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1.
J Transl Med ; 18(1): 40, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000807

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver tumour, and is closely related to liver cirrhosis. Previous studies have focussed on the pathogenesis of liver cirrhosis developing into HCC, but the molecular mechanism remains unclear. The aims of the present study were to identify key genes related to the transformation of cirrhosis into HCC, and explore the associated molecular mechanisms. METHODS: GSE89377, GSE17548, GSE63898 and GSE54236 mRNA microarray datasets from Gene Expression Omnibus (GEO) were analysed to obtain differentially expressed genes (DEGs) between HCC and liver cirrhosis tissues, and network analysis of protein-protein interactions (PPIs) was carried out. String and Cytoscape were used to analyse modules and identify hub genes, Kaplan-Meier Plotter and Oncomine databases were used to explore relationships between hub genes and disease occurrence, development and prognosis of HCC, and the molecular mechanism of the main hub gene was probed using Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis. RESULTS: In total, 58 DEGs were obtained, of which 12 and 46 were up- and down-regulated, respectively. Three hub genes (CDKN3, CYP2C9 and LCAT) were identified and associated prognostic information was obtained. CDKN3 may be correlated with the occurrence, invasion, and recurrence of HCC. Genes closely related to changes in the CDKN3 hub gene were screened, and Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway analysis identified numerous cell cycle-related genes. CONCLUSION: CDKN3 may affect the transformation of liver cirrhosis into HCC, and represents a new candidate molecular marker of the occurrence and progression of HCC.

2.
Sci Rep ; 9(1): 8401, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182739

RESUMO

Mitogen-activated protein kinase kinase kinase 3 (MAP3K3), a member of the serine/threonine protein kinase family, is ubiquitously expressed and acts as an oncogene. However, the expression and exact molecular mechanism of MAP3K3 in ovarian carcinoma (OC) remain unclear. Here, we found that MAP3K3 protein was highly expressed in 70.5% of high-grade serous ovarian carcinoma (HGSOC) samples. MAP3K3 overexpression was significantly associated with the FIGO stage and chemotherapy response. Additionally, MAP3K3 overexpression was associated with reduced disease-free survival and overall survival. In vitro experiments showed that MAP3K3 overexpression promoted cell proliferation, inhibited apoptosis, and enhanced the migration and invasion of OC cells. Moreover, in vivo tumourigenesis experiments confirmed that silencing MAP3K3 significantly reduced the growth rate and volume of transplanted tumours in nude mice. Drug sensitivity experiments demonstrated that differential expression of MAP3K3 in OC cell lines correlates with chemotherapy resistance. Functionally, the MAP3K3 gene regulated the malignant biological behaviour of OC cells by mediating NF-κB signalling pathways, affecting the downstream epithelial-mesenchymal transition and cytoskeletal protein expression. Our results unveiled the role of MAP3K3 in mediating NF-κB signalling to promote the proliferation, invasion, migration, and chemotherapeutic resistance of OC cells, highlighting a potential new therapeutic and prognostic target.

3.
Exp Neurol ; 313: 124-134, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30586594

RESUMO

Mitochondria, as primary energy generators and Ca2+ biosensor, are dynamically coupled to neuronal activities, and thus play a role in neuroplasticity. Here we report that respiratory neuroplasticity induced by daily acute intermittent hypoxia (dAIH) evoked adaptive changes in the ultrastructure and postsynaptic distribution of mitochondria in the pre-Bötzinger complex (pre-BötC). The metabolic marker of neuronal activity, cytochrome c oxidase (CO), and dendritic mitochondria were examined in pre-BötC neurons of adult Sprague-Dawley rats preconditioned with dAIH, which is known to induce long-term facilitation (LTF) in respiratory neural activities. We performed neurokinin 1 receptor (NK1R) pre-embedding immunocytochemistry to define pre-BötC neurons, in combination with CO histochemistry, to depict ultrastructural alterations and CO activity in dendritic mitochondria. We found that the dAIH challenge significantly increased CO activity in pre-BötC neurons. Darkly CO-reactive mitochondria at postsynaptic sites in the dAIH group were much more prevalent than those in the normoxic control. In addition, the length and area of mitochondria were significantly increased in the dAIH group, implying a larger surface area of cristae for ATP generation. There was a fine, structural remodeling, notably enlarged and branching mitochondria or tapered mitochondria extending into dendritic spines. Mitochondrial cristae were mainly in parallel-lamellar arrangement, indicating a high efficiency of energy generation. Moreover, flocculent or filament-like elements were noted between the mitochondria and the postsynaptic membrane. These morphological evidences, together with increased CO activity, demonstrate that dendritic mitochondria in the pre-BötC responded dynamically to respiratory plasticity. Hence, plastic neuronal changes are closely coupled to active mitochondrial bioenergetics, leading to enhanced energy production and Ca2+ buffering that may drive the LTF expression.


