RESUMEN
We report a case of a 26-year-old Chinese man who had experienced three grand mal seizures in the past two months. Magnetic resonance imaging revealed a relatively well-circumscribed lesion in the left frontal lobe. A craniotomy with total excision of the tumor was performed. Histopathological investigations confirmed a grade 2 ependymoma according to the World Health Organization classification. Genetic analysis revealed a tumor harboring FAM118B fusion to YAP1, and no other genetic alterations or methylation of the O6 -methylguanine-DNA methyltransferase gene promoter were detected. This is the second case report of ependymoma with YAP1:FAM118B fusion.
Asunto(s)
Ependimoma/genética , Ependimoma/patología , Lóbulo Frontal/patología , Neoplasias Supratentoriales/genética , Neoplasias Supratentoriales/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Ependimoma/diagnóstico , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Convulsiones/patología , Neoplasias Supratentoriales/diagnóstico , Factor de Transcripción ReIA/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAPRESUMEN
Diffuse midline glioma with histone H3-K27M mutation is a new tumor entity defined by the 2016 WHO Classification of Tumors of the Central Nervous System. A 51-year-old Chinese woman presented with neck pain for a month. Subsequent MRI revealed an intramedullary neoplasm extending from C5 to C7. Histologically, the cellular area of the tumor was composed of primitive, poorly differentiated, small cells with scant cytoplasm, nuclear molding, and brisk mitotic activity, exhibiting PNET-like appearance, while in the hypocellular area, oligodendroglioma-like cells were observed. More importantly, neuropil-like islands were observed in the cellular area. Microvascular proliferation was noted, with no necrosis. Besides histone H3K27M mutation, immunohistochemical staining also showed that the tumor cells were positive for oligodendrocyte lineage transcription factor 2 and ATRX. The neuropil-like areas were positive for synaptophysin, intermingled with scattered neuronal nuclear antigen positive cells. The Ki-67 proliferation index was about 30%, and tumor cells were highly immunopositive for p53. Sequencing for IDH1 codon 132 and IDH2 codon 172 gene mutations showed negative results. Furthermore, fluorescent analysis revealed 1p deletion in the lesion but no 19q deletion. Based on these findings, the tumor was diagnosed as diffuse midline gliomas with histone H3-K27M mutation in the spinal cord, corresponding to WHO grade IV. After 4 months of remission, the tumor recurred; 2 months later, the patient died. Herein, we report an extremely rare case of diffuse midline glioma with histone H3K27M mutation, which was morphologically characterized simultaneously by primitive neuroectodermal tumor-like appearance and neuropil-like islands.
Asunto(s)
Glioma/patología , Histonas/genética , Mutación , Neoplasias de la Médula Espinal/patología , Vértebras Cervicales , Femenino , Glioma/diagnóstico , Glioma/diagnóstico por imagen , Glioma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Persona de Mediana Edad , Tumores Neuroectodérmicos Primitivos/patología , Neurópilo/patología , Factor de Transcripción 2 de los Oligodendrocitos/metabolismo , Oligodendroglioma/patología , Neoplasias de la Médula Espinal/diagnóstico , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2α at protein level but not at messenger RNA level, and hypoxia-inducible factor 2α upregulated vascular endothelial growth factor at both protein and messenger RNA levels. This is the first study to show hypoxia-inducible factor 2α as a downstream effector of liver kinase B1 in lung cancer cells. Our results indicate that HPV16 E6/E7 indirectly upregulated the expression of vascular endothelial growth factor by inhibition of liver kinase B1 expression and upregulation of hypoxia-inducible factor 2α expression, thus propose a human papillomavirus-liver kinase B1-hypoxia-inducible factor 2α-vascular endothelial growth factor axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of liver kinase B1 in the pathogenesis of human papillomavirus-related lung cancer and suggests novel therapeutic targets.