RESUMO
Oral cancer is causally associated with environmental carcinogens, and the susceptibility to carcinogen-mediated tumorigenesis is proposed to be genotype-dependent. Leptin (LEP) and leptin receptor (LEPR) both play a crucial role in the mediation of physiological reactions and carcinogenesis and may serve as a candidate biomarker of oral cancer. The current case-control study aimed to examine the effects of LEP -2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) single-nucleotide polymorphisms (SNPs) with or without interacting to environmental carcinogens on the risk for oral squamous cell carcinoma. The SNPs of three genetic allele, from 567 patients with oral cancer and 560 healthy controls in Taiwan were analyzed. The results shown that the patients with polymorphic allele of LEP -2548 have a significant low risk for the development of clinical stage (A/G: adjusted odds ratio [AOR] = 0.670, 95% confidence interval [CI] = 0.454-0.988, P < 0.05; A/G + G/G: AOR = 0.676, 95% CI = 0.467-0.978, P < 0.05) compared to patients with ancestral homozygous A/A genotype. In addition, an interesting result was found that the impact of LEP -2548 G/A SNP on oral carcinogenesis in subjects without tobacco consumption is higher than subjects with tobacco consumption. These results suggest that the genetic polymorphism of LEP -2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) were not associated to the susceptibility of oral cancer; SNP in LEP -2548 G/A showed a poor clinicopathological development of oral cancer; population without tobacco consumption and with polymorphic LEP -2548 G/A gene may significantly increase the risk to have oral cancer.
Assuntos
Carcinogênese/genética , Progressão da Doença , Predisposição Genética para Doença , Leptina/genética , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único/genética , Fumar/genética , Carcinogênese/patologia , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Receptores para Leptina/genéticaRESUMO
Licochalcone A is widely studied in different fields and possesses antiasthmatic, antibacterial, anti-inflammatory, antioxidative, and anticancer properties. Its antimalignancy activity on renal, liver, lung, and oral cancer has been explored. However, limited studies have been conducted on the inhibitory effects of licochalcone A in human nasopharyngeal carcinoma cells. We determined cell viability using MTT assay. Cell cycle distribution and apoptotic cell death were measured via flow cytometry. Caspase activation and mitogen-activated protein kinase-related proteins in nasopharyngeal cancer cells in response to licochalcone A were identified by Western blot analysis. Results indicated that licochalcone A reduces cell viability and induces apoptosis, as evidenced by the upregulation of caspase-8 and caspase-9, caspase-3 activation, and cleaved-poly ADP-ribose polymerase expression. Treatment with licochalcone A significantly increases ERK1/2, p38, and JNK1/2 activation. Co-administration of a JNK inhibitor (JNK-IN-8) or p38 inhibitor (SB203580) abolishes the activation of caspase-9, caspase-8, and caspase-3 protein expression during licochalcone A treatment. These findings indicate that licochalcone A exerts a cytostatic effect through apoptosis by targeting the JNK/p38 pathway in human nasopharyngeal carcinoma cells. Therefore, licochalcone A is a promising therapeutic agent for the treatment of human nasopharyngeal cancer cells.