Assuntos
Dendritos/patologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hipóxia/enzimologia , Hipóxia/patologia , Mitocôndrias/patologia , Centro Respiratório/enzimologia , Trifosfato de Adenosina/biossíntese , Animais , Dendritos/ultraestrutura , Espinhas Dendríticas/patologia , Espinhas Dendríticas/ultraestrutura , Metabolismo Energético , Potenciação de Longa Duração , Mitocôndrias/ultraestrutura , Plasticidade Neuronal , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/biossíntese
4.
Future Oncol ; 14(20): 2005-2011, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29513033

RESUMO

AIM: To explore the association between the determinant factors including HLA-DQB1*03, DRB1-*07, -*13 and high-risk HPV infection, the cervical squamous cell carcinoma (CSCC) pathogenesis among Chinese Uighur and Han population. MATERIALS & METHODS: HLA alleles were genotyped by PCR sequence-specific primers. RESULTS: HPV16 infection rate was significantly higher among the Uighurs and Hans with CSCC as compared with healthy controls, respectively. HLA-DQB1*03 significantly increased among Uighurs with CSCC, while HLA-DRB1*07 significantly increased among Hans with CSCC. Similar tendencies were observed for DQB1*03 with HPV16-positive Uighurs CSCC and DRB1*07 with HPV16-positive Hans CSCC. CONCLUSION: This study suggests that HLA-DQB1*03 and DRB1*07 alleles may influence the immune response to HPV16 infection and increase the risk of CSCC among the Uighurs and Hans in China.


Assuntos
Alelos , Grupos Étnicos/genética , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , China/epidemiologia , Feminino , Papillomavirus Humano 16 , Humanos , Pessoa de Meia-Idade , Razão de Chances , Infecções por Papillomavirus/virologia , Medição de Risco , Análise de Sequência de DNA , Neoplasias do Colo do Útero/virologia , Adulto Jovem
5.
Oncotarget ; 8(13): 21526-21538, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28423526

RESUMO

M2 macrophages was domesticated by tumor microenvironment to produce some angiogenic molecules and protease, facilitating angiogenesis and matrix breakdown, promoting tumor invasive and metastasis. However, The function of M2 macrophages to progression of eophageal carcinoma, especially Kazakh esophageal carcinoma is still dimness. This study aims to investigate M2 macrophages correlated with matrix metalloproteinase-9 (MMP9) and microvessel density, and the role in the progression of Kazakh esophageal squamous cell carcinoma. CD163 and CD34 as the marker of M2 macrophages and endothelial cells, were used to identify the M2 macrophages density and microvessel density, respectively. Immunohistochemistry staining was evaluated the expression of MMP9. The number of infiltrated CD163-positive M2 macrophages in tumor islets and stroma was significantly higher than in cancer adjacent normal tissues. The increased of M2 macrophages and microvessel density were significantly correlated with more malignant phenotypes including lymph node metastasis and clinical stage progression. Meanwhile, the expression of MMP9 showed much higher level in esophageal squamous cell carcinoma than that in cancer adjacent normal tissues, and high expression of MMP9 in Kazakh esophageal squamous cell carcinoma was significantly associated with age, depth of tumor invasion, lymph node metastasis, and tumor clinical stage. The quantity of M2 macrophages in tumor stroma was positively associated with microvessel density and the expression of MMP9, and as an independent poorly prognostic factor for overall survival time of Kazakh esophageal squamous cell carcinoma. These findings suggest the increased number of M2 macrophages correlated with high expression of MMP9 and high microvessel density may contribute to the tumor aggressiveness and angiogenesis, promoting the progression of Kazakh esophageal squamous cell carcinoma.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Macrófagos/imunologia , Neovascularização Patológica/patologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Grupo com Ancestrais do Continente Asiático , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Ativação de Macrófagos/imunologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Receptores de Superfície Celular/imunologia
6.
Exp Neurol ; 287(Pt 2): 165-175, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27240519

RESUMO

The rostral ventrolateral medulla (RVLM) contains cardiovascular-related catecholaminergic neurons and respiratory-related pre-Bötzinger complex (pre-BötC) neurons, which are intermingled and functionally connected for coordinating cardiorespiratory activities. Daily acute intermittent hypoxia (dAIH) is known to elicit respiratory plasticity. However, it is unclear if the catecholaminergic neurons directly synapse onto pre-BötC neurons, and if the local circuitry exhibits plasticity when exposed to dAIH. The present study was aimed to determine the synaptic phenotypes between dopamine-ß-hydroxylase (DßH)-immunoreactive (ir) catecholaminergic neurons and neurokinin 1 receptor (NK1R)-ir pre-BötC neurons, and the effect of dAIH on the neuronal network. Immunofluorescence histochemistry was used to reveal immunoreactivities of DßH and NK1R in the RVLM of normoxic and dAIH rats. Synaptic phenotypes were examined with double-labeling immunoelectron microscopy. We found that DßH immunoreactivity was expressed in somata and processes, some of which were in close apposition to NK1R-ir pre-BötC neurons. DßH-ir gold particles were localized to somata, dendrites, and axonal terminals. DßH-ir terminals formed asymmetric synapses, and occasionally, symmetric synapses in the pre-BötC, featuring the local circuitry. Of the synapses, 28% in normoxic and 29.6% in dAIH groups were apposed to NK1R-ir dendrites. Significant increases in DßH expression and NK1R-ir processes were found in the dAIH group. Moreover, the area and number of processes in close appositions were significantly elevated, strongly suggesting that dAIH induced plasticity with increased connections and interactions between the cardiovascular- and respiratory-related neurons in the local circuitry. In conclusion, asymmetric synapses are predominant in the crosstalk between catecholaminergic and pre-BötC neurons in the RVLM, elaborating excitatory transmission driving the coupling of cardiorespiratory activities. The neural network manifests plasticity in response to dAIH challenge.