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Papillomavirus Humano 16/genética , Neoplasias Pulmonares/genética , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Represoras/genética , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Quinasas de la Proteína-Quinasa Activada por el AMP , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Papillomavirus Humano 16/patogenicidad , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/virología , Proteínas Serina-Treonina Quinasas/genética , Activación Transcripcional/genética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Hemangioblastoma is a well-circumscribed, highly vascular, lipid-rich and low-grade tumor of uncertain histogenesis. Its histopathological features have been well established. Herein, we present a case of cerebellar hemangioblastoma in a 43-year-old woman. Histologically, the tumor was predominantly composed of cellular areas showing eosinophilic or vacuolated stromal cells arranged in nests and sheets. Focally, conventional reticular areas could be seen. Additionally, in some areas, the stromal cells were arranged radially around blood vessels, exhibiting perivascular pseudorosette structures, which were similar mostly to those of ependymomas. Immunohistochemically, the stromal cells markedly showed diffused staining for Vimentin, S-100, CD56, NSE, inhibin-a, podoplanin, alpha-Thalassemia/mental retardation syndrome X and carbonic anhydrase IX, and were negative for cytokeratin, epithelial membrane antigen, oligodendrocyte transcription factor 2, neuronal nuclear antigen, synaptophysin, isocitrate dehydrogenase 1 (R132H), P53 and CD34. Interestingly, the reticular and cellular areas either showed no or individual scattering of the GFAP-positive cells, respectively, while, the perivascular pseudorosette areas strongly and diffusely expressed GFAP. Nuclear mitosis and necrosis were not observed. The MIB-1 antibody labeling index was especially low (about 3%). Based on these findings, the patient was diagnosed with cerebellar hemangioblastoma. In the present case, we documented a distinctive histological appearance of perivascular pseudorosettes in hemangioblastoma and provided the evidence for stromal cells with glial differentiation.
Asunto(s)
Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/patología , Hemangioblastoma/diagnóstico , Hemangioblastoma/patología , Neuroglía/patología , Adulto , Diferenciación Celular , Neoplasias Cerebelosas/irrigación sanguínea , Femenino , Hemangioblastoma/irrigación sanguínea , Humanos , Células del Estroma/patologíaRESUMEN
High-risk human papillomavirus (HPV) infection may play an important role in non-small cell lung carcinoma (NSCLC) development. However, some recent studies have proved that it was not directly associated with lung cancer. The aim of this study was to evaluate the underlying molecular mechanism that HPV16 regulate the expression of GLUT1 and may promote the development of lung cancer. HPV16, HIF-1α, and GLUT1 were detected in pleural effusions of patients with lung cancer (n = 95) and with benign lung disease (n = 55) by immunocytochemistry. Western blotting and qRT-PCR were used to detect the expression chances of HPV16 E6/E7, HIF-1α, and GLUT1 in lung cancer cells. HPV16, HIF-1α, and GLUT1 were significantly more likely to be expressed in the malignant group than in the benign group as detected by immunocytochemistry (ICC), and HIF-1α was significantly correlated with HPV16 or GLUT1 in the malignant group (P < 0.01). Expression changes of E6 and E7 significantly promoted the protein expression of HIF-1α, the expression of both protein and mRNA of GLUT1, but had no effect on the expression of HIF-1α mRNA in lung cancer cells. After inhibition of HIF-1α, it obviously downregulated the expression of both protein and mRNA of GLUT1 in lung cancer cells. E6 and E7 regulated the expression of GLUT1 may be due to the mediation of HIF-1α in lung cancer cells. These results suggest that both E6 and E7 play the important role in the regulation of Warburg effect and may be a valuable therapeutic target for HPV-related cancer.
