RESUMO
PURPOSE: Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells. METHODS: Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2. RESULTS: Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells. CONCLUSION: Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.
Assuntos
Curcumina , Glicoproteínas , Neoplasias Pancreáticas , Humanos , Curcumina/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Mensageiro , Proliferação de CélulasRESUMO
Heat shock-related 70-kDa protein 2 (HSPA2) is known to correlate with tumor development and progression. This work aimed to determine the expression and prognostic roles of HSPA2 in pancreatic carcinoma. Tumor and their corresponding non-tumor tissues were obtained from 80 patients with pancreatic carcinoma. HSPA2 expression in tumor and non-tumor tissues was evaluated by immunohistochemistry. Expression of vascular endothelial growth factor (VEGF) and CD31 in tumor tissues were also evaluated by immunostaining. The relationships of HSPA2 with clinicopathological data, tumor angiogenesis and prognosis were analyzed. The results showed that HSPA2 expression was significantly elevated in tumor tissues compared with adjacent non-tumor tissues (P < 0.05). High HSPA2 expression was significantly associated with aggressive clinicopathological characteristics. HSPA2 staining was positively correlated with VEGF (r = 0.466, P < 0.001) and microvessel density (MVD) (r = 0.366, P = 0.001) in tumor tissues. Patients with high HSPA2 expression showed worse relapse-free survival (RFS) (P < 0.001) and overall survival (OS) (P < 0.001) than those with low HSPA2 expression. Multivariate analysis indicated that high HSPA2 expression was an independent predictor for poor RFS (P < 0.001) and OS (P = 0.001). Taken together, overexpressed HSPA2 is correlated with tumor angiogenesis and poor prognosis in pancreatic carcinoma. HSPA2 may play an important role in tumor progression, and serve as a potential biomarker for the prediction of adverse prognosis in pancreatic carcinoma.
Assuntos
Proteínas de Choque Térmico HSP70/biossíntese , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Biomarcadores Tumorais , Capilares/patologia , Intervalo Livre de Doença , Feminino , Proteínas de Choque Térmico HSP70/genética , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/complicações , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Prognóstico , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Neoplasias PancreáticasRESUMO
PURPOSE: To evaluate the effect of Honokiol (HK) in the ROS-JNK pro-apoptotic pathway and NF-κB, Nrf2 anti-apoptotic pathways, in order to seek a possible explanation for its anticancer efficacy. METHODS: The Raji and Molt4 cell lines were utilized for the determination of anticancer activity against lymphoid malignant cells. BALB/C nude mice, weighing 18-20g each and aged 4-5 weeks, were procured from the central animal house facility. For establishing non-Hodgkin lymphoma in BALB/C, the nude mice were subcutaneously administered 1×10(7) Raji cells, suspended in 0.2 mL sterile PBS on the back. The mice were then randomly divided into 3 groups (6 mice in each group). HK cytotoxicity was determined using the colorimetric MTT assay. RESULTS: In colorimetry-based MTT assay, the cytotoxicity of HK was determined at different time intervals, in lymphoid malignant Raji and Molt4 cell lines. HK exhibited prominent cytotoxicity against Raji cell lines with IC50 of 0.092 ± 0.021 µM. In Molt4 cells, the administration of HK caused significant cytotoxicity with IC50 of 0.521 ± 0.115 µM. The treatment of HK caused significant increase in the activity of reactive oxygen species (ROS) in Raji cells at various time intervals. Moreover, the level of NF-κB was significantly reduced in the presence of HK, which could be easily understood by a decreased level of p-65. Furthermore, in the presence of ROS inhibitor NAC (10mM) for 24 hrs, the JNK pathway was markedly activated, together with inhibition of NF-κB activity and a reduced level of Nrf2 expression. To further confirm the in vitro results by in vivo activity, HK was observed to inhibit the proliferation of Raji cells in vivo, which might be attributable to its inhibitory effect against the progression of the tumor (p<0.05). CONCLUSION: The present study suggests that HK causes considerable induction of apoptosis in lymphoid malignant cells, both in vitro and in vivo, whereas the generation of ROS might serve as an underlying mechanism for inducing apoptosis.
Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Linfoma/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , NF-kappa B/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Linfoma/metabolismo , Linfoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Heat shock protein A2 has been reported to be tightly associated with tumorigenesis and tumor progression. This study aimed to determine the oncogenic and immunological roles of Heat shock protein A2 in pancreatic cancer by bioinformatics. METHODS: Expression of Heat shock protein A2 in tumorous and normal specimens of pancreatic cancer was analyzed using the Cancer Genome Atlas and the Cancer Genome Atlas + Genotype-Tissue Expression data sets, respectively. Relationships of Heat shock protein A2 expression with immune infiltrates in pancreatic cancer were assessed. Heat shock protein A2-associated coexpressed genes in pancreatic cancer were obtained, followed by the implementation of enrichment analysis. RESULTS: The data demonstrated that Heat shock protein A2 was significantly overexpressed in tumorous samples compared with normal samples. Heat shock protein A2 expression was remarkably positively interrelated with CD8+ T cell, neutrophil, dendritic cell, and macrophage, but not with CD4+ T and B cells. Heat shock protein A2 expression was markedly positively relevant to both cancer-associated fibroblast and endothelial cell. Enrichment data revealed that Heat shock protein A2 was intimately involved in the tumorigenesis and progression of pancreatic cancer. CONCLUSION: Heat shock protein A2 is upregulated in pancreatic cancer and is closely associated with tumor immunity and aggressive progression.
Assuntos
Proteínas de Choque Térmico HSP70 , Neoplasias Pancreáticas , Carcinogênese/genética , Biologia Computacional , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/imunologia , Humanos , Neoplasias Pancreáticas/genética , Neoplasias PancreáticasRESUMO
BACKGROUND: Heat shock protein A2 (HSPA2) is known to relate to the pathogenesis and progress of cancer. This study aimed to investigate the connection between HSPA2 and early postsurgical relapse of pancreatic cancer (PC). METHODS: Expression of HSPA2 in 85 pairs of cancerous and matched noncancerous samples was determined by immunostaining method. The relationship between HSPA2 expression and early postsurgical recurrence was assessed using logistic regression. The performance and potential application of HSPA2 expression to predict early postsurgical recurrence was evaluated by receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). RESULTS: HSPA2 expression in tumor specimens was markedly elevated compared with non-tumor specimens. Logistic regression analysis indicated that HSPA2 upregulation was an independent risk marker for early postsurgical recurrence of PC. ROC curve analysis and DCA demonstrated that both the area under the curve (AUC) and the net benefit of HSPA2 expression were higher than those of other clinicopathologic features in predicting early postsurgical relapse of PC. The combination of HSPA2 expression with other malignant clinicopathologic characteristics had greater AUC and net benefit relative to them alone in predicting early postsurgical recurrence. CONCLUSIONS: Upregulated HSPA2 independently predicts early postsurgical recurrence of PC and has superior predictive performance and potential application value when combined with malignant clinicopathologic features. Our findings reveal that HSPA2 is a promising predictor for early postoperative relapse of PC.
RESUMO
BACKGROUND: Severe acute pancreatitis (SAP) features fatal pathogenetic conditions and high mortality rate. The study of SAP complicated with multiple organ injuries is of important significance. In this study, we explored the protective effect of baicalin on multiple organs of SAP rats and compared it with that of octreotide through light and electron microscopic observations of the pathological changes. METHODS: The improved Aho method was used to prepare SAP rat models. These rats were then randomly divided into a sham-operated group (n=45), a model control group (n=45), baicalin-treated group (n=45) and octreotide-treated group (n=45). Based on the difference in time points after operation, these groups were subdivided into 3, 6 and 12 hour subgroups (n=15). At the corresponding time point after operation, the mortality rate of rats was recorded, and then the rats were humanely killed to take samples of multiple organs that were subsequently examined for pathological changes under light and electron microscopy. RESULTS: At 12 hours after operation, the mortality rate of rats in the baicalin- and octreotide-treated groups was lower than that in the model control group (P<0.05). Compared to the model control group, the pathological changes and pathological scores in the baicalin- and octreotide-treated groups were mitigated and relieved to varying degrees. The pathological changes under electron microscopy were also improved. CONCLUSIONS: Both baicalin and octreotide show good protective effects on multiple organs of SAP rats. Baicalin as a new drug has good prospects in the treatment of SAP.
