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1.
J Food Biochem ; : e13184, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32163601

RESUMO

Yeast extract (YE) is rich in amino acids, nucleotides, peptides, and other flavor substances, and is a natural nutrient, umami, and flavor enhancer. However, certain YE samples impart a yeasty flavor that affects the quality parameters of YE. We compared solid-phase microextraction (SPME), solvent-assisted evaporation (SAFE), dynamic headspace sample preparation (DHS), stir bar sorptive extraction (SBSE), and other pretreatment methods for the extraction of volatiles substances in YE. SPME was selected as a suitable extraction method, and aroma extract dilution analysis (AEDA) was combined with gas chromatography-olfactometry-mass spectrometry (GC-O-MS) for identification of key odor-active compounds in 23 YE samples. The yeast off-odor substances were screened from these compounds. Principal component analysis (PCA) was used to investigate the relationship between strains and the processing of YE products and their yeasty flavor. PRACTICAL APPLICATIONS: YE is prepared primarily from baker's yeast or waste beer yeast by autolysis or enzymatic hydrolysis, and is rich in nucleotides, peptides, amino acids, and other flavor compounds. It is used globally as a common umami and flavor enhancer. However, consumers have observed that YE imparts a certain yeasty flavor that influences the overall flavor negatively. Hence, the yeasty flavor-imparting substances from 23 YE samples were investigated in this study, and the observations (including strains, processing techniques, etc.) were integrated to explain the relationship between the yeasty flavor of the YE products with strain (different yeast strain for production) or processing of YE products (enzymes used, enzymatic hydrolysis conditions, composition of products, concentration conditions of YE, etc.), or storage conditions (temperature, humidity, duration, package, etc.), providing a scientific basis for removal/lowering or masking of yeasty flavor and the improvement of flavor quality of YE products.

2.
J Cell Physiol ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32048287

RESUMO

High-throughput messenger RNA (mRNA) analysis has become a powerful tool for exploring tumor recurrence or metastasis mechanisms. Here, we constructed a signature to predict the recurrence risk of Stages II and III gastric cancer (GC) patients. A least absolute shrinkage and selection operator method Cox regression model was utilized to construct the signature. Using this method, a 16-mRNA signature was identified to be associated with the relapse-free survival of Stages II and III GCs in training dataset GSE62254 (n = 194). Then this signature was validated in an independent Gene Expression Omnibus cohort GSE26253 (n = 297) and a dataset of The Cancer Genome Atlas (TCGA; n = 235). This classifier could successfully screen out the high-risk Stages II and III GCs in the training cohort (hazard ratio [HR] = 40.91; 95% confidence interval [CI] = 5.58-299.7; p < .0001). Analysis in two independent validation cohorts yielded consistent results (GSE26253: HR = 1.69, 95% CI = 1.17-2.43,; p = .0045; TCGA: HR = 2.01, 95% CI = 1.13-3.56, p = .0146). Cox regression analyses revealed that the risk score derived from this signature was an independent risk factor in Stages II and III GCs. Besides, a nomogram was constructed to serve clinical practice. Through gene set variation analysis, we found several gene sets associated with chemotherapeutic drug resistance and tumor metastasis significantly enriched in high-risk patients. In summary, this 16-mRNA signature can be used as a powerful tool for prognostic evaluation and help clinicians identify high-risk patients.

3.
Int J Cancer ; 146(1): 169-180, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31090062

RESUMO

Our previous study demonstrated that heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) is a key gene that facilitates metastasis of hepatocellular carcinoma (HCC). However, the molecular mechanisms behind this relationship are not fully understood. In our study, we utilized long-noncoding RNA (lncRNA) microarrays to identify a HNRNPAB-regulated lncRNA named lnc-ELF209. Our findings from chromatin immunoprecipitation assays indicate that HNRNPAB represses lnc-ELF209 transcription by directly binding to its promoter region. We also analyzed clinical samples from HCC patients and cell lines with quantitative real-time polymerase chain reactions, RNA in situ hybridization and immunohistochemistry, and found that there is a negative relationship between HNRNPAB and lnc-ELF209 expression. Up/downregulation assays and rescue assays indicate that lnc-ELF209 inhibits cell migration, invasion and epithelial-mesenchymal transition regulated by HNRNPAB. This suggests a new regulatory mechanism for HNRNPAB-promoted HCC progression. RNA pull-down and LC-MS/MS were used to determine triosephosphate isomerase, heat shock protein 90-beta and vimentin may be involved in the tumor-suppressed function of lnc-ELF209. Furthermore, we found lnc-ELF209 could stabilize TPI protein expression. We also found that lnc-ELF209 overexpression in HCCLM3 cell resulted in a lower rate of lung metastatic, which suggested a less aggressive HCC phenotype. Collectively, these findings offer new insights into the regulatory mechanisms that underlie HNRNPAB cancer-promoting activities and demonstrate that lnc-ELF209 is a HNRNPAB-regulated lncRNA that may play an important role in the inhibition of HCC progression.


