scholarly journals Significance of Methylation of FBP1 Gene in Non-Small Cell Lung Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Yao Dong ◽  
Sheng Huaying ◽  
Wan Danying ◽  
Zhu Chihong ◽  
Jiang Ruibin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Methylation Status ◽  
Gene Promoter ◽  
Fructose 1,6 Bisphosphatase ◽  
Promoter Dna ◽  
Therapy Target ◽  
Nsclc Patients ◽  
Rate Limiting ◽  
Fbp1 Gene

Because NSCLC has poor overall prognosis and is frequently diagnosed at later stage, we aimed to seek novel diagnosis biomarkers or therapy target of the disease in this study. Fructose-1,6-bisphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis, which was usually lost in NSCLC due to abnormal methylation in promoter DNA sequence. The clinical data indicated that the methylation rate in FBP1 gene promoter was negatively related to the overall survival of the NSCLC patients. DNA methylation transferase inhibitor 5-aza treatment could significantly increase both expression levels of mRNA and protein in A549 cell line. On the other hand, silence of FBP1 in H460 cell line by using specific siRNA against FBP1 dramatically improved the cell proliferation and cell migration according to the date of FACS and transwell assays. All these findings implied the important roles of FBP1 expression in lung cancer development and progression and the potential use of the methylation status detected in FBP1 promoter region as a novel predictor for prognosis and therapeutic target for NSCLC patients.

scholarly journals Elevated Exosome-derived Mirnas Predict Osimertinib Resistance in Non-small Cell Lung Cancer

2020 ◽  
Author(s):  
Xinying Li ◽  
Cen Chen ◽  
Zimu Wang ◽  
Jiaxin Liu ◽  
Wei Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Small Cell ◽  
Small Cell Lung ◽  
Expression Levels ◽  
Exosomal Mirnas ◽  
Nsclc Patients ◽  
Serum Exosomes

Abstract Background: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. In recent years, many studies have been focusing on the ability of exosomal miRNAs secreted by tumor cells to transmit resistance information. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored.Methods: We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients.Results: Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 (p = 0.0325) and miR-3913-5p (p = 0.0169) expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-184 was correlated with lactate dehydrogenase levels (p = 0.018). Exosomal miR-3913-5p was associated with TNM stage (p = 0.045), platelet count (p = 0.024), tumor marker carcinoembryonic antigen (p = 0.045), and distant metastases (p = 0.049), especially bone metastasis (p = 0.03). In the subgroup of patients with EGFR exon 21 L858R point mutation, miR-184 (p = 0.0104) and miR-3913-5p (p = 0.0085) derived from serum exosomes had both significantly increased expression levels. In the subgroup of T790M-positive patients, miR-3913-5p derived from serum exosomes may also be a good indicator of osimertinib resistance (p = 0.013).Conclusions: The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.

14-3-3σ Methylation in Pretreatment Serum Circulating DNA of Cisplatin-Plus-Gemcitabine-Treated Advanced Non–Small-Cell Lung Cancer Patients Predicts Survival: The Spanish Lung Cancer Group

2005 ◽  
Vol 23 (36) ◽  
pp. 9105-9112 ◽  
Author(s):  
José Luis Ramirez ◽  
Rafael Rosell ◽  
Miquel Taron ◽  
Maria Sanchez-Ronco ◽  
Vicente Alberola ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Median Survival ◽  
Methylation Status ◽  
Small Cell ◽  
Small Cell Lung ◽  
Positive Group ◽  
Platinum Based Chemotherapy ◽  
Nsclc Patients ◽  
Pretreatment Serum

Purpose Survival in patients with advanced non–small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3σ, a major G2-M checkpoint control gene, could be a predictor of longer survival. Patients and Methods A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3σ methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine–treated advanced NSCLC patients. Results 14-3-3σ methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3σ methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001). Conclusion Methylation of 14-3-3σ is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

Predicting gene promoter methylation in lung tumors through examination of sputum and serum

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7208-7208
Author(s):  
S. A. Belinsky ◽  
M. Grimes ◽  
D. Johnson ◽  
D. Levy ◽  
J. Schiller
Keyword(s):  
Lung Cancer ◽  
Cell Function ◽  
Biological Fluids ◽  
Methylation Status ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Phase Iii ◽  
Advanced Lung Cancer

7208 Background: Personalized medicine may be a key approach in improving survival for advanced lung cancer. Success for this approach is seen with the response of cancer patients with an activating mutation within the epidermal growth factor receptor to the growth fact inhibitor, gefitinib. Genes involved in all types of normal cell function are targeted for inactivation by promoter hypermethylation during lung cancer development. This makes gene-specific promoter hypermethylation an attractive target for novel treatment strategies. One obstacle to targeted therapy is accessibility of tissue from peripheral tumors for methylation analysis. The purpose of this study was to determine the predictive power of sputum and serum to detect NSCLC through analysis for methylation of genes in these fluids. Methods: Tissue, serum, and sputum were obtained from 72 stage III NSCLC patients participating in a Phase III trial of Carboplatin, Paclitaxel and Radiotherapy, With or Without Thalidomide (ECOG 3598). Methylation specific PCR assessed methylation of the p16, MGMT, DAPK, RASSF1A, PAX5-α, PAX5-β, H-cadherin, and GATA5 genes. Results: At least one gene was methylated in 89% of tumors. Prevalence for methylation ranged from 15–47% and did not differ between gender. Methylation of ≥ 3 genes was seen in ∼50% of tumors. The agreement between sputum or serum in classifying methylation status of any gene in the tumor ranged from 54– 69%. The reduced sensitivity was presumably due in part to absence of tumor DNA in the biological fluids of methylation positive tumors. Logistic regression models revealed 3.1 (CI, 1.2, 8.2) and 4.2 (1.1, 16.1) increased odds for methylation of the p16 and MGMT gene, respectively in tumors if the serum or sputum was positive for methylation. The effect of tumor histology for predicting methylation using sputum and serum is being examined. Conclusion: These studies demonstrate for genes such as p16 and MGMT the possibility of interrogating biological fluids to predict for methylation in the primary tumor. (Supported by CA-89551). No significant financial relationships to disclose.

