RESUMEN
BACKGROUND: To improve the prognosis of patients with metastatic colorectal cancer (mCRC), investigating predictive biomarkers of their prognosis and chemotherapeutic responsiveness is necessary. This study aimed to analyze the clinical significance of serum proteinase-3 (PRTN3) as a predictor for prognosis and chemosensitivity, especially to bevacizumab therapy, in mCRC. METHODS: This single-center retrospective observational study enrolled 79 patients with mCRC in our hospital and 353 patients with colorectal cancer in the TCGA database. Preoperative serum PRTN3 levels were measured using an enzyme-linked immunosorbent assay. The clinicopathological characteristics and prognosis according to serum PRTN3 levels were then evaluated. PRTN3 expression in tumor and stromal cells was evaluated immunohistochemically. The impact of PRTN3 levels on angiogenesis and bevacizumab sensitivity was evaluated using the tube formation assay. RESULTS: Serum PRTN3 levels were an independent poor prognostic factor for progression-free survival (PFS) (hazard ratio, 2.082; 95% confidence interval, 1.118-3.647; P=0.010) in patients with mCRC. Similarly, prognostic analysis with TCGA data sets showed poorer overall survival in patients with PRTN3 expression than that in patients without PRTN3 expression, especially in patients with stage IV. Immunohistochemical analysis of resected specimens revealed that stromal neutrophils expressed PRTN3, and their expression level was significantly correlated with serum PRTN3 levels. Interestingly, the effectiveness of first-line chemotherapy was significantly poorer in the high serum PRTN3 level group. High serum PRTN3 was significantly associated with poor PFS (hazard ratio, 3.027; 95% confidence interval, 1.175-7.793; P=0.0161) in patients treated with bevacizumab, an anti-angiogenic inhibitor. The tube formation assay revealed that PRTN3 administration notably augmented angiogenesis while simultaneously attenuating the anti-angiogenic influence exerted by bevacizumab therapy. CONCLUSIONS: Serum PRTN3 levels could be a novel predictive biomarker of PFS of first-line chemotherapy, especially for bevacizumab therapy, in patients with mCRC.
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Neoplasias del Colon , Neoplasias Colorrectales , Mieloblastina , Neoplasias del Recto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Biomarcadores , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo , Péptido Hidrolasas , Pronóstico , Supervivencia sin Progresión , Neoplasias del Recto/tratamiento farmacológico , Mieloblastina/sangreRESUMEN
Metastasis is the leading cause of death in breast cancer patients due to the lack of effective therapies. Elevated levels of paxillin expression have been observed in various cancer types, with tyrosine phosphorylation shown to play a critical role in driving cancer cell migration. However, the specific impact of the distinct tyrosine phosphorylation events of paxillin in the progression of breast cancer remains to be fully elucidated. Here, we found that paxillin overexpression in breast cancer tissue is associated with a patient's poor prognosis. Paxillin knockdown inhibited the migration and invasion of breast cancer cells. Furthermore, the phosphorylation of paxillin tyrosine residue 31 (Tyr31) was significantly increased upon the TGF-ß1-induced migration and invasion of breast cancer cells. Inhibiting Fyn activity or silencing Fyn decreases paxillin Tyr31 phosphorylation. The wild-type and constitutively active Fyn directly phosphorylate paxillin Tyr31 in an in vitro system, indicating that Fyn directly phosphorylates paxillin Tyr31. Additionally, the non-phosphorylatable mutant of paxillin at Tyr31 reduces actin stress fiber formation, migration, and invasion of breast cancer cells. Taken together, our results provide direct evidence that Fyn-mediated paxillin Tyr31 phosphorylation is required for breast cancer migration and invasion, suggesting that targeting paxillin Tyr31 phosphorylation could be a potential therapeutic strategy for mitigating breast cancer metastasis.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/metabolismo , Movimiento Celular , Paxillin/metabolismo , Fosforilación , Tirosina/metabolismoRESUMEN
49-year-old woman, who diagnosed advanced breast cancer with, ER-positive, HER2-positive, T4bN1M1, Stage â £. At the time of initial diagnosis, liver damage equivalent to Child-Pugh classification C due to diffuse liver metastasis was observed, but trastuzumab/pertuzumab(HP)and paclitaxel(PTX)adjusted according to liver function were administered every 3 weeks, resulting in rapid improvement of liver function, PR of the primary tumor(90% reduction), PR of the liver metastases(70% reduction), and improvement of tumor markers. Currently, chemotherapy has been switched to docetaxel (DTX)due to peripheral neuropathy caused by PTX, and treatment is continuing. In the case of HER2-positive breast cancer, good disease control may be achieved with aggressive treatment and intervention under dose adjustment and careful systemic management, even in the setting of liver injury.