Assuntos
Carcinoma Hepatocelular/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/fisiologia , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/fisiologia , Animais , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Metástase Neoplásica/genética
4.
Aging (Albany NY) ; 11(18): 7473-7491, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527303

RESUMO

Gastric cancer (GC) is a common disease globally with high mortality rate. It is therefore necessary to develop novel therapies targeting specific events in the pathogenesis of GC. Some hnRNP family members are involved in multiple cancer biological behaviors. However, the potential function and mechanism of hnRNPR, a new molecule of hnRNP family in GC remains unknown. We found that the expression of hnRNPR was significantly overexpressed in multiple cancers compared to the normal tissues. Functionally, hnRNPR promoted cancer cell proliferation, migration, and invasion. Knockdown of hnRNPR in two type mice models, with two types of tumors models decreased the tumor aggressiveness and metastasis. Mechanistically, hnRNPR targeted oncogenic pathways by stabilizing the expression of CCNB1 and CENPF mRNA level. Knockdown of CCNB1 and CENPF abolished the hnRNPR-induced cell growth and invasion, respectively. Furthermore, the protein level of hnRNPR in the tumor was positively correlated with the expression of CCNB1 and CENPF in clinical samples. Together, these results indicate that overexpression of hnRNPR promoted the aggressiveness of GC by increasing the mRNA expression of CCNB1 and CENPF. HnRNPR-CCNB1/CENPF axis may be a potential therapeutic target for GC treatment.

5.
Theranostics ; 9(16): 4779-4794, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31367257

RESUMO

Natural killer (NK) cell can inhibit tumor initiation and regulates metastatic dissemination, acting as key mediators of the innate immune response. Intrinsic factors modulating NK cells infiltration and its anticancer activity remain poorly characterized. We investigated the roles of dysregulation of micro(mi)RNAs and NK cells in progression of hepatocellular carcinoma (HCC). Methods: Small RNA sequencing were used to detect the miRNA profiles of tumor tissues from HCC patients with (n=14) or without (n=13) pulmonary metastasis and HCC cell lines with different pulmonary metastatic potentials. Chemokine expression profiling and bioinformatics were used to detect the downstream target of candidate target. In gain- and loss-of-function assays were used to investigate the role of miRNA in HCC progression. Different subsets of NK cells were isolated and used for chemotaxis and functional assays in vivo and in vitro. In situ hybridization and immunohistochemical analyses were performed to detect the expression of miRNA in tumor tissues from 242 HCC patients undergoing curative resection from 2010. Results: Three miRNAs (miR-137, miR-149-5p, and miR-561-5p) were identified to be associated with pulmonary metastasis in patients with HCC. miR-561-5p was most highly overexpressed in metastatic HCC tissues and high-metastatic-potential HCC cell lines. In gain- and loss-of-function assays in a murine model, miR-561-5p promoted tumor growth and spread to the lungs. Yet, miR-561-5p did not appear to affect cellular proliferation and migration in vitro. Bioinformatics and chemokine expression profiling identified chemokine (C-X3-C motif) ligand 1 (CX3CL1) as a potential target of miR-561-5p. Furthermore, miR-561-5p promoted tumorigenesis and metastasis via CX3CL1-dependent regulation of CX3CR1+ NK cell infiltration and function. CX3CR1+ NK cells demonstrated stronger in vivo anti-metastatic activity relative to CX3CR1- NK cells. CX3CL1 stimulated chemotactic migration and cytotoxicity in CX3CR1+ NK cells via STAT3 signaling. Blockade of CX3CL1, CX3CR1, or of pSTAT3 signaling pathways attenuated the antitumor responses. Clinical samples exhibited a negative correlation between miR-561-5p expression and levels of CX3CL1 and CX3CR1+ NK cells. High miR-561-5p abundance, low CX3CL1 levels, and low numbers of CX3CR1+ NK cells were associated with adverse prognosis. Conclusion: We delineated a miR-561-5p/CX3CL1/NK cell axis that drives HCC metastasis and demonstrated that CX3CR1+ NK cells serve as potent antitumor therapeutic effectors.