Asunto(s)
Adenocarcinoma/genética , Transportador de Glucosa de Tipo 1/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Neoplasias Pulmonares/genética , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/genética , Proteínas Represoras/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/virología , Adulto , Anciano , Estudios de Casos y Controles , Línea Celular Tumoral , Femenino , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Regulación Viral de la Expresión Génica , Transportador de Glucosa de Tipo 1/metabolismo , Papillomavirus Humano 16/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/virología , Masculino , Persona de Mediana Edad , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/virología , Proteínas Represoras/metabolismo , Activación Transcripcional , Regulación hacia ArribaRESUMEN
BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been reported to promote tumorigenesis and progression in several human malignancies. The purpose of this study was to explore the function of BDNF in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC). METHODS: The expression of BDNF was examined in 110 samples of lung SCC and ADC by immunohistochemistry. The protein level of BDNF was examined in 25 lung SCC or ADC samples and paired non-tumors by western blot. BDNF expression was also evaluated in human bronchial epithelial cells (HBE) and 4 lung cancer cell lines using western blot. Three BDNF mRNA variants containing exons IV, VI and IX were evaluated in HBE, two SCC (SK, LK2) and two ADC (A549, LTE) cell lines by RT-PCR. The expression and secretion of BDNF were also determined in cells using western blot and ELISA. Then the shRNA specific for BDNF was transfected into LK2 or A549 cells to further elucidate the BDNF knockdown on cell proliferation, apoptosis and invasion, which were confirmed by MTT, flow cytometry and transwell examinations. RESULTS: 71.8 % (79 out of 110) of lung SCC and ADC samples were detected positive BDNF, and high expression of BDNF was significantly correlated with histological type and T stage. Compared with non-tumorous counterparts, BDNF was apparently overexpressed in SCC and ADC tissues. In cell studies, the extensive expression and secretion of BDNF were demonstrated in lung cancer cells compared with HBE cells. Interestingly, the expressions of BDNF mRNA variant IV and VI were identical in all cells examined. However, more expression of BDNF mRNA variant IX was found in SK and LK2 cells. The apoptotic cells were increased, and the cell proliferation and invasion were both attenuated once the expression of BDNF was inhibited. When retreated by rhBDNF, BDNF knockdown cells showed less apoptotic or more proliferative and invasive. CONCLUSIONS: Our data show that BDNF probably facilitates the tumorigenesis of lung SCC and ADC. The expression of BDNF mRNA variant IX is probably more helpful to the upregulation of BDNF in SCC, and intervening the production of BDNF could be a possible strategy to lung cancer therapy.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Apoptosis/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Carga TumoralRESUMEN
Large tumor suppressor (LATS) is a Ser/Thr kinase originally isolated from Drosophila. Recent studies demonstrate that LATS is an important member of the Hippo pathway which can regulate organ size and cell proliferation. However, little is known about the expression and clinical significance of LATS in lung cancer. In this study, we aimed to assess the clinical significance and biological functions of LATS1 in non-small-cell lung cancer (NSCLC). We investigated the expression of LATS1 in 136 cases of NSCLC tissue and 30 cases of normal lung tissue by immunohistochemical staining. The results confirmed that LATS1 expression was higher in normal lung tissues, but significantly lower in NSCLC tissues. Moreover, the expression of LATS1 in NSCLC was significantly correlated with p-TNM stage (p = 0.038) and lymph node metastasis (p = 0.014). Importantly, the loss of LATS1 expression was associated with short overall survival. Further study in NSCLC cell lines in which LATS1 was either overexpressed or depleted confirmed that LATS1 markedly inhibited cell proliferation and invasion and could regulate the nuclear location of yes-associated protein (YAP). These results indicate that LATS1 may play an important role in NSCLC, and may serve as a novel therapeutic target of NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinasas/biosíntesis , Factores de Transcripción/genética , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Ciclo Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.