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Neoplasias de la Mama , Neoplasias Hepáticas , Femenino , Humanos , Neoplasias de la Mama/patología , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trastuzumab , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Phyllodes tumors are uncommon breast neoplasms that constitute 1-2% of breast malignancies. Invasive ductal carcinoma in the epithelial component of phyllodes tumor is very rare. When carcinoma is detected within the specimen, the management of treatment changes completely. We report a rare case of invasive ductal carcinoma arising in a giant borderline malignancy phyllodes tumor in a 51-year-old female patient. A painful 20 cm mass was found in her right breast, and a needle biopsy revealed fibroadenoma or benign phyllodes tumor, and a total mastectomy was performed. Pathological results showed that a borderline malignant phyllodes tumor coexisted with invasive ductal carcinoma. We explained that axillary surgery was necessary because invasive cancer was diagnosed after surgery, but the patient requested follow-up using images. Endocrine therapy was performed as postoperative adjuvant therapy, and the follow-up is underway without recurrence.
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Neoplasias de la Mama , Carcinoma Ductal , Fibroadenoma , Tumor Filoide , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/patología , Tumor Filoide/cirugía , Tumor Filoide/diagnóstico , Mastectomía , Fibroadenoma/diagnóstico , Carcinoma Ductal/cirugíaRESUMEN
A questionnaire survey was conducted by 17 doctors from 14 hospitals regarding treating elderly breast cancer in Yamaguchi Prefecture. The survey items are the implementation status of the geriatric assessment(GA)for the elderly, the state at the start of treatment(fit/vulnerable/frail), and the setting of restrictions on the indication of surgery and drug treatment (endocrine therapy/chemotherapy/molecular targeted therapy). Only one institution(6%)was used for GA; the tools used were the G8 and Charlson comorbidity index. Regarding surgical treatment, most facilities did not set restrictions according to age or condition. Endocrine and molecular-targeted therapies(anti-HER drugs)are highly tolerated, and most facilities do not have age restrictions. On the other hand, 40% of the respondents set age restrictions on chemotherapy. Four(24%) therapists said they would limit their age to 70 to 75 if the patient had a frail condition. These results tended to be similar to the reports of NCD-registered elderly breast cancer treatment.
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Neoplasias de la Mama , Humanos , Anciano , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Encuestas y Cuestionarios , Evaluación Geriátrica/métodos , Anciano FrágilRESUMEN
Understanding the behavioral and psychological symptoms of dementia (BPSD) is important for caregivers in long-term geriatric care facilities. In this study performed in 43 long-term care facilities, we evaluated the ability of caregivers to recognize BPSD through the development and validation of self-assessment scales. Reliability and validity of the scales were determined using Cronbach's alpha coefficient, the test/retest method, exploratory factor analysis, confirmatory factor analysis, criteria-related validity, and construct validity. We analyzed cross-sectional data from 310 participants. Factor analysis showed a positive correlation for all scale items (rs = .43-.73). Significant correlations arose from the test/retest method (rs = .48-.76). The α coefficient of all items except one was .70 or more, indicating sufficient reliability. Criteria-related validity (rs = .43-.73) and construct validity (rs = .13-.52) revealed a positive correlation. The BPSD Team Care Self-Assessment Scale is reliable and could ensure BPSD competency in caregivers.
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Demencia , Autoevaluación (Psicología) , Anciano , Estudios Transversales , Demencia/diagnóstico , Humanos , Grupo de Atención al Paciente , Psicometría , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Patient is 69-year-old man, who underwent a high anterior resection with laparoscopic support for rectal cancer. The patient was diagnosed with anastomotic recurrent rectal cancer after 14 months after surgery. The pelvic MRI scan showed invasion of the prostate and seminal vesicles, so NACRT was performed. Tumors were found to have decreased in size, although there was still some residual invasion of the prostate and seminal vesicle. Laparoscopic total pelvic exenteration (Lap-TPE), and combined excision of the anal elevator muscle and bladder were performed. Preoperative diagnosis was ycT4b, N0, M0, ycStage â ¡, and pathological diagnosis was pT4b (prostate and seminal vesicles), INF b, Ly2, v2, Pn1b, pPM0, pDM0, pRM0, and pN0. Laparoscopic surgery allowed to operate safely, with minimal blood loss and a good field of vision. After postoperative adjuvant chemotherapy, lung and liver metastasis appeared after 6 months after surgery, but there was no local recurrence. The patient is treated with chemotherapy, and the metastases are under control. The patient is survive 17 months after Lap-TPE.
