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1.
Cell Death Dis ; 10(12): 890, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31767831

RESUMO

Kindlin-2 plays an important role in the regulation of cardiac structure and function. Depletion of Kindlin-2 contributes to cardiac hypertrophy and progressive heart failure, however, the precise mechanisms involved in this process remain unclear. GATA4 is a critical transcription factor in regulating cardiogenesis. We found that Kindlin-2 suppresses the expression of GATA4 through binding to its promoter and prevents cardiomyocytes from hypertrophy induced by isoproterenol (ISO) treatment. Mechanistically, Kindlin-2 interacts with histone methyltransferase SUV39H1 and recruits it to GATA4 promoter leading to the occupancy of histone H3K9 di- and tri-methylation. Furthermore, to confirm the function of Kindlin-2 in vivo, we generated mice with targeted deletion of cardiac Kindlin-2. We found that 6-month-old Kindlin-2 cKO mice have developed hypertrophic cardiomyopathy and that this pathological process can be accelerated by ISO-treatment. GATA4 expression was markedly activated in cardiac tissues of Kindlin-2 cKO mice compared to wild-type animals. Collectively, our data revealed that Kindlin-2 suppresses GATA4 expression by triggering histone H3K9 methylation in part and protects heart from pathological hypertrophy.

2.
Nat Commun ; 10(1): 5076, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31700061

RESUMO

Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.

3.
J Cancer ; 10(26): 6754-6760, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31777605

RESUMO

Previous studies have suggested a relationship between ABO blood group and clinical outcome of various cancers. Nevertheless, little is known about the association between ABO blood group and survival in patients with ovarian carcinoma. This study aimed to investigate the prognostic significance of ABO blood group in patients with ovarian carcinoma. 941 patients who were newly diagnosed with ovarian carcinoma between February 2007 and February 2016 were enrolled in the present study. The relationship between ABO blood type and clinical features in patients with ovarian cancer was analyzed using chi-square tests. Overall survival (OS) stratified by B antigen was evaluated using log-rank test and Kaplan-Meier method. Presence of the B antigen (B/AB) had a worse OS than those in the absence of the B antigen (A/O) in all patients with ovarian cancer, especially in patients with FIGO stage I, IV, and menopause. Presence of the B antigen (B/AB) was significantly correlated with OS than those with non-B antigen (A/O) (hazard ratios 1.342; 95% confidence interval 1.069-1.685; P=0.011). Multivariate analyses revealed that presence of the B antigen (B/AB) was independently associated with OS (hazard ratios 1.532; 95% confidence interval 1.111-2.112; P=0.009). This study indicated that presence of the B antigen (B/AB) was an unfavorable prognostic factor in ovarian carcinoma, especially in patients with FIGO stage I, IV, and menopause.

4.
Sci Rep ; 9(1): 15234, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645619

RESUMO

Activated platelets play a multifaceted role in tumorigenesis and progression. Platelet distribution width (PDW) is generally applied platelet parameters from routine blood test. Preoperative PDW has been considered a prognostic factor in many cancers. Nevertheless, the prognostic value of PDW in esophageal squamous cell carcinoma (ESCC) remains unknown. The study aimed to investigate whether preoperative PDW could serve as a prognostic factor in patients with ESCC. A total of 495 patients with ESCC undergoing curative surgery were enrolled. The relationship between PDW and clinical features in ESCC was analyzed using chi-square tests. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value. Overall survival (OS) and disease-free survival (DFS) stratified by PDW were evaluated by Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression were used to evaluate the prognostic effect of PDW. Of the 495 patients, elevated PDW was observed in 241(48.7%) of the patients, respectively. An elevated PDW was correlated with depth of tumor (T stage, P = 0.031), nerve infiltration (P = 0.016), hospital time after operation (P = 0.020), platelet (P < 0.001), red cell distribution width (P < 0.001), and aspartate transaminase (P = 0.001). Moreover, elevated PDW (PDW ≥ 13.4 fL) predicted a worse OS and DFS in patients with ESCC (both P < 0.001). Multivariate analyses revealed that PDW was independently associated with OS (hazard ratios 1.194; 95% confidence interval 1.120-1.273; P < 0.001) and DFS (hazard ratios 2.562; 95% confidence interval 1.733-3.786; P < 0.001). Our findings indicated that elevated PDW could serve as an independent worse survival in ESCC.