RESUMEN
OBJECTIVE: To investigate the expression of SOCS3 and Pyk2 and their correlations in non-small cell lung cancer (NSCLC). METHODS: The expression of SOCS3 and Pyk2 was detected in 100 cases of NSCLC, human bronchial epithelial cells (HBE) and 6 lung cancer cell lines by immunohistochemistry and immunofluorescence staining. The methylation status of SOCS3 was investigated in A549 cells by methylation-specific PCR. A549 cells were either treated with a demethylation agent 5-aza-2'-deoxycytidine (5-aza) or transfected with three SOCS3 mutants with various functional domains deleted. Besides, the cells were pretreated with a proteasome inhibitor ß-lactacystin where indicated. The effects of SOCS3 on Pyk2 expression, Pyk2 Tyr 402 and ERK1/2 phosphorylations were assessed by Western blot. RT-PCR was used to estimate Pyk2 mRNA levels. Transwell experiments were performed to evaluate cell migration. RESULTS: SOCS3 (43.0%, 43/100) and Pyk2 (65.0%, 65/100) were expressed in NSCLC. A significant negative correlation was found between SOCS3 and Pyk2 in both NSCLC tissues and cell lines. SOCS3 was aberrantly methylated and 5-aza restored SOCS3 expression. Transfection studies indicated that exogenous SOCS3 interacted with Pyk2, and both Src homology 2 (SH2) and kinase inhibitory region (KIR) domains contributed to Pyk2 binding. Furthermore, SOCS3 was found to inhibit Pyk2-associated ERK1/2 activity in A549 cells. SOCS3 possibly promoted degradation of Pyk2 in a SOCS-box-dependent manner and interfered with cell migration. CONCLUSIONS: The data indicates that SOCS3 definitely plays roles in regulating Pyk2 signaling, and cell motility. Decreased SOCS3 induced by methylation may confer a migration advantage to A549 cells.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Quinasa 2 de Adhesión Focal/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular , Metilación de ADN , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis Linfática , Mutación , Fosforilación , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genéticaRESUMEN
OBJECTIVE: To study the mechanism of interleukin 7/interleukin 7 receptor (IL-7/IL-7R) in promoting cell proliferation and inducing lymphangiogenesis of non-small cell lung cancer (NSCLC) in vivo and in vitro. METHODS: Immunohistochemical study for IL-7, IL-7R, cyclin D1 and vascular endothelial growth factor-D (VEGF-D) was carried out in NSCLC tissues from 95 patients. The relationship between IL-7/IL-7R expression and various parameters was analyzed. The mechanism of IL-7/IL-7R in promoting cell proliferation and inducing lymphangiogenesis was studied by methylthiazolyldiphenyl-tetrazolium bromide, fluorescence-activated cell sorting, reverse transcriptase-PCR, Western blot, co-immunoprecipitation, chromatin immunoprecipitation and nude mice experiments with xenograft tumors. RESULTS: IL-7 (63.2%, 60/95), IL-7R (61.1%, 58/95), cyclin D1 (52.6%, 50/95) and VEGF-D (58.9%, 56/95) showed that high level of expression in NSCLC. IL-7/IL-7R over-expression correlated with cyclin D1 expression (P < 0.01, P < 0.01), VEGF-D expression (P < 0.01, P < 0.01), increased lymphovascular density (P = 0.005, P = 0.013), advanced clinical stage (P = 0.008, P = 0.005) and presence of lymph node metastasis (P < 0.01, P < 0.01). IL-7/IL-7R could promote proliferation of A549 cell, increase cyclin D1 and VEGF-D expression, and enhance c-Fos/c-Jun expression and phosphorylation, resulting in formation of heterodimer. Furthermore, IL-7/IL-7R could induce binding of c-Fos/c-Jun to cyclin D1/VEGF-D promoters and regulate their transcription. IL-7/IL-7R could also promote proliferation and lymphangiogenesis of lung cancer xenograft tumors. CONCLUSIONS: IL-7/IL-7R promotes c-Fos/c-Jun expression and activity in NSCLC. This further facilitates cyclin D1 expression and accelerates proliferation of cells and VEGF-D-induced lymphovascular formation.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Interleucina-7/metabolismo , Neoplasias Pulmonares/patología , Linfangiogénesis , Receptores de Interleucina-7/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Ciclina D1/metabolismo , Femenino , Humanos , Interleucina-7/fisiología , Neoplasias Pulmonares/metabolismo , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Estadificación de Neoplasias , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptores de Interleucina-7/fisiología , Factor D de Crecimiento Endotelial Vascular/metabolismoRESUMEN
INTRODUCTION: Diffuse midline glioma with H3-K27M mutation is an infiltrative high-grade glioma, with predominantly astrocytic differentiation. PATIENT CONCERNS: A 54-year-old Chinese woman presented with memory loss for a month and walking instability for 15 days. DIAGNOSIS: Magnetic resonance imaging showed a mass shadow of isometric T1 and slightly longer T2 with mild mixed signals in the third ventricle of the suprasellar region. Histologically, the tumor was primarily sheet-like, with many "anucleate areas" composed of long and thin fibrillary processes of the bipolar cells, which formed "whorls." The neoplastic nuclei were ovoid and moderate in size. The tumor showed brisk mitotic activity and vascular proliferation, with no necrosis. In addition to histone H3K27M mutation, immunohistochemical staining showed that the tumor cells were positive for glial fibrillary acidic protein, oligodendrocyte transcription factor 2, alpha-thalassemia/mental retardation syndrome X, S-100 and Vimentin. The "anucleate areas" were positive for glial fibrillary acidic protein and negative for synaptophysin. The Ki-67 proliferation index was about 10%. Molecular genetic analyses detected H3F3A K27M mutation, but no mutations in IDH1 or IDH2, TERT promoter mutations, MGMT promoter methylation, KIAA1549-BRAF fusion or deletion of 1p/19q were found. Based on these findings, the patient was diagnosed as diffuse midline glioma with H3-K27M mutation in the third ventricle, corresponding to WHO grade 4. INTERVENTIONS: A craniotomy with total excision of the tumor was performed. OUTCOMES: After surgery, she was routinely treated with temozolomide for chemotherapy and synchronous radiotherapy. It has been 11 months now, and the patient is living well. CONCLUSION: This case report provides information on the microscopic morphological features of diffuse midline glioma with H3K27M mutation, which can help pathologists to make a definitive diagnosis of this tumor.
Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/patología , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Glioma/diagnóstico , Glioma/genética , Glioma/metabolismo , Histonas/genética , Humanos , MutaciónRESUMEN
Biopsy, brushing, and transbronchial needle aspiration (TBNA) are the most common methods for diagnosis of lung adenocarcinoma and are taken during the same diagnostic bronchoscopic procedure. However, it is not clear what the morphological diagnostic criteria of cytology by brushing or TBNA are. A retrospective analysis was performed on 136 patients who underwent video bronchoscopy examination for diagnostic purposes. All the subjects were performed brushing or TBNA and confirmed as lung adenocarcinoma by biopsy or postoperative pathology. An additional 140 randomly selected patients with benign lung diseases were included in the study and used as a control group. The benign cells usually confused with adenocarcinoma cells were ciliated columnar cells, mucous columnar cells, ciliated cuboid cells, and reactive ciliated cells, respectively. The number of cases diagnosed as adenocarcinoma cells, carcinoma cells, suspicious cancer cells, and atypical proliferative cells by cytology was 101, 11, 20, and 4, respectively. The main basis for the interpretation of adenocarcinoma cells is the enlargement of individual nucleus, the arrangements of multistage papillary, and the general enlargement of nuclei, while the main clue for the interpretation of suspicious cancer cells and dysplasia cells comes from escape cells. The results suggested that the degree of nuclear enlargement, multiple papillary arrangement, and escape cells or escape trend cells are important clues for the interpretation of lung adenocarcinoma cells, while the atypical proliferative cells were similar to escape cells or escape trend cells, which were essentially benign cells beside the cancer.
Asunto(s)
Adenocarcinoma del Pulmón/cirugía , Broncoscopía/métodos , Neoplasias Pulmonares/cirugía , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
High-risk human papillomavirus (HPV) infection play an important role in the development of lung cancer. Our previously study showed that E6 and E7 in HPV16 upregulated the expression of GLUT1 in lung cancer cells. However, whether they can promote the glucose uptake by GLUT1 and the underlying molecular mechanism has not been identified. It has been reported that thioredoxin interacting protein (TXNIP) regulates both the expression of GLUT1 and its glucose uptake. We speculate that high risk HPV16 infection may be closely related to TXNIP expression. Therefore, we associate HPV16 with TXNIP to explore the potential molecular mechanism of their regulation of GLUT1 expression and glucose uptake. Using double directional genetic manipulation in lung cancer cells, we showed that HPV16 E6/E7 proteins downregulated the expression of p-PTEN in lung cancer cells, the knockdown of PTEN further inhibited the expression of TXNIP, the inhibition of TXNIP further promoted the accumulation of HIF-1α by inhibiting the translocation of nuclear HIF-1α to the cytoplasm, and subsequently upregulated the expression of GLUT1 at the protein and mRNA levels. More interestingly, we found that the knockdown of TXNIP played a decisive role to promote the glucose uptake by GLUT1. Together, these findings suggested that the PTEN-TXNIP-HIF-1α axis might be related to the E6/E7-mediated expression of GLUT1 and its glucose uptake.