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Laparoscopía , Exenteración Pélvica , Neoplasias del Recto , Anciano , Humanos , Masculino , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/cirugíaRESUMEN
BACKGROUND: Colorectal cancer is the third most common cancer worldwide. If biomarkers can be identified in liquid biopsy, diagnosis and treatment can be optimized even when cancerous tissues are not available. The purpose of this study was to identify proteins from liquid biopsy that would be useful as markers of poor prognosis. METHODS: First, we comprehensively analyzed serum proteins to identify potential biomarkers and focused on serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). The relationship between LOX-1 and the prognosis of patients with colorectal cancer has not been reported. Next, we validated this marker using serum samples from 238 patients with colorectal cancer by ELISA and 100 tissue samples by immunohistochemical staining. RESULTS: The optimal cut-off value of serum LOX-1 was 538.7 pg/mL according to time-dependent receiver operating characteristics curve analysis. The overall survival of patients with high levels of serum LOX-1 was significantly poorer than that of individuals with low levels of LOX-1 in the training and test datasets. In multivariate analysis for overall survival, serum LOX-1 was an independent prognostic factor identified in liquid biopsy (hazard ratio = 1.729, p = 0.027). The prognosis of patients with high LOX-1 expression in tumor tissues was significantly poorer than that of individuals with low expression (p =0.047 ). Additionally, inflammatory factors such as white blood cell count, C-reactive protein level, neutrophil/lymphocyte ratio, and monocyte/lymphocyte ratio were significantly higher in the group with high serum LOX-1 levels. CONCLUSIONS: Serum LOX-1 might be a useful biomarker of poor prognosis in colorectal cancer.
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Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Receptores Depuradores de Clase E/sangre , Anciano , Neoplasias Colorrectales/patología , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neutrófilos/patología , Pronóstico , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
In recent years, breast reconstruction has been increasingly performed in breast cancer surgery with improving the appearance of the breast. We report a case of local breast cancer recurrence after artificial breast reconstruction. The patient was a 52-year-old woman. She had undergone total mastectomy for left breast cancer 11 years ago, and reconstruction with breast implant 3 years ago. She presented to our hospital with the chief complaint of skin redness and induration of the reconstructed breast. A core needle biopsy was performed, and its results showed in the invasive ductal carcinoma. She had an operation of resection of tumor and reconstruction implant. As a result of histopathological diagnosis, it was a local recurrence of breast cancer 11 years ago. After the surgery, she underwent endocrine therapy and there is no recurrence. As the increase in the number of cases of breast reconstruction, the number of recurrences in the reconstructed breast is expected to increase the future. The treatment strategy for cases of local recurrence after breast reconstruction is currently under review, the accumulation of evidence is necessary.
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Implantes de Mama , Neoplasias de la Mama , Mamoplastia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Femenino , Humanos , Mastectomía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugíaRESUMEN
We investigated whether primary tumor resection performed at our department for the purpose of local control affects the disease progression of Stage â £ breast cancer. Fifteen patients who underwent primary tumor resection between 2009 and 2017 were investigated. The median age at the time of surgery was 63 years. There were two postoperative deaths(1 at<1 year postoperatively and 1 at<2 years postoperatively). The median postoperative stable disease(SD)period was 11 months overall and was 12 months or longer in 7 patients. SD was attained by all patients with the first drug treatment after primary tumor resection. Patients who tended to have a longer postoperative SD period did not receive preoperative drug treatment, were luminal HER2-positive, and had one metastatic organ. Regardless of surgery timing and reason, there were no cases of rapid postoperative disease progression. In all patients, postoperative local control was satisfactory, and continuation of medical treatment was feasible for distant metastatic tumors. These data signify that primary tumor resection can be considered to treat Stage â £ breast cancer for the purpose of local control.