Assuntos
Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antineoplásicos/farmacologia , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
Glabridin, a flavonoid extracted from licorice (Glycyrrhiza glabra), possesses various biological properties, including anticancer activities. However, the effect of glabridin on oral cancer cell apoptosis and the underlying molecular mechanisms has not been elucidated. In this study, we demonstrated that glabridin treatment significantly inhibits cell proliferation in human oral cancer SCC-9 and SAS cell lines. Flow cytometric assays demonstrated that glabridin induced several features of apoptosis, such as sub-G1 phase cell increase and phosphatidylserine externalization. Furthermore, glabridin induced apoptosis dose-dependently in SCC-9 cells through caspase-3, -8, and -9 activation and poly (ADP-ribose) polymerase cleavage. Moreover, glabridin increased the phosphorylation of the extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase (JNK) pathways in a dose-dependent manner. Moreover, the inhibition of the JNK1/2 inhibitor significantly reversed the glabridin-induced activation of the caspase pathway. In conclusion, our findings suggest that glabridin induces oral cancer cell apoptosis through the JNK1/2 pathway and is a potential therapeutic agent for oral cancer.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Neoplasias Bucais/patologia , Fenóis/farmacologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Neoplasias Bucais/metabolismo , Fosforilação/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Single nucleotide polymorphism (SNP) in some genes is a candidate for having or developing a cancer. Cathepsin B (CTSB) is considered to be the biomarker of cancers. The study aimed to evaluate the impacts of three SNPs in CTSB gene on the risk and progress of hepatocellular carcinoma (HCC). The SNPs of CTSB C76G (rs12338), CTSB A4383C (rs13332), and CTSB A8422G (rs8898) from 135 patients with HCC and 520 control participants in Taiwan were determined by real-time PCR. Through analyzing by statistics, we found that the polymorphism of rs13332 was significantly associated to the risk of HCC cancer; a significantly high frequent tumor size development was observed in HCC patients carrying rs12338 polymorphic genotype than those carrying ancestral genotype. The SNPs of rs12338, rs13332, and rs8898 were irrelevant to the frequencies of HCC clinical status and the levels of HCC clinicopathological markers. In conclusions, CTSB A4383C SNP is observed modestly more often in patients who developed HCC than in healthy controls and might be associated with the risk of HCC. The association between CTSB C76G SNP and greater tumor size may warrant further study in regards to the biology of HCC.
Assuntos
Carcinoma Hepatocelular/etiologia , Catepsina B/genética , Neoplasias Hepáticas/etiologia , Polimorfismo de Nucleotídeo Único/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Uso de Tabaco/efeitos adversosRESUMO
Cancer metastasis refers to the spread of cancer cells from the primary neoplasm to distant sites, where secondary tumors are formed, and is the major cause of death from cancer. Natural phytochemicals containing phenolic compounds have been widely demonstrated to have the capability to prevent cancer metastasis. Among phenolic compounds, flavonoids are a very large subclass, and they are abundant in food and nutraceuticals. The number of reports demonstrating that flavonoids are an effective natural inhibitor of cancer invasion and metastasis is increasing in the scientific literature. Catechin derivatives, (−)-epigallocatechin-3-gallate, (−)-epigallocatechin, (−)-epicatechin-3-gallate,and (−)-epicatechin, are the most studied compounds in this topic so far; genistein/genistin, silibinin, quercetin, and anthocyanin have also been widely investigated for their inhibitory activities on invasion/metastasis. Other flavonoids in dietary vegetable foods that are responsible for anti-invasive and anti-metastatic activities of tumors include luteolin,apigenin, myricetin, tangeretin, kaempferol, glycitein, licoricidin,daidzein, and naringenin. To effectively overcome the metastatic cascade, including cell-cell attachment, tissue barrier degradation, migration, invasion, cell-matrix adhesion,and angiogenesis, it is essential that a bioactive compound prevent tumor cells from metastasizing. This review summarizes the effects of flavonoids on the metastatic cascade and the related proteins, the in vitro anti-invasive activity of flavonoids against cancer cells, and the effects of flavonoids on antiangiogenic and in vivo anti-metastatic models. The available scientific evidence indicates that flavonoids are a ubiquitous dietary phenolics subclass and exert extensive in vitro anti-invasive and in vivo anti-metastatic activities.
