RESUMO
Rho guanine nucleotide exchange factor 40 (ARHGEF40) is a member of the Dbl-family of guanine nucleotide factor proteins. However, its expression pattern and biological function in malignant tumors, notably in nonsmall cell lung cancer (NSCLC) are currently unknown. The present study demonstrated that ARHGEF40 was highly expressed in NSCLC specimens and that its expression was significantly associated with advanced TNM stage (p < 0.001), lymph node metastasis (p = 0.002), and poor prognosis (p = 0.0056). In addition, ARHGEF40 accelerated nuclear translocation of the key component ß-catenin and increased the expression levels of the Wnt signaling pathway targets c-myc, cyclin D1 and MMP7. Moreover, it promoted lung cancer cell proliferation and invasion in vitro and in vivo. To elucidate the underlying molecular mechanism, the current study demonstrated that ARHGEF40 could induce activation of the Wnt signaling pathway by increasing the phosphorylation levels of AKT and GSK3ß via interaction with RhoA. Moreover, the Dbl homology (DH)-pleckstrin homology (PH) domain of ARHGEF40 was responsible for this interaction. Its deletion abolished the binding, which blocked the activation of the Wnt signaling. Taken together, the data indicated that ARHGEF40 promoted the malignant phenotype of lung cancer cells by activating the AKT-Wnt axis. This was achieved by its interaction with RhoA via the DH-PH domain. ARHGEF40 may serve as a novel target for NSCLC treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Nucleotídeos de Guanina , Humanos , Neoplasias Pulmonares/patologia , Metaloproteinase 7 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
OBJECTIVE: To investigate the expression of programmed death ligand-1 (PD-L1) and the levels of CD8+ tumor-infiltrating lymphocytes (TILs) in meningioma as well as determine the association between their levels and the clinical outcomes. METHODS: We performed a retrospective case-control study on 93 patients with meningioma. The patients showed tumor recurrence and were matched with the control patients without recurrence in their age, gender, admission time, tumor sites, tumor volume, peritumoral brain edema (PTBE), Simpson grade resection, WHO grade, postoperative radiotherapy, and the follow-up duration. We reviewed the clinical data of patients and performed immunohistochemistry analysis to investigate the PD-L1 expression and the levels of CD8+ TILs. Multivariate logistic regression was performed to analyze the association between clinical features and immune markers. The conditional logistic regression models were used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and Kaplan-Meier analysis was performed to analyze tumor recurrence. RESULTS: Tumor volume was correlated with the PD-L1 expression (P = 0.003, HR = 5.288, 95%CI, 1.786-15.651). PTBE served as an independent predictor of CD8+ TIL levels (P = 0.001, HR = 0.176, 95%CI 0.065-0.477). The levels of CD8+ TILs were associated with tumor recurrence (P = 0.020, OR = 0.325, 95%CI, 0.125-0.840). CONCLUSION: Tumor volume was associated with PD-L1 expression, and PTBE was an independent predictor of CD8+ TIL levels in meningioma. CD8+ TIL levels correlated with tumor recurrence in meningioma.
Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Antígeno B7-H1/metabolismo , Meningioma/metabolismo , Recidiva Local de Neoplasia/metabolismo , Estudos Retrospectivos , Estudos de Casos e Controles , Linfócitos T CD8-Positivos , Linfócitos do Interstício Tumoral , Neoplasias Meníngeas/metabolismo , PrognósticoRESUMO
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.