5.
Biomed Res Int ; 2019: 2702719, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485440

RESUMO

In esophageal squamous cell carcinoma, an elevated preoperative absolute monocyte count (Pre-AMC) is reported to be a predictor of survival, but the clinical application of postoperative absolute monocyte count change (AMCc) remains unknown. The present study was designed to investigate the prognostic value of AMCc in ESCC. 686 patients of ESCC after radical surgery without preoperative adjuvant therapy were enrolled. The Pre-AMC and AMCc were recorded within one week before the operation and one week after surgery. We considered the median of Pre-AMC as the optimal cut-off value to evaluate the relationship between Pre-AMC and patient survival. AMCc was defined as AMCc increased (higher than Pre-AMC) and AMCc decreased (lower than Pre-AMC). Demographic and clinical characteristics, disease-free survival (DFS), and overall survival (OS) were statistically analyzed. Multivariate analysis revealed that AMCc was a better independent prognostic factor for both OS (P = 0.002, HR = 0.614, 95% CI 0.450-0.837) and DFS (P = 0.023, HR = 0.656, 95% CI 0.456-0.943) than Pre-AMC which was only an independent prognostic factor for OS (P = 0.033, HR = 2.031, 95% CI 1.058-3.898). AMCc could be a better prognostic factor than Pre-AMC in patients with ESCC. AMCc decrease predicts worse OS and DFS in ESCC undergoing curative resection.

6.
J Thorac Dis ; 11(6): 2332-2339, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31372270

RESUMO

Background: Preoperative lymphocyte count (pre-LC) predicts the relapse and survival in patients with esophageal squamous cell carcinoma (ESCC), the clinical application of postoperative lymphocyte count (post-LC) change (LCc) remains unclear. Methods: A retrospective analysis of patients with newly diagnosed ESCC who received curative resection from 2008 to 2015 was conducted. Complete blood counts from preoperative within seven days to postoperative within seven days were analyzed. LCc was defined as LCc increased (post-LC higher than pre-LC) and LCc decreased (post-LC lower than pre-LC). LCc was evaluated for an association with disease-free survival (DFS). Results: A total of 677 patients who reach the standard were enrolled into the study. There were 579 (85.5%) male and 98 (14.5%) female patients with ESCC. The median age was 61 years (range, 39-84 years). In univariate analysis, LCc significantly correlated to DFS (P=0.006, HR =0.593, 95% CI: 0.409-0.862). In multivariate analysis (COX model), LCc was an independent prognostic factor for DFS (P=0.011, HR =0.617, 95% CI: 0.424-0.897). Conclusions: The dynamic change of LC after surgery may serve as a simple and new prognostic factor in patients with newly diagnosed ESCC.

7.
J Cancer ; 10(9): 2057-2062, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205566

RESUMO

Preoperative lymphocyte to monocyte ratio (LMR) has been considered a prognostic factor in various cancers. However, the application of LMR in the assessment of patients with esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to investigate whether preoperative LMR could serve as a prognostic marker in patients with ESCC undergoing curative tumor resection. Medical records of 680 patients of ESCC after curative surgery without preoperative adjuvant therapy were obtained. The median of LMR was determined as the optimal cut off value. The association of LMR with clinical features of ESCC was analyzed using chi-square tests. Spearman's correlation coefficient was used to calculate the correlation. Disease-free survival (DFS) and overall survival (OS) stratified by LMR were evaluated using Kaplan-Meier method and log-rank test. The LMR was negatively correlated with sex (r=-0.245, P<0.001). Low LMR (LMR<3.17) predicted a shorter DFS and OS in patients with ESCC. Multivariate analyses revealed that LMR was independently correlated with DFS (hazard ratios 0.854; 95% confidence interval 0.768-0.949; P=0.003) and OS (hazard ratios 0.864; 95% confidence interval 0.779-0.958; P=0.006). Our study indicated that low LMR could serve as an independent worse prognostic marker in patients with ESCC.