scholarly journals Elevated exosome-derived miRNAs predict osimertinib resistance in non-small cell lung cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xinying Li ◽  
Cen Chen ◽  
Zimu Wang ◽  
Jiaxin Liu ◽  
Wei Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Expression Levels ◽  
Exosomal Mirnas ◽  
Nsclc Patients

Abstract Background Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. Recently, the drug resistance information transmitted by exosomal miRNAs has attracted much attention. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored. Methods We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients. Results Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 and miR-3913-5p expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-3913-5p was associated with TNM stage, platelet count, tumor marker carcinoembryonic antigen, and distant metastases. In patients with EGFR exon 21 L858R mutation, the increased expression levels of miR-184 and miR-3913-5p derived from serum exosomes indicated osimertinib resistance. Similarly, for T790M-positive patients, the level of exosome-derived miR-3913-5p can be used as a predictive marker for osimertinib resistance. Conclusions The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance. Graphic Abstract

CBIO-28. IDENTIFYING THE ROLE OF MISMATCH REPAIR IN TEMOZOLOMIDE-INDUCED ATR ACTIVATION FOR MGMT-METHYLATED GLIOBLASTOMA MULTIFORME

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi32-vi33
Author(s):  
Sachita Ganesa ◽  
Amrita Sule ◽  
Ranjini Sundaram ◽  
Ranjit Bindra
Keyword(s):  
Glioblastoma Multiforme ◽  
Cell Line ◽  
Mismatch Repair ◽  
Methylation Status ◽  
Gene Promoter ◽  
Mgmt Gene ◽  
Mgmt Promoter ◽  
Atr Activation ◽  
Mmr Proteins

Abstract The methylation status of the O6-methyl guanine methyltransferase (MGMT) gene promoter is a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ) in many solid tumors including gliomas and colorectal cancers. It is well established that patients with a methylated MGMT promoter (MGMT-) who are treated with the TMZ have a better overall survival than patients with an unmethylated MGMT promoter (MGMT+). The enzyme produced by the MGMT gene is responsible for removing cytotoxic O6-methylguanine (O6-meG) lesions formed by TMZ. In the MGMT- setting, the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Published work from our group reported differential activation of the ataxia telangiectasia and RAD3 related protein (ATR) in MGMT- and MGMT+ glioblastoma multiforme (GBM) cells in response to TMZ treatment, as demonstrated through the phosphorylation of CHK1. Though it is known that MMR proteins are involved in ATR activation, the specific MMR proteins required for ATR activation by TMZ-induced alkyl lesions remain unknown in the MGMT- setting. Here, we demonstrate that specific mismatch repair proteins, including MSH2, MSH6, and PMS2 play a role in ATR activation in the presence of O6-meG lesions. We show that there is potent synergy with ATRi and TMZ in the MGMT- MMR- proficient GBM cell line, which is abrogated in an shMMR MGMT- GBM cell line. Additionally, we observe decreased levels of pCHK1 in the shMMR MGMT- setting compared to the MGMT- MMR-proficient cells, suggesting that MMR is integral in the activation of ATR upon TMZ treatment. Mechanistic understanding of how the MMR system is involved in ATR activation by TMZ can ultimately be exploited for therapeutic gain.

scholarly journals Relationship of SNP rs2645429 in Farnesyl-Diphosphate Farnesyltransferase 1 Gene Promoter with Susceptibility to Lung Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Mehdi Dehghani ◽  
Zahra Samani ◽  
Hassan Abidi ◽  
Leila Manzouri ◽  
Reza Mahmoudi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Metabolic Pathways ◽  
Mevalonate Pathway ◽  
Gene Promoter ◽  
Nonsmall Cell Lung Cancer ◽  
Protective Role ◽  
Significant Relation ◽  
Nsclc Patients ◽  
Relationship Of ◽  
The Relationship

Background and Purpose. The mevalonate pathway is one of the major metabolic pathways that use acetyl-CoA to produce sterols and isoprenoids. These compounds can be effective in the growth and development of tumors. One of the enzymes involved in the mevalonate pathway is FDFT1. Different variants of this gene are involved in the risk of suffering various diseases. The present study examined the relationship between FDFT1 rs2645429 polymorphism and the risk of nonsmall cell lung cancer (NSCLC) in a population from southern Iran.Method. The genotypes of rs2645429 polymorphism of FDFT1 gene were examined in 95 samples: 34 patients with NSCLC and 61 healthy individuals by RFLP method.Results. The results of this study indicated that C allele of this polymorphism was effectively associated with the risk of NSCLC in the Iranian population (pvalue = 0.023; OR = 2.71; 95% CI = 1.12–6.59) and CC genotype has significant relation with susceptibility to NSCLC (pvalue = 0.029; OR = 3.02; 95% CI = 1.09–8.39). This polymorphism is located in the promoter region FDFT1 gene, and CC genotype may increase the activity of this promoter. This study also found a significant relationship between C allele and metastatic status. C allele was more common in NSCLC patients. (p=0.04).Conclusion. C allele of FDFT1 rs2645429 polymorphism gene can be a risk factor for NSCLC, whereas T allele probably has a low protective role.

Sign in / Sign up

Export Citation Format

Share Document