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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the last decade, high-throughput technologies including genomic, epigenomic, transcriptomic and proteomic have been applied to further our understanding of the molecular pathogenesis of this heterogeneous disease, and to develop strategies that aim to improve the management of patients with lung cancer. Ultimately, these approaches should lead to sensitive, specific and noninvasive methods for early diagnosis, and facilitate the prediction of response to therapy and outcome, as well as the identification of potential novel therapeutic targets. Genomic studies were the first to move this field forward by providing novel insights into the molecular biology of lung cancer and by generating candidate biomarkers of disease progression. Lung carcinogenesis is driven by genetic and epigenetic alterations that cause aberrant gene function; however, the challenge remains to pinpoint the key regulatory control mechanisms and to distinguish driver from passenger alterations that may have a small but additive effect on cancer development. Epigenetic regulation by DNA methylation and histone modifications modulate chromatin structure and, in turn, either activate or silence gene expression. Proteomic approaches critically complement these molecular studies, as the phenotype of a cancer cell is determined by proteins and cannot be predicted by genomics or transcriptomics alone. The present article focuses on the technological platforms available and some proposed clinical applications. We illustrate herein how the "-omics" have revolutionised our approach to lung cancer biology and hold promise for personalised management of lung cancer.
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PMID:High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications. 1964 24

Lung cancer is the leading cause of cancer deaths. Despite optimal diagnosis and early treatment, many patients die of recurrent disease. There are no sufficiently useful biomarkers to predict the risk of tumor recurrence. Here, we show that expression of histone macroH2A1.1 and macroH2A2 predicts lung cancer recurrence, identifying these histone variants as a novel tool for an improved risk stratification of cancer patients. Moreover, macroH2A isoforms are highly expressed in cells undergoing senescence, a known antitumor mechanism, suggesting macroH2A1.1 may be a useful biomarker for senescent cells in tumors.
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PMID:Histone macroH2A isoforms predict the risk of lung cancer recurrence. 1964 62

Cigarette smoke (CS) is a major cause of lung cancer and a contributor to the development of a wide range of other malignancies. There is an acute need to develop a methodology that can rapidly assess the potential carcinogenic properties of the genotoxic agents present in CS. We recently reported that exposure of normal human bronchial epithelial cells (NHBEs) or A549 pulmonary carcinoma cells to CS induces the activation of ATM through its phosphorylation on Ser1981 and phosphorylation of histone H2AX on Ser139 (gammaH2AX) most likely in response to the formation of potentially carcinogenic DNA double-strand breaks (DSBs). To obtain a more complete view of the DNA damage response (DDR) we explored the correlation between ATM activation, H2AX phosphorylation, activation of Chk2 through its phosphorylation on Thr68, and phosphorylation of p53 on Ser15 in NHBE and A549 cell exposed to CS. Multiparameter analysis by laser scanning cytometry made it possible to relate these DDR events, detected immunocytochemically, with cell cycle phase. The CS-dose-dependent induction and increase in the extent of phosphorylation of ATM, Chk2, H2AX, and p53 were seen in both cell types. ATM and Chk2 were phosphorylated approximately 1 h prior to phosphorylation of H2AX and p53. The dephosphorylation of ATM, Chk2, and H2AX was seen after 2 h following CS exposure. The dose-dependency and kinetics of DDR were essentially similar in both cell types, which provide justification for the use of A549 cells in the assessment of genotoxicity of CS in lieu of normal bronchial epithelial cells. The observation that DDR was more pronounced in S-phase cells is consistent with the mechanism of induction of DSBs occurring as a result of collision of replication forks with primary lesions such as DNA adducts that can be caused by CS-generated oxidants. The cytometric assessment of CS-induced DDR provides a means to estimate the genotoxicity of CS and to explore the mechanisms of the response as a function of cell cycle phase and cell type.
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PMID:DNA damage response induced by tobacco smoke in normal human bronchial epithelial and A549 pulmonary adenocarcinoma cells assessed by laser scanning cytometry. 1965 74