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Neoplasias de la Mama , Neoplasias de la Mama/cirugía , Humanos , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
Everolimus and exemestane combination therapy represents a treatment option for estrogen receptor(ER)-positive metastatic breast cancer. We evaluated the efficacy and safety of everolimus and exemestane therapy, retrospectively. After a median follow-up of 10.5 months, the median progression-free survivalin patients was 4.7 months. The clinicalbenefit rate was 27%and the disease controlrate was 64%. The most common all-grade adverse events(AEs)were stomatitis(82%) and non-infectious lung disease(27%). The most commonB3 grade AEs were cellulitis(18%)and hyperglycemia(18%). The AEs reported were mostly grade 1 and 2, and manageable with appropriate intervention. Combination therapy with everolimus and exemestane appears to be a useful addition for ER-positive metastatic breast cancer, with carefulmanage- ment of specific AEs.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Androstadienos/administración & dosificación , Androstadienos/efectos adversos , Neoplasias de la Mama/patología , Sistema Endocrino , Everolimus/administración & dosificación , Everolimus/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , PosmenopausiaRESUMEN
The receptor for gonadotropin-releasing hormone (GnRH) belongs to the G protein-coupled receptors (GPCRs), and its stimulation activates extracellular signal-regulated protein kinase (ERK). We found that the transactivation of ErbB4 was involved in GnRH-induced ERK activation in immortalized GnRH neurons (GT1-7 cells). We found also that GnRH induced the cleavage of ErbB4. In the present study, we examined signal transduction for the activation of ERK and the cleavage of ErbB4 after GnRH treatment. Both ERK activation and ErbB4 cleavage were completely inhibited by YM-254890, an inhibitor of Gq/11 proteins. Down-regulation of protein kinase C (PKC) markedly decreased both ERK activation and ErbB4 cleavage. Experiments with two types of PKC inhibitors, Gö 6976 and bisindolylmaleimide I, indicated that novel PKC isoforms but not conventional PKC isoforms were involved in ERK activation and ErbB4 cleavage. Our experiments indicated that the novel PKC isoforms activated protein kinase D (PKD) after GnRH treatment. Knockdown and inhibitor experiments suggested that PKD1 stimulated the phosphorylation of Pyk2 by constitutively activated Src and Fyn for ERK activation. Taken together, it is highly possible that PKD1 plays a critical role in signal transduction from the PKC pathway to the tyrosine kinase pathway. Activation of the tyrosine kinase pathway may be involved in the progression of cancer.
Asunto(s)
Hormona Liberadora de Gonadotropina/farmacología , Proteína Quinasa C/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular , Activación Enzimática , Humanos , Proteolisis , Receptor ErbB-4/metabolismoRESUMEN
Toll-like receptor 5 (TLR5) is a receptor for flagellin and is present on the basolateral surface of intestinal epithelial cells. However, the pathological roles of TLR5 in intestinal epithelial cells are not clear at present. In previous reports, we demonstrated that treatment of cultured alveolar epithelial cells with flagellin activated the p38 mitogen-activated protein kinase (MAPK) pathway and enhanced epithelial-mesenchymal transition induced by transforming growth factor beta 1 (TGF-ß1). In translating our findings in alveolar epithelial cells to intestinal epithelial cells, we found that both flagellin and TGF-ß1 activated p38 MAPK and its downstream protein kinase, MAPK-activated protein kinase-2 (MAPKAPK-2) in an IEC-6 intestinal epithelial cell line. The phosphorylation of HSP27, one of the substrates for MAPKAPK-2, was also increased. TGF-ß1 increased the protein level of α-smooth muscle actin (αSMA), and flagellin enhanced the effect of TGF-ß1. A wound healing assay revealed that flagellin and TGF-ß1 stimulated the migration of cells. SB203580, an inhibitor of p38 MAPK, and an inhibitor of MAPKAPK-2 inhibited flagellin-stimulated migration. These results suggested that TLR5 is involved in the migration of intestinal epithelial cells through activation of the p38 MAPK pathway.
Asunto(s)
Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Flagelina/farmacología , Intestinos/citología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Línea Celular , Electroforesis en Gel de Poliacrilamida , Humanos , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). A P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by 2-D electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis indicated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in the CRThigh /CD44v9low population was much higher than that in the CRTlow /CD44v9high population. Calreticulin expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and postoperative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.
