Unknown,Transcriptomics,Genomics,Proteomics

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Downstream targets of ID1 transcription factor in Non-Small Cell Lung Carcinoma (NSCLC)

ABSTRACT: ID-1, known as inhibitor of differentiation or a helix loop helix transcription factor which lack the basic DNA binding domain. It is known to bind to bHLH transcription factor and inhibit those bHLH to bind to the promoter thus inhibiting further transcription. Overexpression of ID-1 has been correlated with a variety of human cancers including breast, prostate, pancreatic, ovarian, endometrial, bladder cancer and melanomas. Recently known that if ID-1 is depleted, it abrogates cell proliferation, invasion and migration of cells in NSCLC. Further ID-1 expression is induced by Nicotine and EGF through the activation of nAChRs and EGFR. Here microarray analysis was done to compare differential gene expression patterns upon nicotine and EGF stimulation of A549 and H1650 cells and how ID1 depletion changes these patterns. We find that multiple genes are affected and the role of these genes in lung cancer will be elucidated. In this study we show that ID-1 regulates the expression of three genes STMN3, TPD52 and GSPT1 in NSCLC by activating the promoter of these genes either directly or indirectly. We also show that depletion of STMN3, TPD52 and GSPT1 prevented Nicotine and EGF induced cell proliferation, invasion and migration of cells in NSCLC. Two cell lines (A549, H1650) each having 5 samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Deepak Perumal

PROVIDER: E-GEOD-38944 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The main constituents of electronic cigarette liquids are nicotine, propylene glycol (PG), and vegetable glycerin (VG), together with distilled water and flavors. To assess the toxicity of PG/VG mixtures with and without nicotine as basic components of liquids used in e-cigarettes, a 90-day rat inhalation study according to the Organization for Economic Co-operation and Development test guideline 413 was conducted. Sprague-Dawley (SD) rats were nose-only exposed, 6â€‰h/day, 5 days/week to filtered air, or nebulized vehicle (saline), or three concentrations of PG/VG (0.174 mg PG/l + 0.210 mg VG/l; 0.520 mg PG/l + 0.630 mg VG/l; 1.520 mg PG/l + 1.890 mg VG/l) with (test item) and without (reference item) 23 µg nicotine/L. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared to vehicle exposure, the tested PG/VG aerosols showed only very limited biological effects with no signs of toxicity, both for the standard toxicological endpoints (e.g., histopathology, clinical chemistry) and the systems toxicological analyses (transcriptomics, proteomics, and lipidomics). The addition of nicotine to the PG/VG aerosols (23 Âµg/l) resulted in effects in line with nicotine effects in previous studies. These included up-regulation of xenobiotic enzymes (Cyp1a1 and Fmo3) in the lung and metabolic effects, e.g., reduction in serum lipid concentrations and changes in the expression of metabolic enzymes in the liver. Signs of a generalized stress response to nicotine exposure such as decreased thymus weights were observed; and likely, a subset of the observed metabolic alterations was interlinked with this generalized stress response. Under the conditions of this 90-day SD rat inhalation study, no toxicologically relevant effects of PG/VG aerosols (up to 1.520 mg PG/l + 1.890 mg VG/l) were observed, and the no observed adverse effect level (NOAEL) for PG/VG/nicotine was determined to be 438/544/6.7 mg/kg/day. Further the study demonstrated how complementary systems toxicology analyses can reveal, also in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine.

Project description:The main constituents of electronic cigarette liquids are nicotine, propylene glycol (PG), and vegetable glycerin (VG), together with distilled water and flavors. To assess the toxicity of PG/VG mixtures with and without nicotine as basic components of liquids used in e-cigarettes, a 90-day rat inhalation study according to the Organization for Economic Co-operation and Development test guideline 413 was conducted. Sprague-Dawley (SD) rats were nose-only exposed, 6 h/day, 5 days/week to filtered air, or nebulized vehicle (saline), or three concentrations of PG/VG (0.174 mg PG/l + 0.210 mg VG/l; 0.520 mg PG/l + 0.630 mg VG/l; 1.520 mg PG/l + 1.890 mg VG/l) – with (test item) and without (reference item) 23 µg nicotine/L. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared to vehicle exposure, the tested PG/VG aerosols showed only very limited biological effects with no signs of toxicity, both for the standard toxicological endpoints (e.g., histopathology, clinical chemistry) and the systems toxicological analyses (transcriptomics, proteomics, and lipidomics). The addition of nicotine to the PG/VG aerosols (23 µg/l) resulted in effects in line with nicotine effects in previous studies. These included up-regulation of xenobiotic enzymes (Cyp1a1 and Fmo3) in the lung and metabolic effects, e.g., reduction in serum lipid concentrations and changes in the expression of metabolic enzymes in the liver. Signs of a generalized stress response to nicotine exposure such as decreased thymus weights were observed; and likely, a subset of the observed metabolic alterations was interlinked with this generalized stress response. Under the conditions of this 90-day SD rat inhalation study, no toxicologically relevant effects of PG/VG aerosols (up to 1.520 mg PG/l + 1.890 mg VG/l) were observed, and the no observed adverse effect level (NOAEL) for PG/VG/nicotine was determined to be 438/544/6.7 mg/kg/day. Further the study demonstrated how complementary systems toxicology analyses can reveal, also in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine.

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Downstream targets of ID1 transcription factor in Non-Small Cell Lung Carcinoma (NSCLC)

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