Assuntos
Ependimoma/genética , Ependimoma/patologia , Lobo Frontal/patologia , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Ependimoma/diagnóstico , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Convulsões/patologia , Neoplasias Supratentoriais/diagnóstico , Fator de Transcrição RelA/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
Coiled-coil domain containing 85 B (CCDC85B) is involved in diverse biological processes; however, its expression patterns and functions in human cancers are yet unknown. The present study demonstrated that the expression of CCDC85B in the cytoplasm of the non-small cell lung cancer (NSCLC) tumor cells was significantly higher compared to adjacent normal lung tissues (P < 0.05). Furthermore, CCDC85B expression correlated with advanced TNM stage (P = 0.004) and positive regional lymph node metastasis (P = 0.009) of NSCLC. In addition, in A549 and H1299 lung cancer cell lines, the overexpression of CCDC85B promoted cell proliferation and invasion, while siRNA-mediated CCDC85B knockdown exhibited opposite effects. CCDC85B promoted AKT and GSK3ß phosphorylation and upregulated the levels of active ß-catenin, Wnt targets c-myc, cyclin D1, and MMP7. Besides, the CCDC85B-induced upregulation of phosphorylated GSK3ß and active ß-catenin was rescued following the treatment with PI3 K inhibitor, LY294002. In conclusion, CCDC85B was associated with NSCLC progression as it promoted the proliferation and invasion of lung cancer cells through activated AKT/GSK3ß/ß-catenin oncogenic signaling pathway. Therefore, CCDC85B might serve as a novel target for NSCLC treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/secundário , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/secundário , Proliferação de Células , Neoplasias Pulmonares/patologia , Proteínas Repressoras/metabolismo , Adenocarcinoma/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Grandes/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Transdução de Sinais , Células Tumorais CultivadasRESUMO
BACKGROUND: Myxofibrosarcoma (MFS) is most often found on the limbs of aged male people, but extremely uncommon in the liver. CASE PRESENTATION: A 52-year-old female patient with a liver mass was diagnosed as a primary MFS. It had no obvious abdominal symptoms, and the tumor was resected with an extended margin. Three years after the surgery, the patient was readmitted for peritoneal metastasis and passed away 4 months later. The tumor has a benign presentation, but malignant outcome. CONCLUSIONS: Comprehensive radiological inspection, intensive preoperative evaluation, careful design of operating procedures, wide margin resection, consecutive treatment, and strict periodical follow-ups should be taken to ensure a better prognosis of this kind of neoplastic disease.
Assuntos
Fibrossarcoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Biomarcadores , Biópsia , Diagnóstico Diferencial , Feminino , Fibrossarcoma/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/metabolismo , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo , Prognóstico , Avaliação de Sintomas , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Intracranial meningiomas are relatively rare in young adults, and their specific clinical features remain unclear. The authors analyzed the clinical characteristics of intracranial meningioma in patients younger than 40 years. METHODS: Consecutive patients younger than 40 years with meningioma (n = 223) who underwent surgical treatment at our hospital from 2010 to 2018 were retrospectively reviewed. The study cases was further divided into a younger group (≤ 30 years old; n = 63) and an older group (31-40 years old; n = 160). The clinical information, radiological characteristics, intraoperative findings, and pathological outcomes were extracted from the patients' records and statistically analyzed. RESULTS: Intracranial meningioma is uncommon in patients younger than 40 years (8.6%). The study group's most common symptoms at presentation were headaches (46.7%), visual impairment (27.8%), limb weakness (20.6%), and epilepsy (13.5%). The mean tumor size was larger (51.47 ± 50.36 cm3) in the younger group than in the older group (22.94 ± 27.20 cm3). According to multivariate analyses, young age was an independent predictor of large tumor size, and large tumor size was significantly associated with peritumoral brain edema and intraoperative blood loss. CONCLUSION: Intracranial meningiomas in younger adult patients may have special complexity and perioperative risk due to large tumor sizes. Therefore, individualized treatment strategy is recommended, and the appropriate caution should be taken during surgery.
Assuntos
Edema Encefálico/diagnóstico , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Hemorragia Pós-Operatória/diagnóstico , Adolescente , Adulto , Fatores Etários , Edema Encefálico/etiologia , Criança , Feminino , Seguimentos , Humanos , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Hemorragia Pós-Operatória/etiologia , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
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.