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Calreticulina/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transportadoras de Casetes de Unión a ATP/metabolismo , Antígeno CD47/metabolismo , Línea Celular Tumoral , Humanos , Receptores de Hialuranos/metabolismo , Estimación de Kaplan-Meier , Pronóstico , Modelos de Riesgos Proporcionales , ProteómicaRESUMEN
Breast cancer is the most frequent cancer threatening the lives of women between the ages of 30 and 64. The cancer antigen 15-3 assay (CA15-3) has been widely used for the detection of breast cancer recurrence; however, its sensitivity and specificity are inadequate. We previously found that the breast cancer cell line YMBS secretes mucin 1 possessing 3'-sulfated core1 (3Score1-MUC1) into the medium. Therefore, we here evaluated whether 3Score1-MUC1 is secreted into the blood streams of breast cancer patients, and whether it can serve as an improved breast cancer marker. We developed a lectin-sandwich immunoassay, called Gal4/MUC1, using a 3'-sulfated core1-specific galectin-4 and a MUC1 monoclonal antibody. Using the Gal4/MUC1 assay method, we found that 3Score1-MUC1 was profoundly expressed in the blood streams of patients with recurrent and/or metastatic breast cancer. The positive ratio of the Gal4/MUC1 assay was higher than that of the CA15-3 assay in both primary (n = 240) and relapsed (n = 43) patients, especially in the latter of which the positive ratio of Gal4/MUC1 was 86%. whereas that of CA15-3 was 47%. Furthermore, serum Gal4/MUC1 levels could more sensitively reflect the recurrence of primary breast cancer patients after surgery. Therefore, the Gal4/MUC1 assay should be an excellent alternative to the CA15-3 tumor marker for tracking the recurrence and metastasis of breast cancer.
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Neoplasias de la Mama/metabolismo , Mucina-1/biosíntesis , Recurrencia Local de Neoplasia/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales/química , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Secuencia de Carbohidratos , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Galectina 4/química , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Mucina-1/sangre , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patologíaRESUMEN
Fluorescence in situ hybridization (FISH) with centromeric probes is a method used to detect chromosomal instability (CIN), a hallmark of most cancers. However, no studies thus far have investigated the relationship between centromeric FISH signals and the cell cycle in cancer cells. In this study, the chromosome content in each cell cycle phase was evaluated with respect to the number of centromeric FISH signals in two breast cancer cell lines and eight surgically resected breast cancer specimens using image cytometry. Variations in chromosome number were detected at each phase of the cell cycle but were not associated with proliferative capacity in the cell lines. Furthermore, the chromosome doubling frequency differed in each cell line and clinical specimen. These results reveal two aspects of centromeric FISH signal variation in breast cancers that exhibit CIN, and suggest that chromosome doubling is a remarkable occurrence that may increase the heterogeneity of tumors.
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Aneuploidia , Neoplasias de la Mama/genética , Inestabilidad Cromosómica/genética , ADN de Neoplasias/genética , Ciclo Celular/genética , Línea Celular Tumoral , Centrómero/genética , ADN de Neoplasias/análisis , Femenino , Humanos , Citometría de Imagen , Hibridación Fluorescente in Situ , Células MCF-7 , Transducción de Señal/genéticaRESUMEN
Four transmembrane tyrosine kinases constitute the ErbB protein family: epidermal growth factor receptor (EGFR) or ErbB1, ErbB2, ErbB3, and ErbB4. In general, the structure and mechanism of the activation of these members are similar. However, significant differences in homologous desensitization are known between EGFR and ErbB4. Desensitization of ligand-occupied EGFR occurs by endocytosis, while that of ErbB4 occurs by selective cleavage at the cell surface. Because ErbB4 is abundantly expressed in neurons from fetal to adult brains, elucidation of the desensitization mechanism is important to understand neuronal development and synaptic functions. Recently, it has become clear that heterologous desensitization of EGFR and ErbB4 are induced by endocytosis and cleavage, respectively, similar to homologous desensitization. It has been reported that heterologous desensitization of EGFR is induced by serine phosphorylation of EGFR via the p38 mitogen-activated protein kinase (p38 MAP kinase) pathway in various cell lines, including alveolar epithelial cells. In contrast, the protein kinase C pathway is involved in ErbB4 cleavage. In this review, we will describe recent advances in the desensitization mechanisms of EGFR and ErbB4, mainly in alveolar epithelial cells and hypothalamic neurons, respectively.