Assuntos
Flavonoides/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Animais , Dieta , Flavonoides/química , Flavonoides/farmacologia , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica/prevenção & controleRESUMO
Patients with lung adenocarcinoma are often diagnosed with metastasizing symptoms and die of early and distal metastasis. Metastasis is made up of a cascade of interrelated and sequential steps, including cell adhesion, extracellular matrix degradation, cell movement, and invasion. Hence, substances carrying the ability to stop one of the metastasis-associated steps could be a potential candidate for preventing tumor cells from metastasizing and prolonging the life of cancer patients. Cinnamic acid (CA) was demonstrated to be such a candidate for human lung adenocarcinoma cells. Nevertheless, the effectiveness of CA derivatives on invasion of lung cancer cells is still unclear. The aims of this study were to explore the mechanisms underlying several select CA derivatives against invasion of human lung adenocarcinoma A549 cells. The results revealed that caffeic acid (CAA), chlorogenic acid (CHA), and ferulic acid (FA) can inhibit phorbol-12-myristate-13-acetate (PMA)-stimulated invasion of A549 cells at a concentration of ≥100 µM. The MMP-9 activity was suppressed by these compounds through regulating urokinase-type plasminogen activator (uPA), tissue inhibitor of metalloproteinase (TIMP)-1, plasminogen activator inhibitor (PAI)-1, and PAI-2; the cell-matrix adhesion was decreased by CAA only. The proposed molecular mechanism involved not only decreasing the signaling of MAPK and PI3K/Akt but also inactivating NF-κB, AP-1, and STAT3. In the present study, we selected CAA, CHA, and FA as potential inhibitors for invasive behaviors of human lung adenocarcinoma cells and disclosed the possible mechanisms. The association between structural features and anti-invasive activity of these compounds cannot be determined here and needs to be further verified.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Cinamatos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Antineoplásicos Fitogênicos/química , Ácidos Cafeicos/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Clorogênico/farmacologia , Cinamatos/química , Ácidos Cumáricos/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Transdução de Sinais/efeitos dos fármacosRESUMO
Oral cancer is causally associated with environmental carcinogens, and the susceptibility to carcinogen-mediated tumorigenesis is proposed to be genotype-dependent. Cathepsin B (CTSB) is a lysosomal cysteine protease and may serve as a candidate biomarker of oral cancer. The current study aimed to explore the influences of three single nucleotide polymorphisms (SNPs) in CTSB gene, combined with environmental carcinogens on the risk and clinicopathological development of oral cancer. Three SNPs of CTSB, CTSB C76G (rs12338), CTSB A4383C (rs13332), and CTSB A8422G (rs8898), from 444 male patients with oral cancer and 426 control participants (males not diagnosed with cancer) in Taiwan were analyzed. These three CTSB SNPs all exhibited insignificant (P > 0.05) effects on the risk of oral cancer. However, the risk for developing the poor clinical stage of moderately or poorly differentiated cells was significantly (P < 0.001) increased to 3.325-fold in patients with oral cancer carrying the polymorphic genotype of rs8898 compared to patients with the ancestral genotype. Additionally, while considering the exposure of environmental carcinogens, the presence of these three CTSB SNPs, combined with betel quid chewing [adjusted odds ratio (AOR) was 36.570, 21.772, and 43.962 for rs12338, rs13332, and rs8898, respectively] and/or tobacco use (AOR was 3.794, and 8.972 for rs12338 and rs13332, respectively), robustly elevated the susceptibility to oral cancer. These results suggest that the genetic polymorphism of CTSB A8422G (rs8898) was associated with a high risk for the clinicopathological development of oral cancer and CTSB gene polymorphisms may increase the susceptibility to environmental carcinogens-mediated oral cancer.