RESUMEN
BACKGROUND: There is an immediate need for research on the mechanism underlying telomerase activation and overexpression. MATERIALS & METHODS: A total of 174 patients with lung cancer (n = 106) and benign lung disease (n = 68) were recruited for the current study. The mRNA expression levels of E6, E7, LKB1, Sp1, and hTERC in brushing cells were detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and hTERC amplification was also detected by fluorescence in situ hybridization (FISH). To investigate the potential mechanism, bidirectional genetic manipulation was performed in well-established lung cancer cell lines. RESULTS: Our results indicated that the mRNA expression levels of E6, E7, Sp1, and hTERC and the amplification level of hTERC were significantly increased in the malignant group compared with those of the benign group (p < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group (p < 0.01). The correlation between E6, E7, Sp1, and hTERC expression was positive but was negative with LKB1 (p < 0.01). Our results also showed that HPV16 E6/E7 downregulated the expression of LKB1 at both the protein and mRNA levels. The loss of LKB1 upregulated Sp1 expression, and also promoted Sp1 activity. Sp1 further upregulated hTERC at the mRNA and gene amplification levels. Thus, we proposed a HPV-LKB1-Sp1-hTERC axis of E6/E7 upregulation of hTERC expression. CONCLUSION: We demonstrated for the first time that E6 and E7 promoted hTERC mRNA expression and the amplification of hTERC by relieving the effect of LKB1 on the phosphorylation of Sp1. Sp1 further activated hTERC by directly binding to the promoter regions of hTERC.
RESUMEN
BACKGROUND: HPV16 E6/E7 proteins are the main oncogenes and only long-term persistent infection causes lung cancer. Our previous studies have shown that HPV16 E6/E7 protein up-regulates the expression of GLUT1 in lung cancer cells. However, whether E6 and E7 protein can promote the glucose uptake of GLUT1 and its molecular mechanism are unclear. METHODS: The regulatory relationships of E6 or E7, miR-451, CAB39, PI3K/AKT, and GLUT1 were detected by double directional genetic manipulations in lung cancer cell lines. Immunofluorescence and flow cytometry were used to detect the effect of CAB39 on promoting the translocation to the plasma membrane of GLUT1. Flow cytometry and confocal microscopy were performed to detect the glucose uptake levels of GLUT1. RESULTS: The overexpression both E6 and E7 proteins significantly down-regulated the expression level of miR-451, and the loss of miR-451 further up-regulated the expression of its target gene CAB39 at both protein and mRNA levels. Subsequently, CAB39 up-regulated the expression of GLUT1 at both protein and mRNA levels. Our results demonstrated that HPV16 E6/E7 up-regulated the expression and activation of GLUT1 through the HPV-miR-451-CAB39-GLUT1 axis. More interestingly, we found that CAB39 prompted GLUT1 translocation to the plasma membrane and glucose uptake, and this promotion depended on the PI3K/AKT pathway. CONCLUSION: Our findings provide new evidence to support the critical roles of miR-451 and CAB39 in the pathogenesis of HPV-related lung cancer.
RESUMEN
BACKGROUND AND AIMS: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. METHODS: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. RESULTS: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS. CONCLUSIONS: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirugía , Humanos , Microvasos , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
Liver kinase B1 (LKB1) is a critical tumor suppressor that is frequently mutated in human cancers. LKB1 has serine/threonine protein kinase activity, which regulates gene expression by phosphorylation of Yes-Associated protein (YAP). The phosphorylation-dependent YAP shuttling is critically important intracellular mechanism in the Hippo pathway. In our previous study, we found that the amplification of hTERC was significant higher in the bronchial brushing cells of patients with lung cancer, however, the underlying molecular mechanism is not clear. In this study, we showed that LKB1 overexpression could phosphorylate YAP and promoted its nuclear rejection. Silencing LKB1 could dephosphorylate YAP and promoted its entry into the nucleus. Here, we found that LKB1 inhibited the mRNA expression and the amplification of hTERC. YAP further up-regulated hTERC at mRNA and gene amplification levels. Therefore, we suggest that LKB1 may inhibit the expression and amplification of hTERC through the axis of LKB1-pYAP(YAP)-hTERC.