Assuntos
Glioma/patologia , Histonas/genética , Mutação , Neoplasias da Medula Espinal/patologia , Vértebras Cervicais , Feminino , Glioma/diagnóstico , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Pessoa de Meia-Idade , Tumores Neuroectodérmicos Primitivos/patologia , Neurópilo/patologia , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglioma/patologia , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Inversin, encoded by NPHP2, is one of the 10 NPHP proteins known to be involved in nephronophthisis (an autosomal recessive cystic kidney). Although the previous reports showed that inversin played an important role in embryonic development and renal diseases, its function in cancer was not revealed clearly so far. As measured by immunohistochemical staining, inversin was highly expressed in the cytoplasm of lung cancer samples (63.4%, 161/254) compared with adjacent normal lung tissues (22.0%, 11/50, p < 0.01). Moreover, its expression was positively correlated with differentiation ( p = 0.014), tumor node metastasis staging ( p = 0.007), and lymph node metastasis ( p = 0.020). The overall survival of non-small cell lung cancer patients with inversin positive expression (45.41 ± 1.800 months) was significantly reduced compared with those with inversin negative expression (51.046 ± 2.238 months, p = 0.042). Consistently, we found that the invasion capacity of A549 cells transfected with inversin was significantly stronger than that of control cells ( p < 0.05), while inversin siRNA-treatment significantly reduced cell invasion in H1299 cells ( p < 0.05). Additionally, we demonstrated that inversin could upregulate the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Collectively, these results indicated that inversin might promote the tumorigenicity of lung cancer cells and serve as a novel therapeutic target of non-small cell lung cancer.
Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Prognóstico , Fatores de Transcrição/biossíntese , Células A549 , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/biossíntese , Biomarcadores Tumorais/genética , Caderinas/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Fatores de Transcrição/genética , Vimentina/biossínteseRESUMO
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.
Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/patologia , Hemangioblastoma/diagnóstico , Hemangioblastoma/patologia , Neuroglia/patologia , Adulto , Diferenciação Celular , Neoplasias Cerebelares/irrigação sanguínea , Feminino , Hemangioblastoma/irrigação sanguínea , Humanos , Células Estromais/patologiaRESUMO
FBXO25 is a recently discovered protein that belongs to the Fbx class of the F-box family of proteins, and F-box proteins play a crucial role in tumorigenesis. However, the function of FBXO25 in cancer was not revealed so far. As measured by immunohistochemical staining, FBXO25 was highly expressed in the cytoplasm and nucleus of lung cancer samples (64.2 %, 136/212), compared with adjacent normal lung tissues (23.3 %, 7/30, p < 0.01). In addition, its expression was positively correlated with TNM staging (p < 0.001) and lymph node metastasis (p = 0.017). The overall survival of non-small-cell lung cancer (NSCLC) patients with FBXO25-positive expression (40.646 ± 1.745 months) was significantly reduced compared with those with FBXO25-negative expression (46.548 ± 2.176 months, p = 0.023). Consistently, we found that the proliferation, invasion, and migration capacity of A549 cells transfected with FBXO25 were significantly greater than those of control cells, while interference of FBXO25 could significantly inhibit cell proliferation, invasion, and migration in H1299 cells. Furthermore, we demonstrated that FBXO25 could regulate the expression of ß-catenin, YAP, some cyclins, and matrix metalloproteinases (MMPs). Collectively, these results indicate that FBXO25 may promote the tumorigenicity of lung cancer cells and might serve as a novel therapeutic target of NSCLC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Proteínas F-Box/metabolismo , Neoplasias Pulmonares/patologia , Proteínas do Tecido Nervoso/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Apoptose , Western Blotting , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , CicatrizaçãoRESUMO
Recent studies have implicated ARMc8 in promoting tumor formation in non-small cell lung cancer and breast cancer; however, so far, no studies have revealed the expression pattern or cellular function of ARMc8 in colon cancer. In this study, we used immunohistochemical staining to measure ARMc8 expression in 206 cases of colon cancer and matched adjacent normal colon tissue. Clinically important behaviors of cells, including invasiveness and migration, were evaluated after upregulation of ARMc8 expression in HT29 cells through gene transfection or downregulation of expression in LoVo cells using RNAi. We found that ARMc8 was primarily located in the membrane and cytoplasm of tumor cells, and its expression level was significantly higher in colon cancer in comparison to that in the adjacent normal colon tissues (p < 0.001). ARMc8 expression was closely related to TNM stage (p = 0.006), lymph node metastasis (p = 0.001), and poor prognosis (p = 0.002) of colon cancer. The invasiveness and migration capacity of HT29 cells transfected with ARMc8 were significantly greater than those of control cells (p < 0.001), while ARMc8 siRNA treatment significantly reduced cell invasion and migration in LoVo cells (p < 0.001). Furthermore, we demonstrated that ARMc8 could upregulate the expression of MMP7 and snail and downregulate the expression of p120ctn and α-catenin. Therefore, ARMc8 probably enhanced invasiveness and metastatic capacity by affecting these tumor-associated factors, thereby playing a role in enhancing the tumorigenicity of colon cancer cells. ARMc8 is likely to become a potential therapeutic target for colon cancer.