6.
J Transl Med ; 17(1): 203, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215439

RESUMO

BACKGROUND: Due to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is still a challenge to determine patients' prognosis. We aim to identify new prognostic markers for resected HCC patients. METHODS: 274 patients were retrospectively identified and samples collected from Zhongshan hospital, Fudan University. We analyzed the gene expression patterns of tumors and compared expression patterns with patient survival times. We identified a "9-gene signature" associated with survival by using the coefficient and regression formula of multivariate Cox model. This molecular signature was then validated in three patients cohorts from internal cohort (n = 69), TCGA (n = 369) and GEO dataset (n = 80). RESULTS: We identified 9-gene signature consisting of ZC2HC1A, MARCKSL1, PTGS1, CDKN2B, CLEC10A, PRDX3, PRKCH, MPEG1 and LMO2. The 9-gene signature was used, combined with clinical parameters, to fit a multivariable Cox model to the training cohort (concordance index, ci = 0.85), which was successfully validated (ci = 0.86 for internal cohort; ci = 0.78 for in silico cohort). The signature showed improved performance compared with clinical parameters alone (ci = 0.70). Furthermore, the signature predicted patient prognosis than previous gene signatures more accurately. It was also used to stratify early-stage, HBV or HCV-infected patients into low and high-risk groups, leading to significant differences in survival in training and validation (P < 0.001). CONCLUSIONS: The 9-gene signature, in which four were upregulated (ZC2HC1A, MARCKSL1, PTGS1, CDKN2B) and five (CLEC10A, PRDX3, PRKCH, MPEG1, LMO2) were downregulated in HCC with poor prognosis, stratified HCC patients into low and high risk group significantly in different clinical settings, including receiving adjuvant transarterial chemoembolization and especially in early stage disease. This new signature should be validated in prospective studies to stratify patients in clinical decisions.

7.
Pathol Res Pract ; 215(8): 152454, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146977

RESUMO

Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) is regarded as a rare but highly malignant gastric adenocarcinoma subtype and its clinic pathological presentation mimics hepatocellular carcinoma. However, the underlying mechanism of this disease remains elusive. The level of ANGPTL6 in AFPGC cell lines is much higher than that of common types of gastric cancer cells. A high level of ANGPTL6 confers a poor prognosis and is correlated with the expression of CD34 (an endothelial cell marker). ANGPTL6 promotes endothelial cell migration and tube formation, Moreover, ANGPTL6 knockdown inhibits cancer cell apoptosis and invasiveness. Mechanistically, ANGPTL6 activates the ERK1/2 and AKT pathways. Treatment of ERK1/2 or AKT inhibitor can attenuated cell migration and tube formation. ANGPTL6 loss results in tumor growth in vivo. Our study revealed that ANGPTL6 is an important driver gene of angiogenesis in AFPGC development. These findings provide not only an effective biomarker for diagnosis but also an attractive therapeutic target for use in AFPGC patients.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Neovascularização Patológica/patologia , Neoplasias Gástricas/patologia , alfa-Fetoproteínas/metabolismo , Proteínas Semelhantes a Angiopoietina/genética , Progressão da Doença , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Processos Neoplásicos , Neovascularização Patológica/genética , Estômago/patologia , Neoplasias Gástricas/genética , alfa-Fetoproteínas/genética
8.
Cancer Manag Res ; 11: 63-79, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30588111

