RESUMO
OBJECTIVES: This retrospective cohort study investigated the association of socioeconomic status with survival outcomes among patients with nasopharyngeal carcinoma in an endemic area of China. METHODS: The primary endpoint was overall survival. Survival outcomes were estimated by the Kaplan-Meier method and compared by the log-rank test, and the multivariate Cox proportional hazards model was used to estimate hazard ratios, 95% CIs, and independent prognostic factors. RESULTS: A total of 11 069 adult patients with NPC were enrolled and included in the analysis. Kaplan-Meier survival analysis revealed that overall survival was significantly different among socioeconomic status. Compared with high socioeconomic status patients, low socioeconomic status patients (HR, 1.190; 95% CI, 1.063-1.333) and medium socioeconomic status patients (HR, 1.111; 95% CI, 1.006-1.226) were associated with increased hazard ratio (HR) of overall survival. CONCLUSION: This analysis highlights patients with nasopharyngeal carcinoma who had high socioeconomic status had better overall survival compared with those who had low and medium socioeconomic status.
Assuntos
Neoplasias Nasofaríngeas , Adulto , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Estudos Retrospectivos , Disparidades Socioeconômicas em Saúde , Modelos de Riscos Proporcionais , PrognósticoRESUMO
Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.
Assuntos
Neoplasias Nasofaríngeas , Animais , Camundongos , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Camundongos Nus , Linhagem Celular Tumoral , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Luciferases , Movimento Celular , Invasividade Neoplásica , Metástase NeoplásicaRESUMO
This study aimed to parallelly investigate the cardioprotective activity of Cinnamomi Ramulus formula granules(CRFG) and Cinnamomi Cortex formula granules(CCFG) against acute myocardial ischemia/reperfusion injury(MI/RI) and the underlying mechanism based on the efficacy of "warming and coordinating the heart Yang". Ninety male SD rats were randomly divided into a sham group, a model group, CRFG low and high-dose(0.5 and 1.0 g·kg~(-1)) groups, and CCFG low and high-dose(0.5 and 1.0 g·kg~(-1)) groups, with 15 rats in each group. The sham group and the model group were given equal volumes of normal saline by gavage. Before modeling, the drug was given by gavage once a day for 7 consecutive days. One hour after the last administration, the MI/RI rat model was established by ligating the left anterior descending artery(LAD) for 30 min ischemia followed by 2 h reperfusion except the sham group. The sham group underwent the same procedures without LAD ligation. Heart function, cardiac infarct size, cardiac patho-logy, cardiomyocyte apoptosis, cardiac injury enzymes, and inflammatory cytokines were determined to assess the protective effects of CRFG and CCFG against MI/RI. The gene expression levels of nucleotide-binding oligomerization domain-like receptor family pyrin domain protein 3(NLRP3) inflammasome, apoptosis-associated speck-like protein containing a CARD(ASC), cysteinyl aspartate specific proteinase-1(caspase-1), Gasdermin-D(GSDMD), interleukin-1ß(IL-1ß), and interleukin-18(IL-18) were determined by real-time quantitative polymerase chain reaction(RT-PCR). The protein expression levels of NLRP3, caspase-1, GSDMD, and N-GSDMD were determined by Western blot. The results showed that both CRFG and CCFG pretreatments significantly improved cardiac function, decreased the cardiac infarct size, inhibited cardiomyocyte apoptosis, and reduced the content of lactic dehydrogenase(LDH), creatine kinase MB isoenzyme(CK-MB), aspartate transaminase(AST), and cardiac troponin â (cTnâ ). In addition, CRFG and CCFG pretreatments significantly decreased the levels of IL-1ß, IL-6, and tumor necrosis factor-α(TNF-α) in serum. RT-PCR results showed that CRFG and CCFG pretreatment down-regulated the mRNA expression levels of NLRP3, caspase-1, ASC, and downstream pyroptosis-related effector substances including GSDMD, IL-18, and IL-1ß in cardiac tissues. Western blot revealed that CRFG and CCFG pretreatments significantly decreased the protein expression levels of NLRP3, caspase-1, GSDMD, and N-GSDMD in cardiac tissues. In conclusion, CRFG and CCFG pretreatments have obvious cardioprotective effects on MI/RI in rats, and the under-lying mechanism may be related to the inhibition of NLRP3/caspase-1/GSDMD signaling pathway to reduce the cardiac inflammatory response.
Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Masculino , Animais , Ratos , Ratos Sprague-Dawley , Interleucina-18 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fator de Necrose Tumoral alfa , Caspase 1RESUMO
The aldo-keto reductases family 1 member C2 (AKR1C2) has critical roles in the tumorigenesis and progression of malignant tumours. However, it was also discovered to have ambiguous functions in multiple cancers and till present, its clinical significance and molecular mechanism in oesophageal squamous cell carcinoma (ESCC) has been unclear. The aim of this study was to explore the role of AKR1C2 in the tumorigenesis of ESCC. Here, we showed that AKR1C2 expression was found to be up-regulated in ESCC tissues and was significantly associated with pathological stage, lymph node metastasis and worse outcomes. Functional assays demonstrated that an ectopic expression of AKR1C2 in ESCC cells resulted in increased proliferation, migration and cisplatin resistance, while knockdown led to inversing effects. Bioinformation analyses and mechanistic studies demonstrated that AKR1C2 activated the PI3K/AKT signalling pathway, furthermore, the inhibitor of PI3K or the selective inhibitor of AKR1C2 enzyme activity could reverse the aggressiveness and showed synergistic antitumour effect when combined with cisplatin, both in vitro and in vivo. In conclusion, Our findings revealed that AKR1C2 could function as an oncogene by activating the PI3K/AKT pathway, as a novel prognostic biomarker and/or as a potential therapeutic target to ESCC.
Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Hidroxiesteroide Desidrogenases/genética , Oncogenes/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Linfática/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Regulação para Cima/genéticaRESUMO
Nasopharyngeal carcinoma (NPC) is relatively sensitive to ionizing radiation, and radiotherapy is the main treatment modality for non-metastatic NPC. Radiation therapy generates overproduction of reactive oxygen species (ROS), which can cause DNA damage and induce apoptosis in tumors, thereby killing the malignant cells. Although dietary antioxidant supplementation reduces oxidative stress and promotes tumor progression, the effects of antioxidants on the NPC cells upon radiation have not been reported. In the present study, we showed that antioxidants (ß-Carotene, NAC, GSH) played an anti-apoptotic role in response to radiation via decreasing ROS production and inhibiting MAPK pathway in NPC cells. Based on that, we conclude that the use of supplemental antioxidants during radiotherapy should be avoided because of the possibility of tumor protection and reduced treatment efficacy.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Linhagem Celular Tumoral , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
We aimed to determine the prognostic values of 39 circulating cytokines in Chinese patients with metastatic colorectal cancer (CRC) and to develop a novel cytokine-based prognostic classifier (CBPC) for prognostic prediction. A total of 176 patients were divided into two cohorts based on the date of first-line chemotherapy. The first 99 cases were assigned to the training cohort, and the remaining 77 cases were assigned to the validation cohort. Thirty-nine cytokines were simultaneously analyzed in the patient serum samples using multiplex bead-based Luminex technology. We used support vector machine-based methods and Cox proportional hazards models to develop a CBPC from the training cohort, which we then validated using the second patient cohort. Univariate analysis showed that FGF-2, TGFα, Flt-3L, GM-CSF, INFα2, GRO, IL-10, MCP-3, MDC, sIL-2Rα, IL-2, IL-7, IL-8, MCP-1, MIP-1ß, TNFα and VEGF were significant risk factors affecting the overall survival (OS) of both the training cohort and the validation cohort. We developed a CBPC to predict the OS of metastatic CRC patients using these 17 cytokines (sensitivity, 0.835; specificity, 0.800). In the validation cohort, the CBPC was found to have significant power in predicting the OS of metastatic CRC patients. Our study showed that there were significant associations between cytokine expression and prognosis of the patients with metastatic CRC. The CBPC that we developed includes multiple circulating cytokines and may serve as a novel screening tool for identifying metastatic CRC patients with a high risk of short OS. These high-risk individuals may also be suitable for cytokine-targeted therapies.
Assuntos
Neoplasias Colorretais/mortalidade , Citocinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Nasopharyngeal carcinoma (NPC) originates in the epithelial cells of the nasopharynx and is a common malignant tumor in southern China and Southeast Asia. Metastasis of NPC remains the main cause of death for NPC patients even though the tumor is sensitive to radiotherapy and chemotherapy. Here, we found that the transmembrane protein tetraspanin1 (TSPAN1) potently inhibited the in vitro migration and invasion, as well as, the in vivo metastasis of NPC cells via interacting with the IKBB protein. In addition, TSPAN1 was essential in preventing the overactivation of the NF-kB pathway in TSPAN1 overexpressing NPC cells. Furthermore, reduced TSPAN1 expression was associated with NPC metastasis and the poor prognosis of NPC patients. These results uncovered the suppressive role of TSPAN1 against NF-kB signaling in NPC cells for preventing NPC metastasis. Its therapeutic value warrants further investigation.
Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Tetraspaninas/genética , Tetraspaninas/metabolismoRESUMO
BACKGROUND: Epstein-Barr virus (EBV) is an etiological cause of many human lymphocytic and epithelial malignancies. EBV expresses different genes that are associated with three latency types. To date, as many as 44 EBV-encoded miRNA species have been found, but their comprehensive profiles in the three types of latent infection that are associated with various types of tumors are not well documented. METHODS: In the present study, we utilized poly (A)-tailed quantitative real-time RT-PCR in combination with microarray analysis to measure the relative abundances of viral miRNA species in a subset of representative lymphoid and epithelial tumor cells with various EBV latency types. RESULTS: Our findings showed that the miR-BHRF1 and miR-BART families were expressed differentially in a tissue- and latency type-dependent manner. Specifically, in nasopharyngeal carcinoma (NPC) tissues and the EBV-positive cell line C666-1, the miR-BART family accounted for more than 10% of all detected miRNAs, suggesting that these miRNAs have important roles in maintaining latent EBV infections and in driving NPC tumorigenesis. In addition, EBV miRNA-based clustering analysis clearly distinguished between the three distinct EBV latency types, and our results suggested that a switch from type I to type III latency might occur in the Daudi BL cell line. CONCLUSIONS: Our data provide a comprehensive profiling of the EBV miRNA transcriptome that is associated with specific tumor cells in the three types of latent EBV infection states. EBV miRNA species represent a cluster of non-encoding latency biomarkers that are differentially expressed in tumor cells and may help to distinguish between the different latency types.
Assuntos
Perfilação da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiologia , MicroRNAs/genética , RNA Viral/genética , Latência Viral , Biópsia , Células Cultivadas , Humanos , Leucemia Linfoide/virologia , MicroRNAs/biossíntese , Análise em Microsséries , Neoplasias Epiteliais e Glandulares/virologia , RNA Viral/biossíntese , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in China. However, there are no targets to treat ESCC because the molecular mechanism behind the cancer is still unclear. Here, we found a novel long noncoding RNA LINC02820 was upregulated in ESCC and associated with the ESCC clinicopathological stage. Through a series of functional experiments, we observed that LINC02820 only promoted the migration and invasion capabilities of ESCC cell lines. Mechanically, we found that LINC02820 may affect the cytoskeletal remodeling, interact with splice factor 3B subunit 3 (SF3B3), and cooperate with TNFα to amplify the NF-κB signaling pathway, which can lead to ESCC metastasis. Overall, our findings revealed that LINC02820 is a potential biomarker and therapeutic target for the diagnosis and treatment of ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , RNA Longo não Codificante , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Citoesqueleto/genética , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly lethal tumor type, but studies on the ESCC tumor microenvironment are limited. We found that cystatin SN (CST1) plays an important role in the ESCC tumor microenvironment. CST1 has been reported to act as an oncogene in multiple human cancers, but its clinical significance and underlying mechanism in ESCC remain elusive. METHODS: We performed ESCC gene expression profiling with data from RNA-sequencing and public databases and found CST1 upregulation in ESCC. Then, we assessed CST1 expression in ESCC by RTâqPCR and Western blot analysis. In addition, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were used to estimate the expression of CST1 in ESCC tissue and serum. Moreover, further functional experiments were conducted to verify that the gain and loss of CST1 in ESCC cell lines significantly influenced the proliferation and metastasis of ESCC. Mass spectrometry, coimmunoprecipitation, and gelatin zymography experiments were used to validate the interaction between CST1 and matrix metalloproteinase 2 (MMP2) and the mechanism of CST1 influence on metastasis in ESCC. RESULTS: Here, we found that CST1 expression was significantly elevated in ESCC tissues and serum. Moreover, compared with patients with low CST1 expression, patients with high CST1 expression had a worse prognosis. Overall survival (OS) and disease-free survival (DFS) were significantly unfavorable in the high CST1 expression subgroup. Likewise, the CST1 level was significantly increased in ESCC serum compared with healthy control serum, indicating that CST1 may be a potential serum biomarker for diagnosis, with an area under the curve (AUC) = 0.9702 and p < 0.0001 by receiver operating curve (ROC) analysis. Furthermore, upregulated CST1 can promote the motility and metastatic capacity of ESCC in vitro and in vivo by influencing epithelial mesenchymal transition (EMT) and interacting with MMP2 in the tumor microenvironment (TME). CONCLUSIONS: Collectively, the results of this study indicated that high CST1 expression mediated by SPI1 in ESCC may serve as a potentially prognostic and diagnostic predictor and as an oncogene to promote motility and metastatic capacity of ESCC by influencing EMT and interacting with MMP2 in the TME.