8.
Chem Res Toxicol ; 32(3): 345-347, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30807111

RESUMO

Understanding the toxicological implications of deoxyribonucleic acid (DNA) oxidation arising from cellular oxidative stress depends on identifying DNA oxidation products, their location in the genome, and their interaction with repair, replication, and gene expression.

9.
Int J Biochem Cell Biol ; 105: 41-51, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30287284

RESUMO

Integrin-interacting protein Kindlin-2, as a focal adhesion protein, promotes growth and progression of breast cancer. However, the precise mechanism that underlie the role of Kindlin-2 in breast cancer is elusive. Here, we report that the expression of Kindlin-2 positively correlated with DNA methyltransferase 1(DNMT1) in breast cancer patients. Further, we found that DNMT1 was upregulated in mammary gland tissues of mammary specific Kindlin-2 transgenic mice. More importantly, high expression of DNMT1 was observed in mammary tumors formed by Kindlin-2 transgenic mice. On the basis of these observations, DNMT inhibitor 5-aza-CdR was used and found its treatment strongly decreased Kindlin-2-induced breast cancer cell proliferation and migration. Mechanistically, Kindlin-2 increased the stability of DNA methyltransferase DNMT1 through interaction with DNMT1 and methylated CpG islands in the E-cadherin promoter. Kindlin-2 increased the occupancy of DNMT1 at E-cadherin promoter, thereby suppressing E-cadherin expression. Taken together, our data reveal that Kindlin-2 promotes breast cancer development by enhancing the stability of DNMT1.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Antígenos CD/genética , Neoplasias da Mama/patologia , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ilhas de CpG , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA , Estabilidade Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , Regulação para Cima
10.
Free Radic Biol Med ; 129: 256-267, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30086340

RESUMO

Malignant melanoma is a highly metastatic and life-threatening cancer. Reactive oxygen species (ROS) play important roles in cancer initiation and progression including metastasis. It has been reported that the oxidative stress spontaneously generated in circulating melanoma cells was able to suppress distant metastasis in vivo. However, little is known regarding the effects and mechanism of glutathione reductase (GR) inhibition-induced oxidative stress in regulation of melanoma metastasis. Here, we demonstrate that GR inhibition generates oxidative stress and suppresses lung metastasis and subcutaneous growth of melanoma in vivo. In addition, inhibitory effects by GR activity reduction were observed on cell proliferation, colony formation, cell adhesion, migration and invasion in melanoma cells in vitro. GR inhibition-induced oxidative stress was also found to block epithelial-to-mesenchymal transition (EMT) by decreasing the expression of Vimentin, ERK1/2, transcription factor Snail and increasing the expression of E-cadherin. In addition, actin rearrangement, a key element involved in cell motility, was also affected by GR-mediated oxidative stress possibly through protein S-glutathionylation on actin. In conclusion, this study identifies GR as an effective regulator of oxidative stress that affects the multistep processes of metastasis in melanoma cells, and it becomes a potential target for melanoma therapy.


Assuntos
Acetilcisteína/análogos & derivados , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Glutationa Redutase/genética , Neoplasias Pulmonares/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Tiocarbamatos/farmacologia , Acetilcisteína/farmacologia , Actinas/genética , Actinas/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Glutationa Redutase/antagonistas & inibidores , Glutationa Redutase/metabolismo , Isoenxertos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Carga Tumoral/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo
11.
J Am Chem Soc ; 140(31): 9783-9787, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-29944356

RESUMO

Single-nucleotide-resolution sequencing of DNA damage is required to decipher the complex causal link between the identity and location of DNA adducts and their biological impact. However, the low abundance and inability to specifically amplify DNA damage hinders single-nucleotide mapping of adducts within whole genomes. Despite the high biological relevance of guanine oxidation and seminal recent advances in sequencing bulky adducts, single-nucleotide-resolution whole genome mapping of oxidative damage is not yet realized. We coupled the specificity of repair enzymes with the efficiency of a click DNA ligation reaction to insert a biocompatible locator code, enabling high-throughput, nucleotide-resolution sequencing of oxidative DNA damage in a genome. We uncovered thousands of oxidation sites with distinct patterns related to transcription, chromatin architecture, and chemical oxidation potential. Click-code-seq overcomes barriers to DNA damage sequencing and provides a new approach for generating comprehensive, sequence-specific information about chemical modification patterns in whole genomes.