Assuntos
Proteínas do Domínio Armadillo/biossíntese , Biomarcadores Tumorais/biossíntese , Neoplasias do Colo/genética , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas do Domínio Armadillo/genética , Biomarcadores Tumorais/genética , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Colo/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genéticaRESUMO
Chromosome 6 open reading frame 106 (C6orf106) is a newly discovered protein; its expression and clinical pathological significance in human tumors remains unclear. Immunohistochemistry, Western blot, and immunofluorescence were performed to assess C6orf106 expression in non-small cell lung cancer (NSCLC). In addition, the relationships between subcellular localization and clinical pathological factors were analyzed. Through C6orf106 overexpression and repression, respectively, in lung cancer cell lines, we explored the effect of this molecule on NSCLC invasion abilities. C6orf106 was highly expressed in the cytoplasm of lung cancer tissue cells (60.4 %, 75/124), compared with adjacent normal lung tissues (15.2 %, 7/46, p < 0.001). In addition, its expression was positively correlated with differentiation (p = 0.001), TNM stage (p = 0.011), lymph node metastasis (p = 0.018), and poor prognosis (p = 0.006). Furthermore, C6orf106 overexpression enhanced NSCLC cell invasion. Moreover, C6orf106 was shown to increase vimentin expression, while decreasing E-cadherin and P120ctn. C6orf106 is highly expressed in NSCLC and correlates with clinical and pathological factors, as well as poor prognosis. C6orf106 promotes invasion in NSCLC cells. Finally, C6orf106 upregulates vimentin, and downregulates E-cadherin and P120ctn.
Assuntos
Caderinas/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Cateninas/biossíntese , Proteínas de Neoplasias/genética , Vimentina/biossíntese , Idoso , Caderinas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cateninas/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Fases de Leitura Aberta/genética , Prognóstico , Vimentina/genética , delta CateninaRESUMO
ARMC8 proteins are novel armadillo repeat containing proteins, which are well conserved in eukaryotes and are involved in a variety of processes such as cell migration, proliferation, tissue maintenance, signal transduction, and tumorigenesis. Armadillo repeat proteins include well-known proteins such as ß-catenin and p120ctn. Our current knowledge of ARMC8, especially its role in cancer, is limited. In this study, we quantified ARMC8 expression in 112 non-small cell lung cancer (NSCLC) tissues and adjacent non-cancerous tissues, and seven lung cancer cell lines using immunohistochemistry staining and Western blotting. ARMC8 level was significantly higher in NSCLC tissues than in the adjacent normal tissues (67.9 % versus 5.4 %, p < 0.05) and was significantly associated with TNM stage (p = 0.022), lymph node metastasis (p = 0.001), and poor prognosis (p < 0.001) in NSCLC patients. Cox regression analysis demonstrated that ARMC8 was an independent prognostic factor for NSCLC. Consistent with this, ARMC8α downregulation by siRNA knockdown inhibited growth, colony formation, and invasion in A549 lung cancer cells, while ARMC8α overexpression promoted growth, colony formation, and invasion in H1299 lung cancer cells. In addition, ARMC8α knockdown downregulated canonical Wnt-signaling pathway activity and cyclin D1 and matrix metalloproteinase (MMP)-7 expression. Consistent with this, ARMC8α overexpression upregulated canonical Wnt-signaling pathway activity and cyclin D1 and MMP-7 expression. These results indicate that ARMC8α upregulates cyclin D1 and MMP7 expression by activating the canonical Wnt-signaling pathway and thereby promoting lung cancer cell proliferation and invasion. Therefore, ARMC8 might serve as a novel therapeutic target in NSCLC.