Assuntos
Catepsina B/genética , Neoplasias Bucais/etiologia , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Carcinógenos Ambientais/toxicidade , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/genética , Estudos de Casos e Controles , Exposição Ambiental , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/enzimologia , Fatores de Risco , TaiwanRESUMO
BACKGROUND: Matrix metalloproteinase (MMP)-14 is one of the pericellular collagenases to degrade extracellular matrix (ECM), which is involved to the modulation of susceptibility or clinicopathological features of a cancer. The contributions of MMP-14 on the susceptibility or clinicopathological features of certain cancers have been well documented, and the expression of MMP-14 in oral squamous cell carcinoma (OSCC) also has been observed. This study was designed to examine the association of MMP-14 gene polymorphisms with the susceptibility and clinicopathological development of OSCC. METHODS: A total of 363 patients with OSCC and 506 healthy control subjects were recruited. Six single nucleotide polymorphisms (SNPs) of MMP-14 genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism genotyping and haplotype-base analysis. RESULTS: MMP-14 +7096 TC/CC genotypes might lower the risk of OSCC, and MMP-14 +6767 GA/AA genotypes cause a poor clinical status in OSCC patients. The +6727 C: +6767 G: +7096 T: +8153 G haplotype and diplotype increased the risk for OSCC by 1.706-fold (95% confidence interval (CI) 1.383-2.105) and 2.276-fold (95% CI = 1.531-3.384), respectively, compared with the reference. The diplotype with at least one CGTG exhibited a high risk (adjusted odds ratio, 1.639; 95% CI, 1.005-2.673) for developing a poor clinicopathological diagnosis of OSCC compared with the others/other diplotype. CONCLUSIONS: The +7096 and +6767 polymorphic genotypes and haplotype +6727 C: +6767 G: +7096 T: +8153 G of MMP-14 gene might contribute to the prediction of susceptibility and pathological development of OSCC.
Assuntos
Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença/genética , Metaloproteinase 14 da Matriz/genética , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Frequência do Gene , Genes Neoplásicos , Haplótipos , Humanos , Masculino , Neoplasias Bucais/patologia , Razão de Chances , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is seldom available because of the lack of reliable markers. Survivin is an anti-apoptotic protein that is implicated in the regulation of apoptosis and cell cycle, and it is undetectable in normal adult tissues but is overexpressed in various types of cancers. Survivin is thus commonly considered to be a marker of malignancy. The aim of this study was to explore the association between survivin gene polymorphisms and the risk and diagnostic progress of HCC. METHODS: A total of 135 patients with HCC and 496 healthy control subjects were recruited. Five single nucleotide polymorphisms (SNPs) of survivin genes were determined by real-time polymerase chain reaction (real-time PCR) and further analyzed statistically. RESULTS: We first found that the -241 C/T and -235 G/A genetic polymorphisms of survivin did not occur frequently enough or even lacked in Taiwanese population. The +9809 C/C polymorphism exhibited a significant (P < .05) low risk of 0.525-fold (95% confidence interval [95% CI] = 0.297-0.930) to have HCC compared with the wild-type homozygotes and a low ratio of 0.214-fold (95% CI = 0.051-0.890) for positive anti-HCV was shown in the individuals with survivin +9809 polymorphic CC allele compared with the TT/TC genotypic subgroup. CONCLUSIONS: Survivin +9809 polymorphic genotype is associated with the risk of HCC, and the HCC patients with survivin +9809 CC homozygotes might have a low risk of developing infected HCV-dependent HCC. The results suggest that the survivin T9809C SNP might contribute to the prediction of susceptibility and pathological development to HCC.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Predisposição Genética para Doença , Proteínas Inibidoras de Apoptose/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Idoso , Alanina Transaminase/sangue , Povo Asiático/genética , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/sangue , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Intervalos de Confiança , Feminino , Humanos , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Estatísticas não Paramétricas , Survivina , Taiwan , Sequências Repetidas Terminais/genética , alfa-Fetoproteínas/metabolismoRESUMO