RESUMO

Background and aim: To investigate the value of the aspartate aminotransferase-to-platelet ratio index (APRI) and build a new nomogram for hepatocellular carcinoma (HCC) patients undergoing postoperative adjuvant transarterial chemoembolization (PATACE). Methods: We retrospectively reviewed 351 patients with HCC undergoing PATACE. We collected baseline HCC patient characteristics to obtain the risk factors for determining poor disease-free survival (DFS) and early time to recurrence (TTR) after PATACE. The multivariate Cox proportional hazards model was used to build new nomogram based on significant prognostic factors of outcomes. Results: We generated the cutoff value of the APRI as 0.50 using the X-tile to distinguish patients with different outcomes in the whole cohort. Two hundred seventeen patients with high APRI had poorer survival (P<0.001) than did 134 patients with low APRI. Furthermore, a nomogram, including tumor size, alanine aminotransferase (ALT) level, white blood cell counts, Barcelona Clinic Liver Cancer grade, and APRI was built for DFS, while factors including hepatitis B surface antigen, tumor size, ALT, microvascular invasion, and APRI was built for TTR. Internal validation with 500 bootstrapped sample sets had a good concordance index of 0.729 for DFS and 0.730 for TTR. Additionally, nomogram based on APRI conferred more prognostic value than previous biomarkers. Conclusion: High APRI was associated with worse survival and shorter TTR for HCC patients undergoing PATACE. This simple nomogram based on APRI conferred personalized survival and recurrence data for HCC patients undergoing PATACE.

9.
Biomed Res Int ; 2019: 6710428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31915699

RESUMO

Aims: Both hepatoid adenocarcinoma of stomach (HAS) and alpha-fetoprotein-positive gastric cancer (AFPGC) are rare but aggressive subtypes of gastric cancer, but few studies focus on the clinicopathologic differences and prognostic factors between them because of their rarity and histologic overlap. And the significance of AFP level in HAS prognosis was not well studied. Methods: 41 patients with AFPGC and 52 patients with HAS were included in this study. The clinicopathologic features were compared by Chi-square analysis. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed with the Kaplan-Meier method. Results: The patients with HAS were of a younger age compared with AFPGC, and nearly 60% of tumor located in the gastric antrum and the gastric fundus of cardia. The OS of AFPGC was shorter than that of HAS, due to a higher rate of metastasis. Furthermore, the survival analysis showed that HAS with high AFP expression (AFPHigh HAS) had a significantly poorer OS compared to HAS with low AFP expression (AFPLow HAS) (P=0.046). Conclusions: Compared with AFPGC, the patients of HAS were of a younger age and had less rate of liver and other organ metastasis. The serum AFP level was a sensitive prognostic indicator for OS. Therefore, much attention should be paid to AFPHigh HAS in clinical practice.

10.
J Oncol ; 2018: 3979135, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849630

RESUMO

Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation.

11.
Biomed Res Int ; 2018: 6784607, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29951542

RESUMO

Hepatocellular carcinoma (HCC), which accounts for 85-90% of primary liver cancer, is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide, but the pathological mechanism of HCC is still not fully elucidated. miRNAs are evolutionarily endogenous small noncoding RNAs that negatively regulate gene expression via posttranscriptional inhibition or target mRNA degradation in several diseases, especially human cancer. Therefore, discovering the roles of miRNAs is appealing to scientific researchers. Emerging evidence has shown that the aberrant expressions of numerous miRNAs are involved in many HCC biological processes. In hepatocarcinogenesis, miRNAs with dysregulated expression can exert their function as oncogenes or tumor suppressors depending on their cellular target during the cell cycle, and in tumor development, differentiation, apoptosis, angiogenesis, metastasis, and progression of the tumor microenvironment. In this review, we summarize current findings on miRNAs and assess their functions to explore the molecular mechanisms of tumor progression in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs , Carcinoma Hepatocelular/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Oncogenes
12.
Cell Physiol Biochem ; 45(5): 1731-1746, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29495008

RESUMO

BACKGROUND/AIMS: Breast cancer is a common cause of cancer mortality throughout the world. The cross-talk between cancer cells and interstitial cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. CXC is one of four chemokine families involved in mediating survival, angiogenesis, and immunosensitization by chemoattracting leukocytes, and it incentivizes tumor cell growth, invasion and metastasis in the tumor microenvironment. However, the differential expression profiles and prognostic values of these chemokines remains to be elucidated. METHODS: In this study, we compared transcriptional CXC chemokines and survival data of patients with breast carcinoma (BC) using the ONCOMINE dataset, Kaplan-Meier Plotter, TCGA and cBioPortal. RESULTS: We discovered increased mRNA levels for CXCL8/10/11/16/17, whereas mRNA expression of CXCL1/2/3/4/5/6/7/12/14 was lower in BC patients compared to non-tumor tissues. Kaplan-Meier plots revealed that high mRNA levels of CXCL1/2/3/4/5/6/7/12/14 correlate with relapse-free survival (RFS) in all types of BC patients. Conversely, high CXCL8/10/11 predicted worse RFS in BC patients. Significantly, high transcription levels of CXCL9/12/13/14 conferred an overall survival (OS) advantage in BC patients, while high levels of CXCL8 demonstrated shorter OS in all BC sufferers. CONCLUSIONS: Integrative bioinformatics analysis suggests that CXCL8/12/14 are potential suitable targets for precision therapy in BC patients compared to other CXC chemokines.