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação para Cima , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Transição Epitelial-Mesenquimal , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Metastasis is one of the main obstacles impeding the survival of nasopharyngeal carcinoma (NPC) patients, with the molecular mechanism underlying NPC metastasis still unclear. RESULTS: In this study, Cystatin A (CSTA) was found downregulated in NPC tissues with metastasis compared with those without metastasis. Shorter overall survival and distant metastasis-free survival were found in NPC patients with lower CSTA expression. Using functional assays, we found that CSTA prevented both the in vitro motility of NPC cells and their ability to metastasize in vivo. Transcriptome sequencing and western blot analysis revealed that CSTA inhibited the phosphorylation of AKT. Moreover, activating AKT using AKT agonist SG79 rescued the motility of CSTA-overexpressing NPC cells, whereas, treatment with AKT inhibitor MK2206 inhibited the motility of CSTA-knockdown NPC cells. Mechanically, immunoprecipitation coupled mass spectrometry found that CSTA interacted with the N6-adenosine-methyltransferase subunit METTL3 and promoted its ubiquitin-proteasome-mediated degradation following the upregulation of NKX3-1 and LHPP, which are negative regulators of AKT. Furthermore, knock-down of NKX3-1 and LHPP enhanced the motility of CSTA-overexpressing NPC cells. CONCLUSIONS: The inhibitory effect of CSTA upon NPC metastasis mainly depended on suppressing AKT signaling by the upregulation of NKX3-1 and LHPP expression resulting from the binding between CSTA and METLL3. Our study suggests that the CSTA-METLL3-NKX3-1/LHPP-AKT axis could be of therapeutic value for inhibiting NPC metastasis.
Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma/patologia , Cistatina A , Transição Epitelial-Mesenquimal , Metiltransferases , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Nasopharyngeal carcinoma (NPC) has the highest metastatic potential among head and neck cancers. Distant metastasis is the major cause of treatment failure. The role of interleukin-8 (IL-8) in NPC progression remains unknown. Our multivariate survival analyses of 255 patients with NPC revealed that higher IL-8 expression in primary NPC tissue was an independent prognostic factor for overall survival, disease-free survival, and distant metastasis-free survival of the patients. In vitro study revealed that IL-8 was highly expressed in the established high-metastasis NPC clone S18 relative to the low-metastasis cells. Suppression of IL-8 by short-hairpin RNA reduced the expression of IL-8 in S18 cells and subsequently inhibited migration, invasion, and hepatic metastasis of the cells without influencing cellular growth. Overexpression of IL-8 in S26 cells resulted in increased migration, invasion, and metastasis capabilities of the cells without affecting cellular growth. Exogenous IL-8 enhanced the migration and invasion of low-metastasis CNE-2 cells in a dose-dependent manner. An epithelial-mesenchymal transition (EMT) could be induced by IL-8 in various NPC cell lines. The high level of phosphorylated AKT in S18 cells could be suppressed by knocking down IL-8 expression. Further, IL-8-promoted migration and invasion could be abolished by either the application of the phosphoinositide-3-kinase inhibitor LY294002 or the knock down of AKT expression by using small-interfering RNA. In summary, IL-8 serves as an independent prognostic indicator of overall survival, disease-free survival, and metastasis-free survival for patients with NPC. IL-8 promotes NPC metastasis via autocrine and paracrine means, involving activation of AKT signaling and inducing EMT in NPC cells.
Assuntos
Transição Epitelial-Mesenquimal , Interleucina-8/fisiologia , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sequência de Bases , Primers do DNA , Ativação Enzimática , Ensaio de Imunoadsorção Enzimática , Humanos , Neoplasias Nasofaríngeas/enzimologia , Prognóstico , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor ß. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC). METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib. RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-ß was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-ß, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 µmol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells. CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.