BACKGROUND: The levels of urokinase plasminogen activator (uPA) system in tumor tissues are implicated as prognostic biomarkers in a wide range of malignancies. However, their possible impact on the risk and prognosis of oral cancer and the susceptibility of environmental carcinogens to oral cancer remains poorly investigated. METHODS: The genetic polymorphisms of uPA, uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 253 patients with oral cancer and 344 healthy controls. RESULTS: There was no significant effect of uPA system genes on the susceptibility of oral cancer; however, the impact of uPA system gene polymorphisms on the susceptibility of betel nut and tobacco consumptions to oral cancer was revealed, except for that of uPAR gene polymorphism on tobacco consumption. Patients with oral cancer with at least one 5G allele of PAI-1 gene have a low risk for the development of clinical stage III or IV (p ≤ 0.05) and lymph node metastasis (p ≤ 0.05) compared with those with 4G/4G homozygotes. CONCLUSIONS: Our results suggest that the combination of uPA system gene polymorphisms and environmental carcinogens was related to the risk of oral cancer, and the genetic polymorphism of PAI-1 was associated with a low risk to the clinicopathological development of oral cancer.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Inativadores de Plasminogênio/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Carcinoma de Células Escamosas/secundário , Estudos de Casos e Controles , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Prognóstico , Fatores de Risco , Taxa de Sobrevida , NicotianaRESUMO
BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is seldom available because of the lack of reliable markers. Matrix metalloproteinase (MMP) 14 is a cell surface proteinase that displays a broad spectrum of activity against extracellular matrix components and promotes the invasion/metastasis of cells. MMP14 is overexpressed in HCC, and the level is correlated with poor overall survival. The purpose of this study was to examine whether the MMP14 gene polymorphisms are associated with the susceptibility and clinicopathological development of HCC. METHODS: A total of 135 patients with HCC and 496 healthy control subjects were recruited. Six single nucleotide polymorphisms (SNPs) of MMP14 genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping and haplotype-base analysis. RESULTS: A significant (p < 0.05) lower risk for HCC was shown in the individuals with MMP14 +6767 G/A and +7096 C/C genotypes compared with those with corresponding wild-type homozygotes; high frequency for anti-hepatitis C virus and cirrhosis positive were shown in the HCC patients with MMP14 +7096 TC/CC genotype after adjusting for other confounding factors. The distribution frequency of -165 T: +221 T: +6727 C: +6767 G: +7096 T: +8153 G haplotype and diplotype was significantly higher in the HCC patients than healthy control subjects. CONCLUSIONS: The +6767 and +7096 polymorphic genotypes and haplotype -165 T: +221 T: +6727 C: +6767 G: +7096 T: +8153 G of MMP14 gene might contribute to the prediction of susceptibility and pathological development to HCC.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Metaloproteinase 14 da Matriz/genética , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único/genética , Carcinoma Hepatocelular/secundário , Estudos de Casos e Controles , DNA de Neoplasias/genética , Feminino , Seguimentos , Genótipo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase em Tempo Real , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The urokinase plasminogen activator (uPA) system is a serine proteinase system involved in extracellular matrix (ECM) degradation. The levels of uPA system components in tumor tissues are implicated as prognostic biomarkers in a wide range of malignancies. Although the contributions of uPA system components to the formation of many types of cancer are well known, their possible association with the prediction of risk and prognosis of hepatocellular carcinoma (HCC) remains poorly investigated. METHODS: A total of 102 HCC patients and 344 controls were recruited. Genetic polymorphisms of uPA system genes, including uPA, uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1, were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping analysis. RESULTS: When individuals were classified into male and female subgroups to estimate adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) of each uPA system gene, the HCC risks of males and females with PAI-1 5G/5G genotype were 6.06-fold (95% CI = 1.39-26.36) and 0.04-fold (95% CI = 0.003-0.69), respectively, as compared with those with PAI-1 4G/4G genotype. High risk for hepatitis B surface antigen (HBsAg)-positive clinical status and significantly higher serum aspartate aminotransferase (AST) concentration were exhibited in HCC patients with PAI-1 4G/5G and 5G/5G genotypes as compared with 4G/4G homozygotes. CONCLUSIONS: The results suggest that PAI-1 genotypes could be an important factor contributing to increased susceptibility and pathological development of HCC in Taiwanese population.