Assuntos
Catecolaminas/metabolismo , Hipóxia/patologia , Bulbo/patologia , Neurônios/fisiologia , Centro Respiratório/patologia , Sinapses/metabolismo , Animais , Dopamina beta-Hidroxilase/metabolismo , Dopamina beta-Hidroxilase/ultraestrutura , Masculino , Microscopia Imunoeletrônica , Neurônios/ultraestrutura , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-1/ultraestrutura , Centro Respiratório/ultraestrutura , Sinapses/ultraestrutura
7.
Exp Mol Pathol ; 102(1): 15-21, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27939650

RESUMO

Tumor associated macrophages (TAMs) play an important role in the growth, progression, and metastasis of tumors. The distribution of TAMs in Kazakh esophageal squamous cell carcinoma (ESCC) is not determined. We aimed to investigate the role of TAMs in the occurrence and progression of Kazakh ESCC. CD163 was used as the TAM marker, and immunohistochemistry (IHC) counts were used to quantify the density of TAMs in tumor nest and surrounding stroma. IHC staining was used to evaluate the expression of vascular endothelial growth factor C (VEGF-C) in Kazakh ESCC and cancer adjacent normal (CAN) tissues. The density of TAMs in Kazakh ESCCs tumor nest and stromal was significantly higher than that in CAN tissues. The increased number of CD163-positive TAMs in tumor nest and tumor stromal was positively associated with Kazakh ESCC lymph node metastasis and clinical stage progression. Meanwhile, the expression of VEGF-C in Kazakh ESCCs was significantly higher than that in CAN tissues. Overexpression of VEGF-C in Kazakh ESCCs was significantly associated with gender, depth of tumor invasion, lymph node metastasis and tumor clinical stage. The increased number of TAMs, either in the tumor nests or tumor stroma was positively correlated with the overexpression of VEGF-C, which may promote lymphangiogenesis and play an important role in the invasion and metastasis of Kazakh ESCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Macrófagos/metabolismo , Fator C de Crescimento do Endotélio Vascular/biossíntese , Análise de Variância , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Neoplasias Esofágicas/patologia , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Receptores de Superfície Celular/metabolismo , Fatores Sexuais
8.
J Transl Med ; 14(1): 137, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27188458

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressively malignant tumors with dismal prognosis. Profilin 2 (PFN2) is an actin-binding protein that regulates the dynamics of actin polymerization and plays a key role in cell motility. Recently, PFN2 have emerged as significant regulators of cancer processes. However, the clinical significance and biological function of PFN2 in ESCC remain unclear. METHODS: PFN2 protein expression was validated by immunohistochemistry (IHC) on tissue microarray from Chinese Han and Kazakh populations with ESCC. The associations among PFN2 expression, clinicopathological features, and prognosis of ESCC were analyzed. The effects on cell proliferation, invasion and migration were examined using MTT and Transwell assays. Markers of epithelial-mesenchymal transition (EMT) were detected by Western blot analysis. RESULTS: Compared with normal esophageal epithelium (NEE), PFN2 protein expression was markedly increased in low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and ESCC, increased gradually from LGIN to ESCC, and finally reached high grade in HGIN in the Han population. Similarly, PFN2 protein was more overexpressed in ESCC than in NEE in the Kazakh population. The results of Western blot analysis also showed that PFN2 expression was significantly higher in the ESCC tissue than in a matched adjacent non-cancerous tissue. PFN2 expression was positively correlated with invasion depth and lymph node metastasis. High PFN2 expression was significantly correlated with short overall survival (OS) (P = 0.023). Cox regression analysis revealed that PFN2 expression was an independent prognostic factor for poor OS in ESCC. Downregulation of PFN2 inhibited, rather than proliferated, cell invasion and migration, as well as induced an EMT phenotype, including increased expression of epithelial marker E-cadherin, decreased mesenchymal marker Vimentin, Snail, Slug and ZEB1, and morphological changes in ESCC cells in vitro. CONCLUSIONS: Our findings demonstrate that PFN2 has a novel role in promoting ESCC progression and metastasis and portending a poor prognosis, indicating that PFN2 could act as an early biomarker of high-risk population. Targeting PFN2 may offer a promising therapeutic strategy for ESCC treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Terapia de Alvo Molecular , Profilinas/metabolismo , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Linhagem Celular Tumoral , Movimento Celular , Forma Celular , Progressão da Doença , Transição Epitelial-Mesenquimal , Epitélio/metabolismo , Epitélio/patologia , Carcinoma de Células Escamosas do Esôfago , Grupos Étnicos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Prognóstico , Modelos de Riscos Proporcionais , RNA Interferente Pequeno/metabolismo , Curva ROC , Transfecção , Regulação para Cima
9.
Oncotarget ; 7(2): 1777-95, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26657507