Assuntos
Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Células Endoteliais/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/patologia , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Ultra-high dose rate FLASH irradiation (FLASH-IR) has been shown to cause less normal tissue damage compared with conventional irradiation (CONV-IR), this is known as the "FLASH effect." It has attracted immense research interest because its underlying mechanism is scarcely known. The purpose of this study was to determine whether FLASH-IR and CONV-IR induce differential inflammatory cytokine expression using a modified clinical linac. MATERIALS AND METHODS: An Elekta Synergy linac was used to deliver 6 MeV CONV-IR and modified to deliver FLASH-IR. Female FvB mice were randomly assigned to three different groups: a non-irradiated control, CONV-IR, or FLASH-IR. The FLASH-IR beam was produced by single pulses repeated manually with a 20-s interval (Strategy 1), or single-trigger multiple pulses with a 10 ms interval (Strategy 2). Mice were immobilized in the prone position in a custom-designed applicator with Gafchromic films positioned under the body. The prescribed doses for the mice were 6 to 18 Gy and verified using Gafchromic films. Cytokine expression of three pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukin-6 [IL-6]) and one anti-inflammatory cytokine (IL-10) in serum samples and skin tissue were examined within 1 month post-IR. RESULTS: The modified linac delivered radiation at an intra-pulse dose rate of around 1 × 106 Gy/s and a dose per pulse over 2 Gy at a source-to-surface distance (SSD) of 13 to 15 cm. The achieved dose coverage was 90%-105% of the maximum dose within -20 to 20 mm in the X direction and 95% within -30 to 30 mm in the Y direction. The absolute deviations between the prescribed dose and the actual dose were 2.21%, 6.04%, 2.09%, and 2.73% for 6, 9, 12, and 15 Gy as measured by EBT3 films, respectively; and 4.00%, 4.49%, and 2.30% for 10, 14, and 18 Gy as measured by the EBT XD films, respectively. The reductions in the CONV-IR versus the FLASH-IR group were 4.89%, 10.28%, -7.8%, and -22.17% for TNF-α, IFN-γ, IL-6, and IL-10 in the serum on D6, respectively; 37.26%, 67.16%, 56.68%, and -18.95% in the serum on D31, respectively; and 62.67%, 35.65%, 37.75%, and -12.20% for TNF-α, IFN-γ, IL-6, and IL-10 in the skin tissue, respectively. CONCLUSIONS: Ultra-high dose rate electron FLASH caused lower pro-inflammatory cytokine levels in serum and skin tissue which might mediate differential tissue damage between FLASH-IR and CONV-IR.
Assuntos
Interleucina-10 , Fator de Necrose Tumoral alfa , Animais , Elétrons , Feminino , Interferon gama , Interleucina-6 , CamundongosRESUMO
Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that commonly occurs worldwide. Usually, Asia, especially China, has a high incidence of esophageal cancer. ESCC often has a poor outcome because of a late diagnosis and lack of effective treatments. To build foundations for the early diagnosis and treatment of ESCC, we used the gene expression datasets GSE20347 and GSE17351 from the GEO database and a private dataset to uncover differentially expressed genes (DEGs) and key genes in ESCC. Notably, we found that replication factor C subunit 4 (RFC4) and guanine monophosphate synthase (GMPS) were upregulated but have been rarely studied in ESCC. In particular, to the best of our knowledge, our study is the first to explore GMPS and ESCC. Furthermore, we found that high levels of RFC4 and GMPS expression may result from an increase in DNA copy number alterations. Furthermore, RFC4 and GMPS were both upregulated in the early stage and early nodal metastases of esophageal carcinoma. The expression of RFC4 was strongly correlated with GMPS. In addition, we explored the relationship between RFC4 and GMPS expression and tumor-infiltrating immune cells (TILs) in esophageal carcinoma. The results showed that the levels of RFC4 and GMPS increased with a decrease in some tumor-infiltrating cells. Upregulated RFC4 and GMPS with high TILs indicate a worse prognosis. In summary, our study shows that RFC4 and GMPS have potential as biomarkers for the early diagnosis of ESCC and may played a crucial role in the process of tumor immunity in ESCC.