Menin upregulates transcription of cell-cycle inhibitors to suppress endocrine tumors, but it is poorly understood how menin suppresses non-endocrine tumors such as lung cancer. Here, we show that menin inhibits proliferation of human lung cancer cells and growth of lung cancer in mice. The menin-mediated tumor suppression requires repression of growth factor pleiotrophin (PTN), which binds to its cell surface receptor, anaplastic lymphoma kinase (ALK) that is activated in certain lung adenocarcinomas. Menin represses PTN transcription and PTN-induced proliferation of human lung cancer cells, and menin expression is substantially reduced in primary human lung adenocarcinomas. Notably, menin binds the PTN locus and enhances Polycomb gene Enhancer of Zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27m3), a negative mark for gene transcription but does not affect histone H3K4 methylation that is usually upregulated by menin in endocrine cells. Together, our findings indicate that menin suppresses lung cancer partly through increasing Polycomb gene-mediated H3K27 methylation and repressing PTN transcription, unraveling a novel, epigenetically regulated PTN-ALK signaling pathway in suppressing lung cancer.
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PMID:Suppression of lung adenocarcinoma through menin and polycomb gene-mediated repression of growth factor pleiotrophin. 1974 96

PURPOSE Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by both histone and nonhistone-mediated mechanisms. It also enhances the anticancer effects of platinum compounds and taxanes in non-small-cell lung cancer (NSCLC) cell lines. This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and paclitaxel in patients with advanced-stage NSCLC. PATIENTS AND METHODS Patients with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned (2:1) to carboplatin (area under the curve, 6 mg/mL x min) and paclitaxel (200 mg/m(2) day 3) with either vorinostat (400 mg by mouth daily) or placebo. Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a maximum of six cycles. The primary end point was comparison of the response rate. Results Ninety-four patients initiated protocol therapy. Baseline patient characteristics were similar between the two arms. The median number of cycles was four for both treatment arms. The confirmed response rate was 34% with vorinostat versus 12.5% with placebo (P = .02). There was a trend toward improvement in median progression-free survival (6.0 months v 4.1 months; P = .48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P < .05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more frequent with vorinostat. CONCLUSION Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy for treatment of NSCLC.
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PMID:Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. 1993 8

Epigenetics is a mechanism of reversible and heritable regulation of gene transcription in contrast to genetic or DNA-coding information. In higher vertebrae, epigenetics consist of methylation of cytosine and histone modification. Mainly as detection is easier, aberrant DNA methylation was studied since the middle of '80s and recently convenient kit makes easy for study of histone modification. DNA methylation and histone modification meet in the end of '90s and regulation of transcription has being revealed. In this review, a history of epigenetics is commented briefly and recent proceedings of epigenetic change in lung cancer including micro RNA inactivation by DNA methylation and multigenetic analyses in non-small cell lung cancer is discussed.
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PMID:[Recent proceedings in epigenetics research of lung cancer]. 1999 29

Recent studies have identified FKBP51 (FK506-binding protein 51) as a sensitive biomarker of corticosteroid responsiveness in vivo. In this work, we have elucidated the molecular mechanisms underlying the induction of FKBP51 by the glucocorticoid receptor (GR) in human A549 lung cancer cells showing robust accumulation of FKBP51 mRNA in response to dexamethasone exposure. Our quantitative chromatin immunoprecipitation scans and enhancer activity analyses indicate that activation of the FKBP51 locus by glucocorticoids in vivo is triggered by the loading of GR to enhancers at about 34 kb 5' and about 87 kb 3' of the transcription start site. Interestingly, the region encompassing these enhancers is bordered by CCCTC-binding factor- and cohesin-binding sites. Dexamethasone treatment also decreased the histone density at several regions of the gene, which was paralleled with the occupancy of SWI/SNF chromatin remodeling complexes within the locus. Moreover, silencing of BRM subunit of the SWI/SNF complex blunted the glucocorticoid induction of the locus. The proximal promoter region along with the major intronic enhancer at approximately 87 kb, at which the GR binding peaked, had elevated levels of histone 3 acetylation and H3K4 trimethylation, whereas H3K36 trimethylation more generally marked the gene body and reflected the occupancy of RNA polymerase II. The occurrence of these active chromatin marks within the FKBP51 locus before glucocorticoid exposure suggests that it is poised for transcription in A549 cells. Taken together, these results indicate that the holo-GR is capable of activating transcription and evoking changes in chromatin structure through distant-acting enhancers.
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PMID:Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. 2009 18