RESUMO

Phospholipase C epsilon 1 (PLCE1) is a susceptibility gene in esophageal squamous cell carcinoma (ESCC). Nevertheless, the role of PLCE1 in ESCC tumorigenesis has not been elucidated. In this study, we determined the function of PLCE1 and its regulatory microRNA (miRNA) in ESCC. PLCE1 protein was excessively expressed in ESCC and precancerous lesions compared with that in normal tissues. High PLCE1 expression levels in ESCC were significantly linked with poor overall survival. Knockdown of PLCE1 promoted the apoptosis, cytokine-induced apoptosis, and sensitivity of cancer cells to chemotherapeutic drugs but abrogated the proliferation and EMT phenotype of ESCC in vitro. Notably, miR-145 was newly identified as a potent repressor of PLCE1 expression by directly targeting the 3'UTR of PLCE1. MiR-145 also inhibited cell proliferation, migration, and metastasis, as well as controlled the cytoskeleton dynamics of esophageal cancer. Moreover, miR-145 was expressed at low levels in a large cohort of patients with ESCC and was inversely correlated with PLCE1 protein expression in cancer cells and tissues. These findings demonstrate that PLCE1 functions as tumor promoter in ESCC and can be suppressed by miR-145 through inhibition of PLCE1 translation. Hence, delivery of PLCE1-targeting miR-145 is a potential therapeutic approach for esophageal cancer.


Assuntos
Carcinoma de Células Escamosas/genética , Proliferação de Células/genética , Neoplasias Esofágicas/genética , MicroRNAs/genética , Fosfoinositídeo Fosfolipase C/genética , Regiões 3' não Traduzidas/genética , Apoptose/genética , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Fosfoinositídeo Fosfolipase C/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Int J Clin Exp Pathol ; 8(8): 9293-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26464679

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with a strong tendency toward familial aggregation and a higher incidence as well as mortality in Kazakh population. Tumor necrosis factor-alpha (TNF-α) is an important inflammatory cytokine that plays a role in controlling the progression of lung cancer, hepatocellular cancer, breast cancer and gastric cancer. But the association between TNF-α-308G/A and ESCC still remains unclarified. MATERIALS AND METHODS: Here, we investigated the potential associations between the TNF-α-308G/A and susceptibility to ESCC in 212 cases and 200 controls from a pure ethnic population of Kazakh. DNA extraction and Real-time PCR were performed to detect the TNF-α-308G/A expression levels and odd ratios (ORs) with the corresponding 95% confidence interval (CI) were to evaluate their association with TNF-α-308G/A polymorphism. RESULTS: We found that the frequencies of TNF-α-308G/A in the cases were similar to that of the controls with no differences being statistically significant (χ(2)=1.23, P>0.05). Using the G allele as the reference genotype, individuals who carried A allele had a significantly increased risk of developing ESCC (OR=2.64, 95% CI=1.31~5.35). Especially, the G/A+A/A genotype are associated with increased risk of metastatic as compared with GG genotype individuals (OR=2.08, 95% CI=1.14-3.80, P=0.02). CONCLUSIONS: Our findings suggest that though the TNF-α-308G/A polymorphism may not be correlated with the susceptibility to Kazakh's ESCC in Xinjiang, patients who carry A allele tend to poorly differentiated and lymph node metastasis.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Alelos , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Neoplasias Esofágicas/patologia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Cazaquistão , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
J Transl Med ; 13: 321, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26444413

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly lethal cancer, and its underlying molecular mechanisms are poorly understood. Recent large-scale genome-wide association studies in Chinese Han populations have identified an ESCC susceptibility locus within the SLC39A6 gene. Here, we sought to explore the expression and biological function of SLC39A6 in ESCC. METHODS: Multiethnic validation of SLC39A6 protein expression was performed in different cohorts of patients from Chinese Han and Kazakh populations in the Xinjiang region by immunohistochemistry. The associations among SLC39A6 expression, clinicopathological parameters, and prognosis outcomes of ESCC were analyzed. And the effects of SLC39A6 silencing by siRNA on cell proliferation, apoptosis, and invasiveness, as well as the proteins involved in epithelial-to-mesenchymal transition (EMT) of esophageal cancer cells, were studied. RESULTS: SLC39A6 protein expression increased progressively from normal esophageal epithelium (NEE) to low-grade intraepithelial neoplasia to ESCC, and finally reached the highest in high-grade intraepithelial neoplasia from Han ethnic. Similarly, SLC39A6 protein was significantly overexpressed in Kazakh ethnic ESCC compared with that in NEE. Increased expression of SLC39A6 was found to be closely correlated with histological grade and early Tumor-Node-Metastasis stage I/II. High tumorous SLC39A6 expression was significantly correlated with shorter overall survival (OS). Cox regression analysis confirmed that SLC39A6 expression was an independent prognostic factor for poor OS in ESCC. Experimentally, the suppression of SLC39A6 expression promoted ESCC cell apoptosis but abrogated proliferation and invasion, and induced an EMT phenotype that included enhanced expression of E-cadherin, loss of vimentin, and morphological changes in ESCC cells in vitro. CONCLUSIONS: Combined, our findings highlight a tumor-promoting role for SLC39A6 in ESCC, suggesting that SLC39A6 could serve as an early detector of high-risk subjects and prognostic biomarker. The targeting of SLC39A6 might be a potential therapeutic strategy for blocking ESCC.