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Fígado/patologia , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Idoso , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Genótipo , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , PrognósticoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. The insulin-like growth factors (IGFs) system consists of a group of proteins which may induce cell proliferation and inhibit cell apoptosis through several signal pathways, leading to transformation of normal cells into cancer cells. However, the impact of genetic polymorphisms of the IGFs system on HCC has not been clarified. METHODS: In this case-control study, a total of 102 HCC patients and 306 age- and gender-matched controls were recruited. The genetic polymorphisms of the IGFs system genes, including IGF-1, IGF-2, IGF-1receptor (IGF-1R), IGF-2R, IGF binding protein (IGFBP-3), and insulin (INS) genes, were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and real-time PCR genotyping analysis. RESULTS: A significant difference (p = 0.02) between case and control group in the distribution frequency of IGF-2 +3580 polymorphism was observed. Multiple regression model analysis showed that the presence of AA or AG at IGF-2R may exhibit a potential protective effect against hepatitis C [odds ratio (OR) = 0.35, 95% confidence interval (CI) = 0.15-0.82]. The combination of IGF-2 +3580 AA genotype and IGF-2R GG genotype may present a significantly lower risk of HCC (OR = 0.20, 95% CI = 0.05-0.87). Additionally, no polymorphisms of any IGFs system genes were associated with liver-related clinicopathological markers in serum. CONCLUSIONS: Among IGFs system genes, IGF-2 and IGF-2R gene polymorphisms and combination could be considered as the most important factors contributing to increased susceptibility and pathological development of HCC.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Predisposição Genética para Doença , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Polimorfismo Genético/genética , Somatomedinas/genética , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 2/genética , Fatores de RiscoRESUMO
Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths worldwide. It has a very poor prognosis with over a 5-year survival rate of only 50%. Thus, it is important to identify effective therapeutic interventions against oral cancer. Apoptosis and autophagy have reported genetically regulated in physiology and diseases, which close relationship. Many natural compound study objects anticancer effect have been studied between apoptosis and autophagy relationship. The present study was designed to evaluate the effect of erianin on human oral cancer cell proliferation. Results of the study revealed that treatment with erianin significantly reduced the viability of different OSCC cell lines. Erianin exerted its cytotoxic effect by inducing cell cycle arrest and caspase-dependent apoptotic pathways. Both intrinsic and extrinsic pathways were found to be involved in erianin-mediated cell death. In addition, treatment with erianin also increased autophagy in OSCC cells. With further analysis, it was found that erianin induced both apoptosis and autophagy by regulating MAPK signaling pathways. Taken together, our study indicates that erianin plays an important role in reducing oral cancer cell viability, and thus, can be considered as a potential anticancer agent.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Bibenzilas/farmacologia , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/tratamento farmacológico , Fenol/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Humanos , Estrutura MolecularRESUMO
Ganoderma lucidum has been reported to be associated with suppressed motility, invasion and metastasis of several types of cancers, but its mechanism of action remains unclear. In our previous study, lucidenic acids A, B, C and N were isolated from a new strain of G.lucidum and all of them were found to have potential anti-invasive activity on phorbol-12-myristate-13-acetate (PMA)-induced HepG(2) cells by suppressing the matrix metalloproteinase (MMP)-9 activity. Here, the lucidenic acid B (LAB) was used to explore its mechanisms underlying MMP-9 expression of HepG(2) cells. The results showed that the LAB suppressed PMA-induced MMP-9 activity in a dose-dependent transcriptional level. The suppression of PMA-induced MMP-9 expression of HepG(2) cells by LAB was through inactivating phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The treatment of mitogen-activated protein kinase kinase (MEK) inhibitors (PD98059 and U0126) and LAB to HepG(2) cells could result in a synergistic reduction on the MMP-9 expression along with an inhibition on cell invasion. Moreover, LAB also strongly inhibited PMA-stimulated nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA-binding activities of HepG(2) cells in dose-dependent manners. A dose-dependent inhibition on protein levels of NF-kappaB, c-Jun and c-Fos in nuclear by LAB treatment was further observed. In conclusion, we demonstrated that the anti-invasive effects of the LAB on the PMA-induced HepG(2) cells might be through inhibiting the phosphorylation of ERK1/2 and reducing AP-1 and NF-kappaB DNA-binding activities, leading to downregulation of MMP-9 expression.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia , Fator de Transcrição AP-1/metabolismo , Triterpenos/farmacologia , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/enzimologia , Invasividade NeoplásicaRESUMO