Assuntos
Mapeamento Cromossômico , Química Click , Dano ao DNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Estresse Oxidativo , Genoma Humano , Humanos , Espécies Reativas de Oxigênio/metabolismo
12.
Cancer Manag Res ; 10: 1527-1533, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29942154

RESUMO

Background: This study aimed to assess the predictive factor of multifocality to identify patients at high risk of central lymph node metastasis (CLNM). Patients and methods: Papillary thyroid microcarcinoma patients who underwent total or hemi-thyroidectomy with effective unilateral or bilateral central lymph node dissection were enrolled. Results: Multifocality, age, sex, tumor size, extrathyroidal extension, and nodular goiter were significantly associated with CLNM. Multifocality was an independent predictor for CLNM in multivariate analysis. Compared with unifocal disease, the odds ratio for CLNM was 1.447 for patients with ≥2 tumor foci (P<0.001) and 2.978 for patients with ≥3 tumor foci (P<0.001). The significant association is at ≥3 foci diseases. Conclusion: Multifocality with ≥3 tumor foci was an independent predictive factor for CLNM in papillary thyroid microcarcinoma. Multifocality should be assessed when selecting patients for prophylactic central neck lymph node dissection, and we speculate that patients with multifocality should undergo more radical treatment.

13.
Clin Lab ; 64(3): 321-327, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29739117

RESUMO

BACKGROUND: Cholesterol is an essential building block of the cell membrane and an important molecule for cell signaling and function. The dysregulation of cholesterol metabolism has been linked to several diseases, including cancer. The aim of this study is to investigate whether serum cholesterol is associated with the survival outcomes of patients with non-small cell lung cancer (NSCLC). METHODS: The concentration of total cholesterol (TC) was measured in pre-operative serum samples of 637 NSCLC patients. The associations of TC with recurrence and overall survival were analyzed using a Cox proportional hazard regression model. Kaplan-Meier survival curves were calculated for overall survival analysis. RESULTS: Our analyses showed that low serum levels of TC were associated with an increased risk of death. The association between TC and overall survival remained significant after patient age at diagnosis, gender, disease stage, histotype, tumor grade, body mass index (BMI), and smoking status were adjusted in the analysis. The patients with low serum TC had a 61% (95% confidence interval: 1.18 - 2.19) higher risk of death compared to those with normal TC. A Kaplan-Meier survival analysis showed similar results. No association was found between TC and recurrence in NSCLC. CONCLUSIONS: Our study suggests that the pre-surgical serum level of TC may be an independent prognostic indicator for NSCLC overall survival.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Colesterol/sangue , Neoplasias Pulmonares/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos
14.
Oncotarget ; 8(37): 61846-61860, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28977909