Assuntos
Proteínas de Transporte de Cátions/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Carcinoma/etnologia , Carcinoma/metabolismo , Carcinoma/terapia , Proliferação de Células , China , Estudos de Coortes , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/etnologia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , RNA Interferente Pequeno/metabolismo , Análise Serial de Tecidos , Resultado do Tratamento , Regulação para Cima
12.
Int J Clin Exp Pathol ; 8(4): 3636-47, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26097545

RESUMO

Renal cell carcinoma (RCC) accounts for approximately 3% of all new cancer cases. Although the classification of RCC is based mainly on histology, this method is not always accurate. We applied comparative genomic hybridization (CGH) to determine genomic alterations in 46 cases of different RCC histological subtypes [10 cases of clear cell RCC (CCRCC), 13 cases of papillary RCC (PRCC), 12 cases of chromophobe RCC (CRCC), 9 cases of Xp11.2 translocation RCC (Xp11.2RCC), 2 cases of undifferentiated RCC (unRCC)], and investigated the relationships between clinical parameters and genomic aberrations. Changes involving one or more regions of the genome were seen in all RCC patients; DNA sequence gains were most frequently (>30%) seen in chromosomes 7q, 16p, and 20q; losses from 1p, 3p, 13q, 14q, and 8p. We conclude CGH is a useful complementary method for differential diagnosis of RCC. Loss of 3p21-25, 15q, and gain of 16p11-13 are relatively particular to CCRCC vs. other types of RCC. Gain of 7p13-22, 8q21-24, and loss of 18q12-ter, 14q13-24, and Xp11-q13/Y are more apparent in PRCC, and gain of 8q21-24 is characteristic of type 2 PRCC vs. type 1 PRCC. Loss of 2q12-32, 10p12-15, and 11p11-15, 13p are characteristic of CRCC, and gain of 3p and loss of 11p11-15 and 13p are significant differentiators between common CRCC and CRCC accompanied by sarcomatous change groups. Gain of Xp11-12 is characteristic of the Xp11.2RCC group. Based on Multivariate Cox regression analysis, aberration in 5 chromosome regions were poor prognostic markers of RCC, and include the gain of chromosome 12p12-ter (P = 0.034, RR = 3.502, 95% CI 1.097-11.182), 12q14-ter (P = 0.002, RR = 5.115, 95% CI 1.847-14.170), 16q21-24 (P = 0.044, RR = 2.629, 95% CI 1.027-6.731), 17p12-ter (P = 0.017, RR = 3.643, 95% CI 1.262-10.512) and the loss of 18q12-23 (P = 0.049, RR = 2.911, 95% CI 1.006-8.425), which may provide clues of new genes involved in RCC tumorigenesis.


Assuntos
Carcinoma de Células Renais/genética , Aberrações Cromossômicas , Neoplasias Renais/genética , Adulto , Idoso , Hibridização Genômica Comparativa , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Translocação Genética
13.
Kaohsiung J Med Sci ; 31(2): 70-6, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25645984

RESUMO

Emerging evidence suggests that activation of the Notch1 signaling pathway inducing epithelial to mesenchymal transition (EMT) mediated by Snail/Slug promotes invasion and metastasis of breast cancer cells in vitro. However, the implication of the Notch1-Snail/Slug-EMT axis in breast cancer patients remains unclear. A total of 200 formalin-fixed paraffin-embedded samples of invasive ductal carcinoma (IDC), and 37 adjacent non-neoplastic tissue (ANNT) samples from patients who had not been treated with neoadjuvant therapy were examined. Expression of Notch1, Slug, Snail, E-cadherin, N-cadherin, and vimentin was determined by immunohistochemistry on tissue microarrays (TMAs). The correlation between protein expression and clinicopathological characteristics of breast cancer patients was also evaluated. Results showed that a significantly high percentage of cases with high expression of Notch1 (74%, 148/200), Slug (36%, 72/200), Snail (62%, 124/200), and N-cadherin (77%, 153/200) and a low percentage of cases with high expression of E-cadherin (27%, 54/200) were observed in IDC compared to those in ANNTs. High Notch1, Slug, Snail, and N-cadherin expression and low E-cadherin expression in patients with IDC were significantly correlated with lymph node metastasis. In addition, correlation analysis results revealed that high Notch1 expression was significantly associated with high Slug, Snail, and N-cadherin expression and low E-cadherin expression in IDC. Furthermore, a high Snail expression was significantly associated with low E-cadherin expression, and a high Slug expression was found to be significantly associated with increased N-cadherin expression in patients with IDC. Hence, our study suggested that the Notch1-Snail/Slug-EMT axis may be implicated in the lymph node metastasis affecting patients with IDC.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição/metabolismo , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Caderinas/metabolismo , Carcinoma Ductal de Mama/secundário , Transição Epitelial-Mesenquimal , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Fatores de Transcrição da Família Snail
14.
Asian Pac J Cancer Prev ; 15(22): 9661-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25520085