From several decades ago to now, cancer continues to be the leading cause of death worldwide, and metastasis is the major cause of cancer-related deaths. For health benefits, there is a great desire to use non-chemical therapy such as nutraceutical supplementation to prevent pathology development. Over 10,000 different natural bioactives or phytochemicals have been known that possessing potential preventive or supplementary effects for various diseases including cancer. Previously, the in vitro and in vivo anti-invasive and anti-metastatic activities of phenolic acids, monophenol, polyphenol and their derivatives and flavonoids and their derivatives have been reviewed. However, a vast number of natural dietary compounds other than phenolics have been demonstrated to potentially possess the ability to inhibit the invasion and metastasis of various cancers. In this review, we summarize the studies in recent decade on in vitro and in vivo effects and molecular mechanisms of natural bioactives, excluding the phenolics in food, in cancer invasion and metastasis. By combining this review of non-phenolics with the previous phenolics reviews, the puzzle for the contribution of natural dietary bioactives on cancer invasive or/and metastatic progress will be almost complete and more clear.
Assuntos
Suplementos Nutricionais/análise , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/administração & dosagem , Animais , Humanos , Metástase Neoplásica , Neoplasias/patologiaRESUMO
Ganoderma lucidum is a well-known mushroom with various pharmacological effects that has been used for health and longevity purposes. The objective of this study was to investigate the anti-invasive effect of lucidenic acids isolated from a new G. lucidum strain (YK-02) against human hepatoma carcinoma (HepG(2)) cells. Triterpenoid components in the ethanol extract of G. lucidum (YK-02) were separated by means of a semi-preparative RP HPLC. Four major peaks were separated and crystallized from triterpenoids fraction, and were identified as lucidenic acids A, B, C, and N according to their spectroscopic values of (1)H NMR and MS. Treatment of the lucidenic acids (50 microM) in the presence of 200 nM phorbol 12-myristate 13-acetate (PMA) after 24 h of incubation all resulted in significant inhibitory effects on PMA-induced MMP-9 activity and invasion of HepG(2 )cells. The results indicate that the lucidenic acids isolated from G. lucidum (YK-02) are anti-invasive bioactive components on hepatoma cells.
Assuntos
Ácidos Cólicos/administração & dosagem , Ácidos Cólicos/isolamento & purificação , Ganoderma/química , Invasividade Neoplásica/prevenção & controle , Terpenos/administração & dosagem , Terpenos/isolamento & purificação , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Humanos , Neoplasias Hepáticas , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz , Terpenos/química , Acetato de Tetradecanoilforbol/farmacologia , Triterpenos/administração & dosagem , Triterpenos/isolamento & purificaçãoRESUMO
Allergic airway disorder is characterized by an increase in the level of reactive oxygen species (ROS). The induction of inflammation and hyperresponsiveness by an allergen was ameliorated by antioxidants in vivo. This study investigated the protective effects and underlying mechanism of diallyl sulfide (DAS) on ovalbumin (OVA)-induced allergic asthma of BALB/c mice. The animals were intraperitoneally sensitized by inhaling OVA to induce chronic airway inflammation. By administering DAS, a decrease of the infiltrated inflammatory cell counts and the levels of IL-4 and IL-10 in bronchoalveolar lavage fluid as well as the OVA-specific immunoglobulin E levels in sera were observed. DAS also effectively inhibited OVA-induced inflammatory cell infiltration and mucus hypersecretion in lung tissue. Several OVA-induced inflammatory factors (ROS, 8-hydroxy-2'-deoxyguanosine, 8-iso-prostaglandin F2α, and NF-κB) were inhibited by DAS. In addition, DAS increased OVA inhalation-reduced levels of Nrf2 activation by regulating microRNA-144, -34a and -34b/c. Together, the pathogenesis of OVA-induced asthma is highly associated with oxidative stress, and DAS may be an effective supplement to alleviate this disease.