Assuntos
Proteínas do Domínio Armadillo/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Neoplasias Pulmonares/metabolismo , Via de Sinalização Wnt , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas do Domínio Armadillo/genética , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Glioma stem cells (GSCs) exhibit diverse molecular subtypes with the mesenchymal (MES) population representing the most malignant variant. The oncogenic potential of Salmonella pathogenicity island 1 (SPI1), an oncogenic transcription factor, has been established across various human malignancies. In this study, we explored the association between the SPI1 pathway and the MES GSC phenotype. Through comprehensive analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas glioma databases, along with patient-derived GSC cultures, we analyzed SPI1 expression. Using genetic knockdown and overexpression techniques, we assessed the functional impact of SPI1 on GSC MES marker expression, invasion, proliferation, self-renewal, and sensitivity to radiation in vitro, as well as its influence on tumor formation in vivo. Additionally, we investigated the downstream signaling cascades activated by SPI1. Our findings revealed a positive correlation between elevated SPI1 expression and the MES phenotype, which in turn, correlated with poor survival. SPI1 enhanced GSC MES differentiation, self-renewal, and radioresistance in vitro, promoting tumorigenicity in vivo. Mechanistically, SPI1 augmented the transcriptional activity of both TGF-ß1 and FKBP12 while activating the non-canonical PI3K/Akt pathway. Notably, inhibition of TGF-ß1/PI3K/Akt signaling partially attenuated SPI1-induced GSC MES differentiation and its associated malignant phenotype. Collectively, our results underscore SPI1's role in activating TGF-ß1/PI3K/Akt signaling through transcriptional upregulation of FKBP12, thereby supporting the aggressive MES phenotype of GSCs. Therefore, SPI1 emerges as a potential therapeutic target in glioma treatment.
Assuntos
Glioma , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteína 1A de Ligação a Tacrolimo/genética , Proteína 1A de Ligação a Tacrolimo/metabolismo , Regulação para Cima , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Ilhas Genômicas , Células-Tronco Neoplásicas/metabolismo , Glioma/patologia , Fenótipo , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
The objective of the current study was to investigate the expression pattern and clinicopathological significance of differentiated embryo-chondrocyte-expressed gene 1 (DEC1) in patients with non-small-cell lung cancer (NSCLC). In 118 archived NSCLC tissues, the positive rate of DEC1 was reduced in human lung cancer samples (36/118, 30.5 %) compared with adjacent normal lung tissues (106/118, 89.8 %), as measured by immunohistochemical staining. Loss of DEC1 was correlated with poor differentiation (p=0.005) and high p-TNM stage (p=0.002). Consistently, downregulation of DEC1 by siRNA knockdown promoted the growth and colony formation in the A549 lung cancer cell line, and overexpression of DEC1 inhibited the growth and colony formation in the BE1 lung cancer cell line. In addition, a significant negative correlation was found between DEC1 and cyclin D1 (p=0.014) in 118 cases of NSCLC. Knockdown of DEC1 resulted in the upregulation of cyclin D1, and overexpression of DEC1 led to the downregulation of cyclin D1. Together with the observation that DEC1 bound directly to the promoter region of cyclin D1 in A549 cells, these results indicate that loss of DEC1 may promote tumor progression in NSCLC through upregulation of cyclin D1, and DEC1 might serve as a novel therapeutic target of NSCLC.
Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Pulmão/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Interferente Pequeno/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genéticaRESUMO
Objective: To investigate the levels of tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) and the expression of programmed cell death receptor ligand 1 (PD-L1) in the tumor microenvironment (TME) of pediatric and adolescent pituitary adenomas (PAPAs) and analyze the correlation between their levels and the clinical characteristics. Methods: A series of 43 PAPAs cases were enrolled over a period of 5 years. To compare the TME of PAPAs and adult PAs, 43 PAPAs cases were matched with 60 adult PAs cases (30 cases were between 20 and 40 years old, and 30 cases were older than 40 years) for main clinical characteristics. The expression of immune markers in PAPAs was detected by immunohistochemistry, and their correlation with the clinical outcomes was analyzed using statistical methods. Results: In the PAPAs group, CD8+ TILs level was significantly lower (3.4 (5.7) vs. 6.1 (8.5), p = 0.001), and PD-L1 expression (0.040 (0.022) vs. 0.024 (0.024), p < 0.0001) was significantly higher as compared with the older group. The level of CD8+ TILs was negatively correlated with the expression of PD-L1 (r = -0.312, p = 0.042). Moreover, CD8+ TILs and PD-L1 levels were associated with Hardy (CD8, p = 0.014; PD-L1, p = 0.018) and Knosp (CD8, p = 0.02; PD-L1, p = 0.017) classification. CD8+ TILs level was associated with high-risk adenomas (p = 0.015), and it was associated with the recurrence of PAPAs (HR = 0.047, 95% CI 0.003-0.632, p = 0.021). Conclusion: Compared with the TME in adult PAs, the TME in PAPAs was found to express a significantly altered level of CD8+ TILs and PD-L1. In PAPAs, CD8+ TILs and PD-L1 levels were associated with clinical characteristics.
Assuntos
Adenoma , Neoplasias Hipofisárias , Adulto , Humanos , Adolescente , Criança , Adulto Jovem , Neoplasias Hipofisárias/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Linfócitos do Interstício Tumoral , Adenoma/metabolismo , Microambiente TumoralRESUMO
AIMS: The two major types of cells of pulmonary sclerosing haemangioma (PSH) with the same origin show significant differences in morphological phenotype. Whether these differences are caused by their different differentiation status is still uncertain. The aim of this study was to analyse their differentiation status by detecting the expression of several stem cell markers in PSH. METHODS AND RESULTS: The expression of stem cell markers was examined by using streptavidin peroxidase (SP) immunohistochemisty in 45 PSH specimens. Also, the two types of cells were, respectively, captured by laser capture microdissection (LCM) from 28 PSH specimens, and total RNA was then extracted followed by reverse transcription-polymerase chain reaction (RT-PCR). The results demonstrated that the expression rates of ABCG2, Notch1 and Notch3 in polygonal cells were significantly higher than those in cuboidal cells (P < 0.05), and the expression levels of ABCG2, Notch3 and Jagged1 in polygonal cells were clearly higher than those in cuboidal cells (P < 0.05). CONCLUSION: The data obtained provided evidence that the two types of cells in PSH may be different in differentiation status. The differentiation difference between the two types of cells might lead to variation in their morphological phenotype.