Assuntos
Quimiocinas CXC/metabolismo , Biologia Computacional/métodos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Quimiocinas CXC/antagonistas & inibidores , Quimiocinas CXC/genética , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Redes Reguladoras de Genes , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Estimativa de Kaplan-Meier , Prognóstico , RNA Mensageiro/metabolismo , Microambiente Tumoral
13.
J Cancer ; 9(6): 1057-1066, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29581785

RESUMO

5-fluorouracil (5-Fu) metabolism associated enzyme, methylenetetrahydrofolate reductase (MTHFR)'s polymorphism C677T can affect enzyme activity and a series of studies have been performed to examine the association of this MTHFR polymorphism with the clinical outcomes of gastric cancer (GC) patients treated with 5-Fu based chemotherapies. However, the results are inconsistent and inconclusive. Therefore, a more comprehensive summary like meta-analysis on this topic is needed. We performed a systematic literature search of PubMed and Embase up to May 20, 2017. Researches exploring MTHFR polymorphisms C677T's relationship with the clinical outcomes (response rate, overall survival and toxicity) of GC patients treated with 5-Fu based chemotherapy were included. The association was measured by odds ratios (ORs) or hazard ratios (HRs) combined with their 95% confidence intervals (CIs) using random/fixed effects model according to the studies' heterogeneity. Subgroup, sensitivity and publication bias analyses were conducted. Thirteen studies were finally included in this meta-analysis. No significant association was found between response rate [TT/ (CC+CT) OR=1.31, 95% CI: 0.62-2.76] or overall survival [(CT+TT)/CC HR=1.05, 95% CI: 0.86-1.26; TT/(CT+CC) HR=1.48, 95% CI: 0.53-4.15] and MTHFR polymorphism C677T. However, GC patients with CC or CT genotype tended to experience less severe hematologic toxicity than those with TT genotype [(CC+CT)/TT OR=0.66, 95% CI: 0.48-0.91]. In conclusion, MTHFR C677T polymorphism predicts severe hematologic toxicity in GC patients receiving 5-Fu based chemotherapy, but not the efficiency.

14.
Oncotarget ; 8(32): 52488-52500, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28881746

RESUMO

Prostate-derived E-twenty-six (ETS) factor (PDEF), an epithelium-specific ETS transcription factor, regulates carcinogenesis and tumor progression. The prognostic importance and biologic functions in hepatocellular carcinoma (HCC) have not been established. We investigated PDEF expression in 400 HCC patients using quantitative real-time polymerase chain reaction, western blot and immunohistochemistry analysis. PDEF expression was significantly lower in tumors than in peritumoral tissues. Lower PDEF levels were associated with poorer prognosis in patients. PDEF was an independent predictor of overall survival in multivariate analysis. PDEF expression was suppressed in highly metastatic HCC cell lines, and shRNA-mediated down-regulation of PDEF in low-metastatic HCC cell lines (with high PDEF) significantly increased cellular proliferative and invasive capacity in vitro and in vivo. RNA sequencing analysis indicated that PDEF may mediate transcription of several genes involved in apoptosis and the cell cycle. PDEF modulated epithelial-mesenchymal transition by up-regulating E-cadherin expression and down-regulating Slug and Vimentin expression, thereby lowering migration and invasion abilities of HCC cells. In conclusion, PDEF is associated with proliferation and invasiveness of HCC cells. It may serve as an independent predictor of prognosis in patients with HCC.