RESUMO

BACKGROUND: A number of studies have identified a shared susceptibility locus in phospholipase C epsilon 1 (PLCE1) for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA). However, the results of PLCE1 expression in esophageal and gastric cancer remain inconsistent and controversial. Moreover, the effects on clinicopathological features remain undetermined. This study aimed to provide a precise quantification of the association between PLCE1 expression and the risk of ESCC and GCA through meta-analysis. MATERIALS AND METHODS: Eligible studies were identified from PubMed, Wanfang Data, ISI Web of Science, and the Chinese National Knowledge Infrastructure databases. Using RevMan5.2 software, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were employed to assess the association of PLCE1 expression with clinicopathological features relative to ESCC or GCA. RESULTS: Seven articles were identified, including 761 esophageal and gastric cancer cases and 457 controls. Overall, we determined that PLCE1 expression was associated with tumor progression in both esophageal cancers (pooled OR=5.93; 95%CI=3.86 to 9.11) and gastric cancers (pooled OR=9.73; 95%CI=6.46 to 14.7). Moreover, invasion depth (pooled OR=3.62; 95%CI=2.30 to 5.70) and lymph node metastasis (pooled OR=4.21; 95%CI=2.69 to 6.59) were linked with PLCE1 expression in gastric cancer. However, no significant associations were determined between PLCE1 overexpression and the histologic grade, invasion depth, and lymph node metastasis in esophageal cancer. CONCLUSIONS: Our meta- analysis results indicated that upregulated PLCE1 is significantly associated with an increased risk of tumor progression in ESCC and GCA. Therefore, PLCE1 expression can be appropriately regarded as a promising biomarker for ESCC and GCA patients.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Fosfoinositídeo Fosfolipase C/biossíntese , Fosfoinositídeo Fosfolipase C/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Cárdia/patologia , Carcinoma de Células Escamosas do Esôfago , Predisposição Genética para Doença , Humanos , Metástase Linfática/patologia , Pessoa de Meia-Idade , Trato Gastrointestinal Superior/patologia
15.
Int J Clin Exp Pathol ; 7(9): 6165-71, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25337265

RESUMO

Human papillomavirus (HPV) infection is a major risk factor for cervical cancer. However, only some high risk human papillomavirus (HR-HPV)-infected women progress to cervical cancer, host immunogenetic factors human leukocyte antigen (HLA) may account for viral antigens presenting individually or together in the progression to cervical cancer. This study examined the association between the development of invasive cervical cancer (ICC) and the determinant factors including HLA-DRB1*1501 and DQB1*0602, HR-HPV infection among Chinese Uighur and Han populations. Blood samples, cervical swabs and biopsies were obtained from 287 patients with ICC (192 Uighurs and 95 Hans) and 312 healthy controls (218 Uighurs and 94 Hans). HPV DNA was detected by PCR and HLA-DRB1*1501 and DQB1*0602 alleles were performed using PCR-SSP method. HPV16 infection rates was significantly higher among Uighur and Han with ICC as compared to healthy controls (OR = 58.317; 95% CI: 39.663-85.744; OR = 33.778; 95% CI: 12.581-90.691; P < 0.05 for all). HLA-DRB1*1501 (OR = 0.305; 95% CI: 0.115-0.813; P < 0.05) and HLA-DRB1*1501-DQB1*0602 haplotype frequencies (OR = 0.274; 95% CI: 0.086-0.874; P < 0.05) were significantly reduced in Han ICC. The HLA-DQB1*0602 frequency significantly decreased among Uighur women with ICC (OR = 0.482; 95% CI: 0.325-0.716; P < 0.05). Similar tendencies were observed for DQB1*0602 with HPV16-positive ICC (OR = 0.550; 95% CI: 0.362-0.837; P < 0.05). This study suggests that HLA-DRB1*1501 and DQB1*0602 alleles may influence the immune response to HPV16 infection and decrease the risk of ICC among Uighurs and Hans in Xinjiang, China.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/prevenção & controle , Adulto , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China/epidemiologia , DNA Viral/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Testes de DNA para Papilomavírus Humano , Papillomavirus Humano 16/genética , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Invasividade Neoplásica , Razão de Chances , Infecções por Papillomavirus/etnologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Fenótipo , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Fatores de Proteção , Fatores de Risco , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia
16.
Int J Clin Exp Pathol ; 7(7): 3673-83, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25120743