Assuntos
Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Guanosina Monofosfato/genética , Proteína de Replicação C/genética , Tionucleotídeos/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Conjuntos de Dados como Assunto , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Guanosina Monofosfato/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Proteína de Replicação C/metabolismo , Tionucleotídeos/metabolismo , Regulação para CimaRESUMO
Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium and has the highest metastatic rate among head and neck cancers. Distant metastasis is the main reason for treatment failure with the underlying mechanisms remaining unclear. By comparing the expression profiling of NPCs versus non-cancerous nasopharyngeal tissues, we found LACTB was highly expressed in the tumor tissues. We found that elevated expression of the LACTB protein in primary NPCs correlated with poorer patient survival. LACTB is known to be a serine protease and a ubiquitous mitochondrial protein localized in the intermembrane space. Its role in tumor biology remains controversial. We found that the different methylation pattern of LACTB promoter led to its differential expression in NPC cells. Overexpressing LACTB in NPC cells promoted their motility in vitro and metastasis in vivo. While knocking down LACTB reduced the metastasis capability of NPC cells. However, LACTB did not influence cellular proliferation. We further found the role of LACTB in promoting NPC metastasis depended on the activation of ERBB3/EGFR-ERK signaling, which in turn, affected the stability and the following acetylation of histone H3. These findings may shed light on unveiling the mechanisms of NPC metastasis.
Assuntos
Sistema de Sinalização das MAP Quinases/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Metástase Neoplásica/genética , Receptor ErbB-3/genética , Transdução de Sinais/genética , beta-Lactamases/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Receptores ErbB/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica/patologia , Regiões Promotoras Genéticas/genéticaRESUMO
PURPOSE: Irbesartan is widely used clinically in the treatment of diabetic nephropathy (DN). It is believed that piperazine ferulate (PF) combined with irbesartan could result in an improved efficacy in the treatment of DN. We present the latest meta-analysis that details the combination of PF and irbesartan therapy. METHODS: Before January 31, 2020, we searched various electronic databases for appropriate articles. Our search was not restricted by keyword or language. We then filtered all articles using certain criteria and assessed the quality of the qualified studies. FINDINGS: The meta-analysis included 12 trials that involved 1300 patients (650 in the experimental group and 650 in the control group). The ages of the patients ranged from 30 to 79 years. Compared with irbesartan alone, the total effective rate of PF combined with irbesartan was significantly higher (odds ratio [OR] = 4.95; 95% CI, 3.11-7.58; P < 0.0001). The blood glucose level was controlled by significantly decreasing the fasting plasma glucose level (mean difference [MD] = -1.40; 95% CI, -2.70 to -0.11; P = 0.03) and 2-h plasma glucose level (MD = -1.65; 95% CI, -2.49 to -0.82; P < 0.0001). The combination therapy significantly decreased the levels of serum creatinine (MD = -10.24; 95% CI, -15.25 to -5.23; P < 0.0001), 24-h urinary protein (MD = -0.07; 95% CI, -0.09 to -0.05; P < 0.0001), urinary albumin excretion rate (MD = -22.52; 95% CI, -30.20 to -14.84; P < 0.0001), urinary ß2-microglobulin (MD = -0.15; 95% CI, -0.17 to -0.13; P < 0.0001), and blood urea nitrogen (MD = -1.54; 95% CI, -2.36 to -0.72; P = 0.0002), which was beneficial for improving and protecting renal function. The renal microcirculation was improved by significantly decreasing the whole blood viscosity low shear (MD = -1.41; 95% CI, -1.84 to -0.99; P < 0.0001), whole blood viscosity high shear (MD = -0.54; 95% CI, -0.63 to -0.45; P < 0.0001), whole blood viscosity (MD = -1.31; 95% CI, -1.79 to -0.83; P < 0.0001), whole blood reduction viscosity (MD = -1.42; 95% CI, -1.79 to -1.06; P < 0.0001), platelet aggregation rate (MD = -0.42; 95% CI, -0.50 to -0.35; P < 0.0001), plasma viscosity (MD = -13.02; 95% CI, -15.47 to -10.56; P < 0.0001), and fibrinogen content (MD = -0.25; 95% CI, -0.42 to -0.09; P = 0.003). IMPLICATIONS: PF combined with irbesartan could improve the efficiency in the treatment of DN. However, these results should be handled carefully. These findings should be verified by several rigorous randomized controlled trials.
Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Irbesartana/uso terapêutico , Piperazina/uso terapêutico , Adulto , Idoso , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Humanos , Pessoa de Meia-IdadeRESUMO
Distant metastasis is the major cause of short survival in ccRCC patients. However, the development of effective therapies for metastatic ccRCC is limited. Herein, we reported that ETV4 was selected from among 150 relevant genes with in vivo evidence of promoting metastasis. In this study, we identified that ETV4 promoted ccRCC cell migration and metastasis in vitro and in vivo, and a positive correlation between ETV4 and FOSL1 expression was found in ccRCC tissues and cell lines. Further investigation suggested that ETV4 increase FOSL1 expression through direct binding with the FOSL1 promoter. Furthermore, ETV4/FOSL1 was proved as a novel upstream and downstream causal relationship in ccRCC in an AKT dependent manner. In addition, both ETV4 and FOSL1 serve as an independent, unfavorable ccRCC prognostic indicator, and the accumulation of the ETV4 and FOSL1 in ccRCC patients result in a worse survival outcome in ccRCC patients. Taken together, our results suggest that the ETV4/FOSL1 axis acts as a prognostic biomarker and ETV4 directly up-regulates FOSL1 by binding with its promoter in a PI3K-AKT dependent manner, leading to metastasis and disease progression of ccRCC.
Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-fos/genética , Regulação para Cima , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Medicina de Precisão , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Transdução de Sinais , Análise de SobrevidaRESUMO
OBJECTIVES: Geographical disparities have been identified as a specific barrier to cancer screening and a cause of worse outcomes for patients with cancer. In the present study, our aim was to assess the influence of geographical disparities on the survival outcomes of patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). DESIGN: Cohort study. SETTING: Guangzhou, China. PARTICIPANTS: A total of 1002 adult patients with NPC (724 males and 278 females) who were classified by area of residence (rural or urban) received IMRT from 1 January 2010 to 31 December 2014, at Sun Yat-sen University Cancer Center. Following propensity score matching (PSM), 812 patients remained in the analysis. MAIN OUTCOME MEASURES: We used PSM to reduce the bias of variables associated with treatment effects and outcome prediction. Survival outcomes were estimated using the Kaplan-Meier method and compared by the log-rank test. Multivariate Cox regression was used to identify independent prognostic factors. RESULTS: In the matched cohort, 812 patients remained in the analysis. Kaplan-Meier survival analysis revealed that the rural group was significantly associated with worse overall survival (OS, p<0.001), disease-free survival (DFS, p<0.001), locoregional relapse-free survival (LRRFS, p=0.003) and distant metastasis-free survival (DMFS, p<0.001). Multivariate Cox regression showed worse OS (HR=3.126; 95% CI 1.902 to 5.138; p<0.001), DFS (HR=2.579; 95% CI 1.815 to 3.665; p<0.001), LRRFS (HR=2.742; 95% CI 1.359 to 5.533; p=0.005) and DMFS (HR=2.461; 95% CI 1.574 to 3.850; p<0.001) for patients residing in rural areas. CONCLUSIONS: The survival outcomes of patients with NPC who received the same standardised treatment were significantly better in urban regions than in rural regions. By analysing the geographic disparities in outcomes for NPC, we can guide the formulation of healthcare policies.
Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Adulto , Carcinoma/radioterapia , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Recidiva Local de Neoplasia , Prognóstico , Estudos RetrospectivosRESUMO
The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is still to be explored. The significant downregulation of protein tyrosine phosphatase nonreceptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. IHC analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 was an independently favorable prognostic factor for progression-free survival (P = 0.0166) and overall survival (P = 0.0343) of patients. The ccRCC cell lines SN12C, 1932, ACHN, and Caki-1 were used to evaluate, both in vitro and in vivo, the biological roles of PTPN3. We observed that overexpression of PTPN3 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. In contrast, the knocking down of PTPN3 elicited opposite effects. Overexpressing PTPN3 inhibited xenograft tumor growth and lung metastasis displayed by the in vivo mice models. PTPN3 inhibited tumor cell motility by suppressing the phosphorylation of AKT, and subsequently inactivating the PI3K/AKT signaling pathway of renal cell carcinoma cells. Furthermore, the inhibition of phospho-AKTThr308 and phospho-AKTSer473 reversed PTPN3-induced silencing in tumor cell migration. Our work revealed that the overexpression of PTPN3 could suppress kidney cancer progression by negatively regulating the AKT signaling pathway, and served as a favorable prognostic factor in patients with ccRCC. Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC. IMPLICATIONS: PTPN3 is an independent favorable prognostic factor for patients with ccRCC and could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.