by the authors suggested that postoperative tetany in patients with Graves disease occurs during the period of bone restoration and resulted from continuation of a calcium flux into bone concomitant with transient hypoparathyroidism induced by surgery. PATIENTS AND METHODS: A prospective study was carried out to investigate sequential changes in serum levels of intact parathyroid hormone (iPTH), calcium and other electrolytes, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)2D), and bone metabolic markers in 109 consecutive patients with Graves disease who underwent subtotal thyroidectomy. RESULTS: Preoperative serum iPTH levels negatively correlated with ionized calcium levels and positively correlated with 1,25(OH)2D or 1,25(OH)2D/25OHD. After the operation, there was a significant decline in levels of ionized calcium, magnesium, and iPTH. Serum iPTH was not detected in 15 patients after surgery. Four of these 15 patients, and 1 patient whose iPTH level was below normal, developed tetany. Preoperative serum ionized calcium levels were significantly lower, and iPTH levels were higher, in the 5 patients with tetany than in the 11 patients who did not develop tetany despite undetectable iPTH levels. The tetany group had significantly lower serum 25OHD levels and higher 1,25(OH)2D levels, and had increased 1,25(OH)2D/25OHD as an index of the renal 25OHD-1-hydroxylase activity than those in the nontetany group. These results suggest that patients with a high serum level of iPTH as a result of low serum calcium levels (secondary hyperparathyroidism) are susceptible to tetany under conditions of hypoparathyroid function after surgery. CONCLUSIONS: Postoperative tetany occurs in patients with secondary hyperparathyroidism caused by a relative deficiency in calcium and vitamin D because of their increased demand for bone restoration after preoperative medical therapy concomitant with transient hypoparathyroidism after surgery. Calcium and vitamin D supplements may be recommended before and/or after surgery for patients in whom postoperative tetany is expected to develop.
Asunto(s)
Enfermedad de Graves/cirugía , Tetania/etiología , Tiroidectomía/efectos adversos , Deficiencia de Vitamina D/etiología , Adolescente , Adulto , Calcio/sangre , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Estudios Prospectivos , Tetania/sangre , Vitamina D/sangreRESUMEN
We examined biopsy samples from one oral cancer and three precancerous lesions of the tongue of an 81-year old woman by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and sequence analyses using 18 oligonucleotide primer pairs of adenomatous polyposis coli (APC) gene and 5 primers of p53 gene. Normal tongue epithelium adjacent to lesions was used as a control. The four lesions harbored the common mutation of APC gene that was not detected in the control. At codon 1621 in exon 15 of the APC gene there was a C to G substitution resulting in serine (TCA) to stop codon (TGA). No mutation of p53 gene was detected in any samples of the control and three precancerous lesions of the tongue. On the other hand, an A to G substitution at codon 170 in exon 5 of p53 gene resulting in glutamic acid (ACG) to glycine (GCG) was detected in the DNA of her tongue cancer. These results may suggest that the four lesions have the same origin, and that multi-step oncogenesis had occurred, the APC gene alteration being one of the early events in the process of tumorigenesis and p53 gene alteration involved in the late events.