RESUMO

Inflammatory myofibroblastic tumour (IMT) is a relatively rare soft tissue malignancy. It exhibits locally aggressive behavior with a tendency for local recurrence and rare metastasis, and rare recurrent IMTs may show histological progression. The genetic hallmark of IMT is ALK rearrangement from chromosome arm 2p, but gene mutations involved in IMT remain poorly understood. The aim of the present study was to perform a pairwise comparison of the gene mutations occurring in primary and recurrent IMT from the same patient. We conducted a high-throughput analysis of 238 known mutations of 19 oncogenes in pairwise comparison primary and recurrent samples from 2 patients of IMT using Sequenom MassARRAY technology. Our results revealed 2 mutations in 2 recurrent lesion samples, including one in exon 11 of the KIT gene, resulting in a T-C substitution at position 1727 (L576P), the recurrent sample underwent histologic progression with "pleomorphic undifferentiated sarcoma-like" transformation; the other mutation was in exon 19 of the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene, resulting in a G-A substitution at position 1624 (E542K). Moreover, no any mutation was found in the primary lesion samples from 2 patients. Our findings suggest that variable genome changes might be present in IMT, especially during the progression from a primary tumour to recurrence. To the best of our knowledge, no such longitudinal study of IMT has been undertaken previously.


Assuntos
Mutação , Miofibroma/genética , Recidiva Local de Neoplasia/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Feminino , Genótipo , Ensaios de Triagem em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Miofibroma/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
17.
Int J Clin Exp Pathol ; 7(7): 4286-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25120811

RESUMO

Accumulated evidence has revealed the presence of Notch receptor polymorphisms in non-tumorous diseases; however, few studies have investigated the association of Notch polymorphisms with breast cancer risk. A total of 100 invasive ductal carcinoma (IDC) and 50 ductal carcinoma in situ (DCIS) patients and 100 usual ductal hyperplasia (UDH) controls were genotyped for the following Notch receptor single nucleotide polymorphisms (SNPs) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry: Notch1, rs3124591; Notch2, rs11249433; Notch3, rs3815188, and rs1043994; and Notch4, rs367398, and rs520692. Immunohistochemistry was used to determine the effect of Notch polymorphisms on corresponding Notch protein expression in successfully genotyped patients. The frequency of rs3124591 TC genotype was significantly higher in IDC (24.7%, 20/81) and DCIS (30%, 12/40) patients than in UDH controls (8%, 8/97) (P = 0.002 and P = 0.011, respectively). However, the distribution of other SNP genotypes was not significantly different between IDC and DCIS patients and UDH controls. The frequency of TC genotype was significantly higher in poorly differentiated tumors than in well-differentiated and moderately differentiated tumors (P = 0.022). Importantly, a positive correlation between the rs3124591 TC genotype and high Notch1 protein expression was observed in DCIS patients (P = 0.043) but not in IDC patients. This is the first study to suggest an increased risk of IDC and DCIS of the breast for the Notch1 rs3124591 variant. Furthermore, given the inconsistent associations between the rs3124591 variant and Notch1 expression in IDC and DCIS, this variant may affect breast cancer risk through mechanisms in the latter stage other than alterations in Notch1 protein expression.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Predisposição Genética para Doença/genética , Receptor Notch1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
18.
Int J Clin Exp Pathol ; 7(7): 4391-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25120824

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) derived from plasmacytoid dendritic cell precursors is a very rare, and characterized by cutaneous and bone marrow involvement and leukemic spread. The neoplasm presents with an aggressive behavior, and the clinical findings include cytopenia, particularly thrombocytopenia. The tumor cells are negative for antigens of T- and B- cell lines. However, these cells express CD4, CD56 and CD123, which are markers of plasmacytoid dendritic cells, and negative for Epstein-Barr virus (EBV). From this point of view, a 71-year-old man who was initially found to have a cutaneous mass on his face and thorax was reported here, and initially was diagnosed as "eczema". The skin rashes then became aggravated on a trial of low dose topical corticosteroid for 2 months. According to skin biopsy, the tumor cells reveal an immature blastic appearance and positive for CD4 and CD56, negative for CD3, CD20, indicating a diagnosis of BPDCN. Here, we report the dismal course of a patient with BPDCN without accepting further therapy, and only survived 3 months.