Assuntos
Flavonoides/farmacologia , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/patologia , Octreotida/farmacologia , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Doença Aguda , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Fármacos Gastrointestinais/farmacologia , Mucosa Intestinal/patologia , Rim/patologia , Fígado/patologia , Pulmão/patologia , Linfonodos/patologia , Masculino , Medicina Tradicional Chinesa/métodos , Insuficiência de Múltiplos Órgãos/mortalidade , Pâncreas/patologia , Pancreatite/mortalidade , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Baço/patologiaRESUMO
AIM: To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP). METHODS: The SAP rats were assigned to model, treated or sham-operated groups. The mortality, pathological changes of mesenteric lymph nodes, expression levels of NF-kappa B, P-selectin, Bax, Bcl-2 and caspase-3 protein and changes in apoptotic indexes in lymph nodes were observed at 3, 6 and 12 h after operation. The blood levels of endotoxin, superoxide dismutase (SOD), malondialdehyde (MDA), and endothelin-1 (ET-1) in blood were determined. RESULTS: SOD content, expression of Bax protein and apoptotic index were significantly higher in the treated group than in the model group at different time points (P < 0.05 or P < 0.01). Other blood-detecting indexes and histopathological scores of mesenteric lymph nodes were lower in the treated than in the model group (P < 0.05, P < 0.01 or P < 0.01). NF-kappa B protein expression was negative in all groups. Comparing P-selectin and caspase-3 expression levels among all three groups, there was no marked difference between the model and treated group. CONCLUSION: Dexamethasone can protect mesenteric lymph nodes. The mechanism may be by reducing the content of inflammatory mediators in the blood and inducing lymphocyte apoptosis.
Assuntos
Anti-Inflamatórios/farmacologia , Dexametasona/farmacologia , Linfonodos/efeitos dos fármacos , Mesentério/efeitos dos fármacos , Pancreatite/metabolismo , Pancreatite/patologia , Doença Aguda , Animais , Apoptose , Caspase 3/metabolismo , Modelos Animais de Doenças , Endotelina-1/sangue , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Malondialdeído/sangue , Mesentério/metabolismo , Mesentério/patologia , NF-kappa B/metabolismo , Selectina-P/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Superóxido Dismutase/sangue , Proteína X Associada a bcl-2/metabolismoRESUMO
AIM: To investigate the protective effects and mechanisms of baicalin and octreotide on hepatic injury in rats with severe acute pancreatitis (SAP). METHODS: The SAP rat models were prepared and randomly assigned to the model control group, baicalin treated group, and octreotide treated group while other healthy rats were assigned to the sham-operated group. Rat mortality, levels of ALT, AST, liver and pancreas pathological changes in all groups were observed at 3, 6 and 12 h after operation. Tissue microarray (TMA) sections of hepatic tissue were prepared to observe expression levels of Bax, Bcl-2 protein and caspase-3, and changes of apoptotic indexes. RESULTS: Rat survival at 12 h, expression levels of Bax, caspase-3 protein and apoptotic indexes of liver were all significantly higher in treated groups than in model control group. While the liver and pancreas pathological scores, contents of ALT, AST, and expression levels of Bcl-2 protein were all lower in treated groups than in the model control group. CONCLUSION: Both baicalin and octreotide can protect rats with SAP by decreasing the contents of ALT, AST and expression levels of Bcl-2 protein, and improving the expression levels of Bax protein, caspase-3 protein, and inducing apoptosis.
Assuntos
Flavonoides/farmacologia , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Octreotida/farmacologia , Pancreatite/tratamento farmacológico , Substâncias Protetoras/farmacologia , Doença Aguda , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Caspase 3/metabolismo , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Pancreatite/complicações , Pancreatite/metabolismo , Pancreatite/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Ácido Taurocólico , Fatores de Tempo , Análise Serial de Tecidos , Proteína X Associada a bcl-2/metabolismoRESUMO
SUMMARY OBJECTIVE: Heat shock protein A2 has been reported to be tightly associated with tumorigenesis and tumor progression. This study aimed to determine the oncogenic and immunological roles of Heat shock protein A2 in pancreatic cancer by bioinformatics. METHODS: Expression of Heat shock protein A2 in tumorous and normal specimens of pancreatic cancer was analyzed using the Cancer Genome Atlas and the Cancer Genome Atlas + Genotype-Tissue Expression data sets, respectively. Relationships of Heat shock protein A2 expression with immune infiltrates in pancreatic cancer were assessed. Heat shock protein A2-associated coexpressed genes in pancreatic cancer were obtained, followed by the implementation of enrichment analysis. RESULTS: The data demonstrated that Heat shock protein A2 was significantly overexpressed in tumorous samples compared with normal samples. Heat shock protein A2 expression was remarkably positively interrelated with CD8+ T cell, neutrophil, dendritic cell, and macrophage, but not with CD4+ T and B cells. Heat shock protein A2 expression was markedly positively relevant to both cancer-associated fibroblast and endothelial cell. Enrichment data revealed that Heat shock protein A2 was intimately involved in the tumorigenesis and progression of pancreatic cancer. CONCLUSION: Heat shock protein A2 is upregulated in pancreatic cancer and is closely associated with tumor immunity and aggressive progression.