RESUMEN
The cytology of peritoneal washing fluids for gastric cancer is the most basic method for judging peritoneal micrometastasis. However, the clinical value of this method is not clear at present. A retrospective analysis was performed on 277 patients with pathologically proven and surgically treated gastric cancer. The peritoneal washing fluids were collected after opening the abdomen and before the operation, and were sent to the cytology laboratory for screening of occult cancer cells in the collected washing fluids. The number of cases diagnosed as cancer cells, reactive mesothelial cells, serosal balls, and traumatic mesothelial cells were 42, 18, 27, and 190, respectively. Typical adenocarcinoma cell nests were found in eight of 10 T4b samples, whereas 34 cases of cancer cells in T3 and T4a showed that these cell nests usually contained mesothelial cells, and the three-dimensional stereoscopic sense of the nests was not obvious. In the specific subcellular morphological changes of both reactive mesothelial cells and serosal balls, the changes of both the contour of nuclear membrane and the polarity of cell alignment were present only in stage T3 and T4a. The presence or absence of mesothelial cells in the nests of cancer cells and the changes of the contour of nuclear membrane and of the polarity of cell alignment in reactive mesothelial cells or serosal balls may help us to predict the depth of invasion of cancer cells.
Asunto(s)
Adenocarcinoma/secundario , Líquido Ascítico/citología , Neoplasias Mesoteliales/secundario , Neoplasias Gástricas/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Líquido Ascítico/patología , Epitelio/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Mesoteliales/diagnóstico , Neoplasias Mesoteliales/patología , Neoplasias Mesoteliales/cirugía , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirugíaRESUMEN
Transcription factor E3 (TFE3) is a useful marker for tumors with Xp11.2 translocation, including alveolar soft part sarcoma and renal cell carcinoma. Recently, TFE3 overexpression was also found in granular cell tumors (GrCTs). However, the case cohorts of these two studies were limited to only 11 and 6 cases. Whether aberrant TFE3 expression is a common feature of Asian patients with GrCT requires further investigation. In the present study, immunohistochemical staining and TFE3 break-apart fluorescence in situ hybridization (FISH) assay were performed in 45 samples of GrCTs obtained from Chinese patients recruited from three medical centers in northeast China. Diffusive and marked nuclear staining for TFE3 was identified in 11/45 (24%) cases, which was lower than previously reported. Focal or weak TFE3 staining was identified in 13/45 (29%) cases. The remaining 21 cases were negative stained. In addition, GrCTs in subcutaneous tissue exhibited a relatively higher ratio (8/45, 18%) for TFE3 expression, compared with those in other sites. Furthermore, according to FISH data, no rearrangement or amplification of TFE3 was identified in these cases, whether they were positively or negatively stained for TFE3. The results from the present study demonstrated that part of patients GrCTs exhibited TFE3 overexpression, which suggested that this may not be derived from gene rearrangement.
RESUMEN
Chronic infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. In our previous studies, we found that HPV16 E6/E7 up-regulated HIF-1α at protein level and further up-regulated GLUT1 at both protein and mRNA levels in well-established lung cancer cell lines. In one of our further mechanism study, the results demonstrated that HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-LKB1-HIF-1α-GLUT1 axis. However, there are multiple pathways involved in HPV16 E6/E7 regulation of HIF-1α expression. In current study, using double directional genetic manipulation in well-established lung cancer cell lines, we showed that both E6 and E7 down-regulated the expression of RRAD at both protein and mRNA levels. Like LKB1, RRAD is one of the cancer suppressor genes. The loss of RRAD further activated NF-κB by promoted cytoplasmic p65 translocated to nucleus, and up-regulated the expression level of the p-p65 in nucleus. Furthermore, p-p65 up regulated HIF-1α and GLUT1 at both protein and mRNA levels. Thus, we proposed HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-RRAD-p65- HIF-1α- GLUT1 axis. In conclusion, we demonstrated for the first time that E6 and E7 promoted the expression of HIF-1α and GLUT1 by relieving the inhibitory effect of RRAD which resulted in the activation of NF-κB by promoting cytoplasmic p65 translocated to nucleus, and up-regulated the expression of the p-p65 in nucleus in lung cancer cells. Our findings provided new evidence to support the critical role of RRAD in the pathogenesis of HPV-related lung cancer, and suggested novel therapeutic targets.