Assuntos
Células Dendríticas/patologia , Neoplasias Hematológicas/patologia , Neoplasias Cutâneas/patologia , Idoso , Biomarcadores Tumorais/análise , Equimose/etiologia , Neoplasias Hematológicas/complicações , Humanos , Masculino , Neoplasias Cutâneas/complicações
19.
Med Oncol ; 31(1): 791, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24307345

RESUMO

This study investigated the expression of the phospholipase C epsilon 1 (PLCE1) and nuclear factor-kappaB (NF-κB)-related proteins in Kazakh patients with esophageal squamous cell carcinoma (ESCC). Tissue microarrays of 90 ethnic Kazakh patients with ESCC and exhibiting clinical characteristics were analyzed for protein expression of PLCE1, IKKß, IKBα, p50, and p65 by immunohistochemistry. Correlations between histoscores of PLCE1 and NF-κB-related proteins were determined using Spearman's rank correlation tests. Expression of PLCE1 and NF-κB-related proteins significantly increased in tumor tissues compared with normal esophageal tissues (P = 9.48 × 10(-7), 1.24 × 10(-5), 0.004, 0.003, and 2.83 × 10(-5), respectively). Upregulation of PLCE1 was significantly correlated with advanced tumor-node-metastasis stages (P = 0.018) and lymph node metastasis (P = 0.003). Overexpression of IKKß and IKBα was associated with ESCC stages I/II (P = 3.36 × 10(-4) and 0.022, respectively). Increased expression of p50 was significantly higher in patients with lymph node metastasis than without lymph node metastasis (P = 0.048). Elevated expression of p65 protein was significantly correlated with poor and moderately differentiated ESCC and depth of tumor invasion (P = 0.026 and 0.010, respectively). Significant positive correlations were observed between the expression of PLCE1 and NF-κB-related proteins, especially IKKß (r = 0.246 and P = 0.025) and p50 (r = 0.244 and P = 0.024). These results suggest, for the first time, that upregulation of PLCE1 is correlated with increased expression of NF-κB-related proteins in Kazakh patients with ESCC, suggesting that interaction between PLCE1 with the NF-κB signal pathway may be responsible for the carcinogenesis of ESCC, such as ESCC-related inflammation.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Subunidade p50 de NF-kappa B/metabolismo , Fosfoinositídeo Fosfolipase C/metabolismo , Adulto , Idoso , Carcinoma de Células Escamosas/etnologia , Neoplasias Esofágicas/etnologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Inflamação , Cazaquistão , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Análise Serial de Tecidos
20.
Zhonghua Bing Li Xue Za Zhi ; 40(5): 324-9, 2011 May.
Artigo em Chinês | MEDLINE | ID: mdl-21756827

RESUMO

OBJECTIVE: To explore the relevance between the promoter methylation status of Notch1 gene and the invasive ductal carcinoma and ductal hyperplastic lesions of the breast. METHODS: Methylation status of Notch1 gene in human breast invasive ductal carcinoma (IDC, n = 89), ductal carcinoma in situ (DCIS, n = 20), atypical ductal hyperplasia (ADH, n = 11) and usual ductal hyperplasia (UDH, n = 20) were quantitatively evaluated by MALDI-TOF MS. The expression of Notch1 protein was detected by immunohistochemical stain (SP method). RESULTS: Positive expression rates of Notch1 protein in IDC and DCIS were 91.0% (81/89) and 75.0% (15/20), respectively, which were significantly higher than those of ADH (4/11) and UDH (30.0%, 6/20;P < 0.05). Notch1 protein expression was correlated significantly with lymph node metastasis, pathological grades and TNM stages of IDC. The mean methylation levels of Notch1 gene at CpG_3, CpG_4.5 and CpG_8 significantly decreased in IDC group compared with those of DCIS, ADH and UDH groups (P < 0.0083). In breast carcinomas, the mean methylation rates of Notch1 gene at CpG_4.5, CpG_10.11, and CpG_14.15.16 loci in cases with axillary node metastasis were significantly lower than those without axillary node metastasis (P < 0.05); and the methylation rates at CpG_14.15.16 and CpG_18 loci in stage Iwere lower than that in stage II, further lower than that in stage III (P < 0.05); and that in CpG_1.2, CpG_12.13 loci in grade I (highly-differentiated group) were higher than that in grade II (moderate-differentiated group) and grade III (poorly-differentiated group) (P < 0.05); and the methylation rates at CpG_3, CpG_8 and CpG_14.15.16 loci in ER(+) PR(+) HER2(-) group were lower than that in ER(-) PR(-) HER2(+) group (P < 0.05). CONCLUSIONS: There is an overall hypomethylation of Notch1 gene in breast invasive ductal carcinomas with corresponding over-expression of Notch1 protein. This inverse correlation show that the alteration of protein expression result from hypomethylation oncogene Notch1, and this change may have important significance in breast tumorigenesis and the development. Specific hypomethylation at CpG_3, CpG_ 4.5 and CpG_8 loci of Notch1 gene may play a role in the pathogenesis of breast carcinoma, suggesting the progression and/or malignant transformation from benign glandular lesions of the breast.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Metilação de DNA , Receptor Notch1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Ilhas de CpG/genética , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Humanos , Hiperplasia , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Regiões Promotoras Genéticas , Receptor Notch1/metabolismo , Adulto Jovem
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