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a highly malignant cancer with poor response to both of chemotherapy and radiotherapy. 2-Acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino) phenyl carbamoylsulfanyl] propionic acid (2-AAPA), an irreversible inhibitor of glutathione reductase (GR), is able to induce intracellular oxidative stress, and has shown anticancer activity in many cancer cell lines. In this study, we investigated the effects of 2-AAPA on the cell proliferation, cell cycle and apoptosis and aimed to explore its mechanism of action in human esophageal cancer TE-13 cells. It was found that 2-AAPA inhibited growth of ESCC cells in a dose-dependent manner and it did not deplete reduced glutathione (GSH), but significantly increased the oxidized form glutathione (GSSG), resulting in decreased GSH/GSSG ratio. In consequence, significant reactive oxygen species (ROS) production was observed. The flow cytometric analysis revealed that 2-AAPA inhibited growth of esophageal cancer cells through arresting cell cycle in G2/M phase, but apoptosis-independent mechanism. The G2/M arrest was partially contributed by down-regulation of protein expression of Cdc-25c and up-regulation of phosphorylated Cdc-2 (Tyr15), Cyclin B1 (Ser147) and p53. Meanwhile, 2-AAPA-induced thiol oxidative stress led to increased protein S-glutathionylation, which resulted in α-tubulin S-glutathionylation-dependent depolymerization of microtubule in the TE-13 cells. In conclusion, we identified that 2-AAPA as an effective thiol oxidative stress inducer and proliferation of TE-13 cells were suppressed by G2/M phase cell cycle arrest, mainly, through α-tubulin S-glutathionylation-mediated microtubule depolymerization. Our results may introduce new target and approach for esophageal cancer therapy through generation of GR-mediated thiol oxidative stress.

15.
Med Sci Monit ; 23: 4619-4632, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28949934

RESUMO

BACKGROUND The immune status within the tumor microenvironment has not been well determined in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the distributions of tumor-infiltrating T lymphocytes (TILs), and analyze their associations with clinical characteristics and prognosis; as well as investigate the expression of programmed death-ligand 1 (PD-L1) which has been identified as a favorable indicator of prognosis in our previous study on ESCC. MATERIAL AND METHODS Five hundred and thirty-six patients who underwent radical surgery for ESCC between January 2008 and April 2012 in Department of Thoracic Surgery at Zhejiang Cancer Hospital were included in the study. Immunohistochemistry was used to investigate the infiltration of various TILs (CD3+, CD4+, CD8+ T lymphocytes) in ESCC tissues. Chi-square test and Cox proportional hazards regression were used to explore the correlations between TILs abundance and clinicopathological variables and survival. RESULTS The infiltration of intraepithelial CD4+ (iCD4+) lymphocytes was markedly higher than it in the stromal region (44.2% for intraepithelial versus 28.9% for stromal, p<0.001). Moreover, increased iCD4+ lymphocytes were significantly associated with longer overall survival (OS, p=0.001) in univariate analysis and were identified as an independent predictor for improved OS in multivariate analysis (hazard ratio [HR]=0.67, 95% confidence interval [CI]: 0.51-0.88, p=0.040). Neither the infiltration of CD3+ nor CD8+ lymphocytes showed the prognostic value in ESCC (p>0.05). Unexpectedly, combined with our previous study results, the TILs infiltration in ESCC showed an inverse association with the expression of PD-L1 (p=0.027). CONCLUSIONS Our results suggested that iCD4+ lymphocytes infiltration could be a favorable indicator for prognosis in ESCC.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Idoso , Antígenos CD/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/patologia , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Microambiente Tumoral/imunologia
16.
J Exp Clin Cancer Res ; 36(1): 121, 2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28882180

RESUMO

BACKGROUND: Next generation sequencing (NGS) is being increasingly applied for assisting cancer molecular diagnosis. However, it is still needed to validate NGS accuracy on detection of DNA alternations based on a large number of clinical samples, especially for DNA rearrangements and copy number variations (CNVs). This study is to set up basic parameters of targeted NGS for clinical diagnosis and to understand advantage of targeted NGS in comparison with the conventional methods of molecular diagnosis. METHODS: Genomic DNA from 1000 Genomes Project and DNA from cancer cell lines have been used to establish the basic parameters for targeted NGS. The following confirmation was conducted by clinical samples. The multiple variants tested by amplification-refractory mutation system (ARMS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were evaluated by targeted NGS to determine the sensitivity. Furthermore, the multiple variants detected by targeted NGS were confirmed by current conventional methods to elucidate the specificity. RESULTS: At sequencing depth of 500×, the maximal sensitivities on detecting single nucletic variances (SNVs) and small insertions/deletions (Indels) can reach 99% and 98.7% respectively, and in 20% of cancer cells, CNV detection can reach to the maximal level. The following confirmation of the sensitivity and specificity was conducted by a large cohort of clinical samples. For SNV and indel detection in clinical samples, targeted NGS can identify all hotspot mutations with 100% sensitivity and specificity. On ALK fusion detection, about 86% IHC-identified cases could be identified by targeted NGS and all ALK fusion detected by targeted NGS were confirmed by IHC. For HER2-amplification, 14 HER2-amplification cases identified by target NGS were all confirmed by FISH and about 93.3% of Her-2 IHC (3+) cases were identified by targeted NGS. Finally, the targeted NGS platform developed here has accurately detected EGFR hotspot mutations in 215 NSCLC patients. CONCLUSIONS: DNA from cancer cell lines is better than standard DNA as a reference to establish basic parameters for targeted NGS. Comparison of the conventional methods using a large cohort of patient samples confirmed the high preformance of targeted NGS on detecting DNA alterations.