Asunto(s)
Receptores ErbB/metabolismo , Animales , Línea Celular , Células Epiteliales/metabolismo , Receptores ErbB/genética , Flagelina/farmacología , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Humanos , Hipotálamo/citología , Hipotálamo/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Neuronas/metabolismo , Fosforilación , Proteína Quinasa C/fisiología , Alveolos Pulmonares/citología , Alveolos Pulmonares/metabolismo , Receptor ErbB-4 , Serina/metabolismo , Transducción de Señal/fisiología , Activación Transcripcional , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Although copy number variations (CNVs) are expected to affect various diseases, little is known about the association between CNVs and breast cancer susceptibility. Therefore, we investigated this relation. Array comparative genomic hybridization was performed to search for candidate CNVs related to breast cancer susceptibility. Subsequent quantitative real-time polymerase chain reaction was carried out for confirmation. We found seven CNV markers associated with breast cancer risk. The means of the relative copy numbers of patients with a history of breast cancer and women in the control group were 0.8 and 1.8 for Hs06535529_cn on 1p36.12 (P < 0.0001), 2.9 and 2.2 for Hs03103056_cn on 3q26.1 (P < 0.0001), 1.2 and 1.8 for Hs03899300_cn on 15q26.3 (P < 0.0001), 1.0 and 1.5 for Hs03908783_cn on 15q26.3 (P < 0.0001), and 1.1 and 1.7 for Hs03898338_cn on 15q26.3 (P < 0.0001), respectively. Interestingly, nine or more copies of Hs04093415_cn on 22q12.3 were found only in 8/193 (4.1 %) patients with a history of breast cancer and in none of the controls (P = 0.0081). Similarly, 12 or more copies of Hs040908898_cn on 22q12.3 were found only in 7/193 (3.6 %) patients with a history of breast cancer and in none of the controls (P = 0.016). A combination of two CNVs resulted in 80.3 % sensitivity, 80.6 % specificity, 82.4 % positive predictive value, and 78.3 % negative predictive value for the prediction of breast cancer susceptibility. These findings may lead to a new means of risk assessment for breast cancer. Confirmatory studies using independent data sets are needed to support our findings.
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Pueblo Asiatico/genética , Neoplasias de la Mama/etiología , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Células Germinativas/metabolismo , Neoplasias de la Mama/sangre , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Hibridación Genómica Comparativa , ADN/sangre , ADN/genética , Femenino , Genotipo , Humanos , Japón/epidemiología , Persona de Mediana Edad , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Tasa de SupervivenciaRESUMEN
It has been reported that tumor necrosis factor α (TNFα) activated the p38 MAP kinase pathway, followed by phosphorylation of epidermal growth factor receptor (EGFR) at serine 1047 (Ser1047). Although the phosphorylation of Ser1047 reportedly induced an internalization of EGFR, a protein kinase responsible for the phosphorylation has not been elucidated. In the present study, we found that treatment with flagellin of A549 cells, an alveolar epithelial cell line, induced the activation of p38 MAP kinase, followed by phosphorylation of EGFR at Ser1047. The phosphorylation was strongly inhibited by SB203580, an inhibitor of p38 MAP kinase. The flagellin treatment activated MAP kinase-activated protein kinase-2 (MAPKAPK-2), a protein kinase downstream of p38 MAP kinase, and MK2a inhibitor, an inhibitor of MAPKAPK-2, inhibited the flagellin-induced phosphorylation of EGFR at Ser1047. Unlike the flagellin treatment, the TNFα treatment induced the phosphorylation of EGFR at both Ser1047 and Tyr1173. SB203580 and MK2a inhibitor strongly inhibited the phosphorylation of Ser1047 but not Tyr1173 in EGFR. Finally, bacterially expressed and activated MAPKAPK-2 phosphorylated EGFR at Ser1047 in vitro. These results suggest that flagellin regulates the residence time of EGFR on the plasma membrane and thus the signaling of EGFR through phosphorylation of Ser1047 by MAPKAPK-2.
Asunto(s)
Células Epiteliales/metabolismo , Receptores ErbB/metabolismo , Flagelina/farmacología , Pulmón/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Sitios de Unión , Línea Celular , Células Epiteliales/efectos de los fármacos , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Unión ProteicaRESUMEN
We report a protocol for entrapping of various water-dispersed nanomaterials: fullerenes, multiwall carbon nanotubes, quantum dots (semiconductor nanoparticles), and gold nanorods, into a DNA-chitosan complex. In contrast to small-size nanomaterial particles, the bulky DNA-chitosan interpolyelectrolyte complex incorporating the dispersed nanomaterials can be easily separated from aqueous media by centrifugation, filtration, or decantation. While the removal of nanoparticles by centrifugation is equally efficient for every type of nanoparticles and reaches 100%, the higher efficiency of the nanomaterials removal by other two methods is favored by larger size of nanoparticles. The application of this entrapping protocol for removal of nanomaterials from water is discussed.