Assuntos
Biomarcadores Tumorais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Hemangioma Esclerosante Pulmonar/metabolismo , Hemangioma Esclerosante Pulmonar/patologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Sequência de Bases , Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular , Primers do DNA/genética , Feminino , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Jagged-1 , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Hemangioma Esclerosante Pulmonar/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch3 , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Serrate-JaggedRESUMO
Overexpression of frequently rearranged in advanced T-cell lymphomas 1 (Frat1) has been reported in several human malignant tumors, but the relationship between Frat1 and ß-catenin in lung cancer is still unclear. Our goal was to investigate the correlation between Frat1 and ß-catenin in patients with lung cancers. Immunohistochemistry was performed in 110 cases of non-small cell lung cancer (NSCLC) with clinical follow-up. Results showed that both Frat1 and ß-catenin were overexpressed in NSCLC. The expression of Frat1 and ß-catenin was significantly correlated with tumor differentiation, TNM stage, and lymph node metastasis. Interestingly, the overexpression of ß-catenin was positively correlated with the overexpression of Frat1 (correlation coefficient = 0.285; P = 0.003). In addition, overexpression of Frat1 and abnormal expression of ß-catenin were found to represent a poor prognosis for the patients. Furthermore, based on the transfection of Frat1 and ß-catenin, we found that Frat1 can upregulate the expression of ß-catenin in BE1 cells.
Assuntos
Adenocarcinoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias de Células Escamosas/genética , Proteínas Proto-Oncogênicas/genética , beta Catenina/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias de Células Escamosas/mortalidade , Neoplasias de Células Escamosas/patologia , PrognósticoRESUMO
Accumulating evidence reveals that aberrant expression of claudins manifests in various tumors; however, their biological functions are poorly understood. Here, we report on the elevated expression of claudin-1 in human breast cancer MCF-7 cells under tumor necrosis factor (TNF)-α treatment. Interestingly, the increased expression of claudin-1 contributes to an anti-apoptotic role in TNF-α-induced apoptosis. In line with this, upon TNF-α stimulus, downregulation of claudin-1 by siRNA knockdown results in a significant increase in cleavage of caspase-8 and poly (ADP-ribose) polymerase, a decrease of cyclinD1 expression, and DNA fragmentation. Consistently, TdT-mediated dUTP nick end labeling assay also shows that loss of claudin-1 increases the susceptibility of MCF-7 cells to TNF-α-induced apoptosis. However, there is no obvious effect on the expression of Bax and p53 after the treatment aforementioned. In addition, TNF-α increases the amount of claudin-1 and the cytoplasmic accumulation of ß-catenin, while claudin-1 siRNA increases the amount of ß-catenin in the cell membrane as well as the amount of E-cadherin in the cytoplasm. In conclusion, our data reveal a novel role of claudin-1 in regulating apoptosis in MCF-7 cells.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Claudina-1/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Western Blotting , Neoplasias da Mama/metabolismo , Caderinas/genética , Caderinas/metabolismo , Caspases/genética , Caspases/metabolismo , Membrana Celular , Proliferação de Células/efeitos dos fármacos , Claudina-1/antagonistas & inibidores , Claudina-1/genética , Citoplasma , Feminino , Imunofluorescência , Humanos , Transporte Proteico , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Frações Subcelulares , Células Tumorais Cultivadas , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Purpose: Patients with intraventricular tumors are more susceptible to postoperative meningitis (POM) than other intracranial tumors. In this study, we explored the risk factors of POM in lateral ventricular trigone meningiomas (LVTMs). Methods: Clinical features of 64 patients with LVTMs were analyzed. Age, gender, body mass index, medical history, intraoperative blood loss (IBL), intraventricular drainage placement, surgical duration, tumor grade, postoperative tumor cavity hemorrhage, and tumor size were included in univariate and multivariate analyses of POM. Results: Of the 64 patients, 14 patients (21.9%) received diagnosis of POM. The univariate analysis revealed IBL ≥400â mL (odds ratio [OR], 9.012; p = 0.003), tumor size ≥50â cm3 (OR, 3.071; p = 0.080), and surgical duration ≥5â h (OR, 2.970; p = 0.085) were considered possible risk factors for POM (p < 0.10). Tumor size (R = 0.514) and surgical duration (R = 0.624) were significantly correlated with IBL (p < 0.05). In the multivariate analysis, only IBL was found to be an independent risk factor for POM. Conclusion: The IBL ≥400â mL is independently associated with the increased risk of POM in LVTM patients. Our results demonstrate the importance of controlling IBL for preventing POM, especially in large tumors and long surgeries.