Assuntos
Variações do Número de Cópias de DNA/genética , Rearranjo Gênico/genética , Mutação INDEL/genética , Neoplasias/genética , Quinase do Linfoma Anaplásico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Projeto Genoma Humano , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/genética , Receptor ErbB-2/genética
17.
Med Sci Monit ; 23: 3715-3721, 2017 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-28759561

RESUMO

BACKGROUND Reg4, a member of the Reg multigene family, is highly upregulated in many gastrointestinal cancers including gastric cancer (GC). The enhanced expression of Reg4 is associated with the resistance of GC to 5-fluorouracil (5-FU), while the underlying mechanism is not clear. The aim of the present study was to explore the resistant mechanism underlying 5-FU resistance. MATERIAL AND METHODS Reg4 expression was assessed by Western blot analysis for SGC-7901, BGC-823, AGS, MKN28, and MKN45. Synthetic short single strand RNA oligonucleotides and Flag-Reg4 plasmid were used to investigate the biological function of Reg4 in vitro. The cell viability assay was performed by MTT. Flow cytometry was carried out to measure the apoptosis caused by 5-FU. Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) was used to examine the expression of 5-FU metabolism related enzymes. The effect of Reg4 on intracellular signaling was evaluated by Western blot. RESULTS Western blot analysis of 5 GC cells showed that Reg4 was low or null in SGC-7901 and BGC-823, while high in AGS, MKN28, and MKN45. Over-expression of flag-Reg4 in SGC-7901 led to an increase in cell viability and lower apoptosis with 5-FU treatment. In contrast, siRNA knockdown of Reg4 enhanced 5-FU induced apoptosis. However, over-expression or knockdown of Reg4 had no significant influence on the expression of 5-FU metabolic enzymes. Further investigation revealed that Reg4 could activate Erk1/2-Bim-caspase3 cascade. CONCLUSIONS Reg4 inhibited apoptosis through regulating MAPK/Erk/Bim signaling pathway and thereby enhanced the resistance of GC to 5-FU.


Assuntos
Proteína 11 Semelhante a Bcl-2/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fluoruracila/farmacologia , Proteínas Associadas a Pancreatite/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Gástricas/patologia
18.
Cancer Med ; 6(6): 1353-1361, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440057