Epigenetic is the study of heritable changes in gene expression that occur without changes in DNA sequence. This process is important for gene expression and genome stability and its disruption is now thought to play a key role in the onset and progression of numerous tumor types. The most studied epigenetic phenomena includes post-translational modifications in DNA and histone proteins as well as microRN As expression. As epigenetic aberrations are potentially reversible, their correction has emerged as a potential strategy for the treatment of cancer. This review highlights the roles of chromatin epigenetic modifications and of microRN As expression in lung tumorigenesis and discusses the emerging epigenetic therapies which are being developed for the treatment of lung cancer.
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PMID:Lung cancer: a modified epigenome. 2013 98

(-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. Nevertheless, the dose-response relationship of the inhibitory activity in vivo has not been systematically characterized. The present studies were conducted to address these issues, as well as the involvement of reactive oxygen species (ROS), in the inhibitory action of EGCG in vivo and in vitro. We characterized the inhibitory actions of EGCG against human lung cancer H1299 cells in culture and in xenograft tumors. The growth of tumors was dose dependently inhibited by EGCG at doses of 0.1, 0.3 and 0.5% in the diet. Tumor cell apoptosis and oxidative DNA damage, assessed by the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylated histone 2A variant X (gamma-H2AX), were dose dependently increased by EGCG treatment. However, the levels of 8-OHdG and gamma-H2AX were not changed by the EGCG treatment in host organs. In culture, the growth of viable H1299 cells was dose dependently reduced by EGCG; the estimated concentration that causes 50% inhibition (IC(50)) (20 microM) was much higher than the IC(50) (0.15 microM) observed in vivo. The action of EGCG was mostly abolished by the presence of superoxide dismutase (SOD) and catalase, which decompose the ROS formed in the culture medium. Treatment with EGCG also caused the generation of intracellular ROS and mitochondrial ROS. Although EGCG is generally considered to be an antioxidant, the present study demonstrates the pro-oxidative activities of EGCG in vivo and in vitro in the described experimental system.
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PMID:Pro-oxidative activities and dose-response relationship of (-)-epigallocatechin-3-gallate in the inhibition of lung cancer cell growth: a comparative study in vivo and in vitro. 2015 51

A number of histone demethylases have been identified and biochemically characterized, but the pathological roles of their dysfunction in human disease like cancer have not been well understood. Here, we demonstrate important roles of lysine-specific demethylase 1 (LSD1) in human carcinogenesis. Expression levels of LSD1 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (p < 0.0001). cDNA microarray analysis also revealed its transactivation in lung and colorectal carcinomas. LSD1-specific small interfering RNAs significantly knocked down its expression and resulted in suppression of proliferation of various bladder and lung cancer cell lines. Concordantly, introduction of exogenous LSD1 expression promoted cell cycle progression of human embryonic kidney fibroblast cells. Expression profile analysis showed that LSD1 could affect the expression of genes involved in various chromatin-modifying pathways such as chromatin remodeling at centromere, centromeric heterochromatin formation and chromatin assembly, indicating its essential roles in carcinogenesis through chromatin modification.
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PMID:Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. 2033 81


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