Assuntos
Antiasmáticos/administração & dosagem , Asma/prevenção & controle , Pulmão/imunologia , MicroRNAs/imunologia , Fator 2 Relacionado a NF-E2/genética , Sulfetos/administração & dosagem , Animais , Asma/induzido quimicamente , Asma/genética , Asma/imunologia , Feminino , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/imunologia , Ovalbumina/efeitos adversosRESUMO
SCOPE: Oxidative stress-aggravated chronic inflammatory diseases of the airway are well documented; hence, treatment with antioxidants to ameliorate oxidative stress might be an effective strategy to reduce airway complications. The aim of this study was to investigate the effect and molecular mechanism of diallyl sulfide (DAS), which is a natural organosulfuric compound found in garlic, on the inhibition of tumor necrosis factor-alpha (TNF-α)- or histamine-induced inflammation in rat aortic smooth muscle A7r5 cells. METHODS AND RESULTS: A7r5 cells were coincubated with DAS before exposure to TNF-α or histamine. DAS significantly blocked the accumulation of the nuclear p65 protein in TNF-α-induced A7r5 cells by attenuating the TNF-α receptor complex through the dissociation of the TNF receptor-associated death domain and TNF receptor-associated factor 2. Moreover, DAS inhibited histamine-induced inflammation by decreasing reactive oxygen species (ROS) levels by enhancing the nuclear factor-erythroid 2-related factor 2-related antioxidative enzyme. DAS also inhibited inflammation by suppressing interleukin-1ß and TNF-α through the inhibition of ROS-induced PI3K/Akt and the downstream NF-κB and activator protein-1. CONCLUSION: Our results demonstrate that DAS is a potential phytochemical to inhibit TNF-α- and histamine-induced inflammation, suggesting that DAS might be an effective dietary agent for the prevention of oxidative stress-induced inflammation of the airway.
Assuntos
Compostos Alílicos/farmacologia , Histamina/efeitos adversos , Inflamação/prevenção & controle , Sulfetos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Antioxidantes/farmacologia , Linhagem Celular , Alho/química , Inflamação/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Miócitos de Músculo Liso , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Compostos Fitoquímicos/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína de Domínio de Morte Associada a Receptor de TNF/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Dietary polyphenols have been reported as an effective phytochemical for health protection and cinnamic acid (CA) is one of the polyphenols that has been demonstrated having chemopreventive potential. It was known that the early and distal metastasis might lead to the high mortality of patients with lung adenocarcinoma. We previously compared and verified the inhibitory effect of cis-CA and trans-CA on phorbol-12-myristate-13-acetate (PMA)-induced invasion of human lung adenocarcinoma A549 cells. The aim of this study was to explore the underlying molecular mechanism. By gelatin zymography and semi-quantitative RT-PCR, the activities and mRNA of MMP-9/MMP-2 exerted a significantly (p<.05) dose-dependent reduction by treating with cis-CA and trans-CA. Western blots further showed that the cis-CA- and trans-CA-inhibited MMPs might partly through modulating TIMP-1 and the PAI-2-regulated uPA activity. In molecular level, the AP-1 and NF-κB as well as the downstream of the MAPK pathway might be involved in cis-CA- and trans-CA-inhibited MMPs expression. This study disclosed the molecular mechanism underlying the anti-invasive activity of cis-CA and trans-CA and concluded the cis- and trans-form of CA should be a safe and potential agent to prevent lung tumor cells from metastasizing.