RESUMO

The aim of this study is to evaluate the efficacy of insulin-like growth factor 1 receptor (IGF-1R) inhibitor Linsitinib, in esophageal squamous cell carcinoma (ESCC), and to characterize special biomarker to screen Linsitinib-sensitive patients as well as explore the molecular-resistant mechanism to Linsitinib in ESCC. Our study evaluated the sensitivity of insulin-like growth factor 1 receptor (IGF-1R) inhibitor, Linsitinib in ESCC cells with MTT assay. After Linsitinib treatment, the expressions of downstream signaling molecules and apoptosis pathways were measured by western blot. And the antitumor effect of Linsitinib and JSH-23, an inhibitor of nuclear factor-κB transcriptional activity, was analyzed both as single agent and in combination in ESCC. Apoptosis, cell viability, and clonogenic survival analysis were also investigated. The sensitivity of Linsitinib was relatively variable in patient-derived primary ESCC cells as well as in human commercial cell lines. And the downstream AKT/mTOR and ERK signaling pathways were inhibited by Linsitinib, while phosphorylation level of NF-κB p65 was obviously activated to reduce apoptosis effect in Linsitinib-resistant cell lines. Most importantly, blockage of NF-κB activity by JSH-23 could sensitize resistant cells to Linsitinib treatment. Results from this study demonstrated that the intrinsic resistance to Linsitinib was predominantly mediated by NF-κB activation in ESCC. Moreover, combination of Linsitinib and JSH-23 as therapy provides a novel strategy to overcome resistance to Linsitinib in ESCC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Imidazóis/farmacologia , NF-kappa B/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Pirazinas/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-6/genética , Interleucina-8/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
19.
Oncotarget ; 8(5): 8835-8842, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-27823974

RESUMO

PURPOSE: To investigate the association between C-reactive protein/albumin ratio (CAR), an inflammation-based prognostic score, and clinicopathological factors, as well as its association with long-term outcomes in patients with operable non-small cell lung cancer (NSCLC). METHODS: A total of 617 operable NSCLC patients were retrospectively evaluated and the data of preoperative serum CRP and serum albumin was collected. The correlation between the CAR and clinicopathological factors was analyzed using the chi-square test. A Cox proportional hazards regression model was performed to evaluate the association between the CAR and outcome. RESULTS: The CAR was significantly related to sex, smoking status, BMI, histology type and clinical stage (p ≤ 0.05). The patients with characteristic of male, smoker, BMI under 18.5, squamous cell carcinoma or clinical stage III had a high level of CAR. Additionally, elevated CAR indicated a worse outcome, and the patients with higher CAR had 2.02-fold risk for disease progression (95% CI 1.48-2.74, p < 0.001) and 2.61-fold risk for death (95 % CI 2.02-3.37, p < 0.001). Multivariate analyses showed the similar results after adjusted by clinicopathological factors and another four inflammation-based prognostic scores. CONCLUSIONS: The CAR is a potential independent predictor for disease progression and death in patients with operable NSCLC.


Assuntos
Biomarcadores Tumorais/sangue , Proteína C-Reativa/análise , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Mediadores da Inflamação/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Albumina Sérica Humana/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Distribuição de Qui-Quadrado , Técnicas de Apoio para a Decisão , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Pneumonectomia/efeitos adversos , Pneumonectomia/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
20.
Oncotarget ; 7(52): 86536-86546, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-27852032

RESUMO

Our previous study found copy number variation of chromosome fragment 5p13.1-13.3 might involve in the progression of ovarian cancer. In the current study, the alteration was validated and complement component 7 (C7), located on 5p13.1, was identified. To further explore the clinical value of C7 in tumors, 156 malignant, 22 borderline, 33 benign and 24 normal ovarian tissues, as well as 173 non-small cell lung cancer (NSCLC) tissues along with corresponding adjacent and normal tissues from the tissue bank of Zhejiang Cancer Hospital were collected. The expression of C7 was analyzed using reverse transcriptase quantitative polymerase chain reaction. As a result, the C7 expression displayed a gradual downward trend in normal, benign, borderline and malignant ovarian tissues, and the decreased expression of C7 was correlative to poor differentiation in patients with ovarian cancer. Interestingly, a similar change of expression of C7 was found in normal, adjacent and malignant tissues in patients with NSCLC, and low expression of C7 was associated with worse grade and advanced clinical stage. Both results from this cohort and the public database indicated that NSCLC patients with low expression of C7 had a worse outcome. Furthermore, multivariate cox regression analysis showed NSCLC patients with low C7 had a 3.09 or 5.65-fold higher risk for relapse or death than those with high C7 respectively, suggesting C7 was an independent prognostic predictor for prognoses of patients with NSCLC. Additionally, overexpression of C7 inhibited colony formation of NSCLC cells, which hints C7 might be a potential tumor suppressor.


Assuntos
Complemento C7/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
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