15.
Oncol Rep ; 37(6): 3313-3320, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28498470

RESUMO

Semaphorin 3A (SEMA3A), a secretory protein, is a founding member of the semaphorin family and functions in both the biological behavior of tumor cells and the modulation of tumor-associated macrophages. However, the role of SEMA3A in hepatocellular carcinoma (HCC) is still not well established. In the present study, we investigated the expression levels of SEMA3A in 80 HCC tissues and cell lines, using RT-qPCR, western blotting and immunohistochemistry. Expression profile analysis revealed that SEMA3A was significantly overexpressed in human HCC patients and positively correlated with the metastatic potential of HCC cells. Lentiviral transfection into PLC/PRF/5 and HCCLM3 cells was performed to stably upregulate and downregulate the expression of SEMA3A in HCC cells. Cell Counting Kit-8 (CCK-8), wound-healing and invasion assays revealed that SEMA3A promoted the proliferation and migration of HCC cells in vitro. Proteome profiler antibody microarray analysis revealed that overexpression of SEMA3A in HCC cells induced a significant increase in the expression levels of gelsolin-like capping protein (CapG), galectin-3, enolase 2 and epithelial cell adhesion molecule (EpCAM). Furthermore, the upregulation of SEMA3A in HCC cells promoted tumor growth and progression in an HCC mouse model. These results indicate that SEMA3A enhances CapG, galectin-3, enolase 2 and EpCAM expression to promote HCC progression and is a potential therapeutic target for HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Semaforina-3A/genética , Animais , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Molécula de Adesão da Célula Epitelial/genética , Feminino , Galectina 3/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Lentivirus/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas Nucleares/genética , Fosfopiruvato Hidratase/genética , Proteoma/genética , Semaforina-3A/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Oncotarget ; 7(32): 51733-51746, 2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27351132

RESUMO

The semaphorins were originally identified as having roles as guidance cues during neural development. Class 3 semaphorins are involved in cancer progression. However, the roles of class 3 semaphorins in hepatocellular carcinoma (HCC) are unknown. We examined the expression levels of class 3 semaphorins in HCC cell lines with different metastatic potential and in carcinoma tissue samples. The results indicated that Semaphorin 3A expression was up-regulated in metastatic cell lines and in samples from patients with tumor recurrence. Cell functional studies revealed that Semaphorin 3A promoted HCC cell proliferation, migration, and invasion. Animal studies indicated that Semaphorin 3A overexpression enhanced tumor growth and lung metastasis. Semaphorin 3A also acted as a chemoattractant involved in direct recruitment of macrophages in vitro, and facilitated tumor-associated macrophage (TAM) infiltration in vivo. Multivariate analysis revealed that Semaphorin 3A expression alone, or combined with the number of TAMs, can be an independent predictor for overall survival time and time to recurrence. Overall, the results suggested that Semaphorin 3A increased TAM infiltration and promoted HCC progression. Semaphorin 3A expression alone, or combined with the number of TAMs, is a new prognostic factor and potential target for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Semaforina-3A/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Estudos de Coortes , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatectomia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Regulação para Cima
17.
Gastroenterology ; 150(7): 1646-1658.e17, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26924089

RESUMO

BACKGROUND & AIMS: Neutrophils can either promote or inhibit tumor progression, depending on the tumor microenvironment, via release of cytokines. Neither the factors produced by tumor-associated neutrophils (TANs) nor their effects on tumor progression have been characterized. We investigated the roles of TANs in progression of hepatocellular carcinoma (HCC) using cell lines and immune cells isolated from patients. METHODS: We performed studies with HepG2, PLC/PRF/5, MHCC97H, and HCCLM3 human and Hepa1-6 and H22 mouse HCC cell lines; expression of chemokines and cytokines were knocked down with small hairpin RNAs. Cells were analyzed in chemotaxis assays and as growth as tumors in mice. HCC tissues and peripheral blood were collected from 20 patients undergoing curative resection or 20 healthy individuals (controls) in 2012 at Zhongshan Hospital in China. TANs and peripheral blood neutrophils (PBNs) were isolated and exposed to conditioned media from HCC cell lines; reverse-transcription polymerase chain reaction was used to quantify the expression of cytokines and chemokines. We collected neutrophils from another 60 patients undergoing curative resection for HCC in 2012 to measure the production of C-C motif chemokine ligand 2(CCL2) and CCL17. Patients were followed up until March 15, 2014. For immunohistochemical analyses, we collected HCC tissues and paired, adjacent, nontumor cirrhotic liver tissues from 832 HCC patients undergoing curative resection from 2006 through 2008. All patients were followed up until March 15, 2013. To study the effects of sorafenib, we collected clinical and pathology data from 46 patients who underwent curative resection in 2010. RESULTS: CCL2 and CCL17 were the cytokines most highly expressed by TANs and HCC cell-activated PBNs. Levels of CCL2 and CCL17 messenger RNAs and proteins were significantly higher in TANs than in PBNs, and increased in patients with HCC recurrence. CCL2 and CCL17 messenger RNA and proteins also increased when PBNs were exposed to conditioned media from HCC cell lines. Immunohistochemical analysis of a tissue microarray showed that CCL2+ and CCL17+ cells, which also expressed the neutrophil marker CD66b, were distributed throughout the HCC stroma, but not in tumor cells or the adjacent nontumor liver cells. The number of CCL2+ or CCL17+ TANs correlated with tumor size, microvascular invasion, tumor encapsulation, tumor differentiation, and stage. Patients whose tumors had lower levels of CCL2+ or CCL17+ cells had longer survival times than those with higher numbers of these cells. TAN-conditioned media, as well as recombinant CCL2 and CCL17, increased the migratory activity of the macrophages and T-regulatory (Treg) cells from patients or mice with HCC to a greater extent that PBN-conditioned media. Neutralizing antibodies against CCL2 and CCL17, or their receptors C-C chemokine receptor 2 and C-C chemokine receptor 4, reduced the migratory activities of macrophage and Treg cells. HCC cell lines injected into mice formed larger tumors when they were co-injected with TANs and formed more pulmonary metastases; these tumors were infiltrated by Ly6G+ cells, F4/80+ macrophages, and Foxp3+ Treg cells. In a phosphokinase array of human PBNs, levels of phosphorylated AKT and P38 increased after exposure to conditioned media from all 4 HCC cell types. Pharmacologic inhibitors of AKT and P38 inhibited secretion of CCL2 and CCL17 by these PBNs. In tumor-bearing mice, sorafenib increased the numbers of TANs and levels of CCL2 and CCL17 in tumors. HCC tissues from patients who received sorafenib before surgery contained more TANs than tissues from patients who did not receive sorafenib. In knockdown cells, HCC cell-derived CXCL5 was the strongest effector of neutrophil migration under hypoxic conditions. In mice, the combination of sorafenib and TAN depletion inhibited tumor growth and neovascularization to a greater extent than sorafenib alone. CONCLUSIONS: TANs recruit macrophages and Treg cells to HCCs to promote their growth, progression, and resistance to sorafenib.


Assuntos
Antineoplásicos/imunologia , Carcinoma Hepatocelular/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Hepáticas/imunologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/imunologia , Animais , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Macrófagos/imunologia , Camundongos , Infiltração de Neutrófilos , Neutrófilos/imunologia , Niacinamida/administração & dosagem , Niacinamida/imunologia , Compostos de Fenilureia/administração & dosagem , Sorafenibe , Linfócitos T Reguladores/imunologia
18.
Tumour Biol ; 36(7): 5283-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25672606

RESUMO

A high preoperative peripheral blood neutrophil-to-lymphocyte ratio (NLR) has been reported to be a predictor of poor survival in patients with various cancers. The aim of this study was to evaluate the predictive significance of the NLR in patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC). From 2005 to 2011, 322 patients who underwent hepatectomy for ICC were enrolled in this retrospective study. Clinicopathological parameters, including NLR, were evaluated to identify predictors of overall and recurrence-free survival after hepatectomy. The best cutoff for NLR was 2.49, and 177 of 322 patients (54.9 %) had an NLR ≥ 2.49. The 5-year survival rate after hepatectomy was 51.1 % in patients with NLR < 2.49 and 24.8 % in those with NLR ≥ 2.49 (P = 0.0001). Univariate analyses revealed that NLR was significantly associated with recurrence-free survival (RFS) and overall survival (OS; both P < 0.05). Multivariable analyses revealed that elevated NLR independently predicted poorer OS (P = 0.003, hazard ratio [HR] = 1.600). In summary, our results indicate that elevated NLR is a promising independent predictor of poor survival after hepatectomy in patients with ICC.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Linfócitos/patologia , Recidiva Local de Neoplasia/patologia , Neutrófilos/patologia , Adulto , Idoso , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/cirurgia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/cirurgia , Colangiocarcinoma/sangue , Colangiocarcinoma/cirurgia , Intervalo Livre de Doença , Feminino , Hepatectomia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/cirurgia , Período Pré-Operatório , Prognóstico
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