Cigarette smoke upregulates Notch-1 signaling pathway and promotes lung adenocarcinoma progression. 2022

Giuseppina Chiappara, and Serena Di Vincenzo, and Claudia Sangiorgi, and Caterina Di Sano, and Claudia D'Anna, and Giovanni Zito, and Chiara Cipollina, and Patrizio Vitulo, and Alessandro Bertani, and Elisabetta Pace
Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy.

Notch-1 pathway plays an important role in lung carcinoma, stem cell regulation, cellular communication, growth and differentiation. Cigarette smoke is involved in the regulation of Notch signaling. However, current data regarding the impact of cigarette smoke on the Notch pathway in lung cancer progression are limited. The present study aimed to explore whether cigarette smoke exposure altered Notch-1 pathway in ex-vivo (surgical samples of lung parenchyma from non-smoker and smoker patients with lung adenocarcinoma) and in vitro (adenocarcinoma A549 cell line) approaches. The expression of Notch-1, Jagged-1 and CD133 in surgical samples was evaluated by immunohistochemistry. A549 were exposed to cigarette smoke extracts (2.5 % and 5 % CSE for 6, 24 and 48 h) and the expression of Notch-1, Jagged-1 and Hes-1 was evaluated by Real-Time PCR and Western Blot (nuclear fractions). Expression and localization of Notch-1, Hes-1, CD133 and ABCG2 were assessed by immunofluorescence. The expression of survivin and Ki-67 was assessed by flow cytometry following CSE exposure and inhibition of Notch-1 signaling. Smokers lung parenchyma exhibited higher expression of Notch-1. CSE exposure increased Notch-1 and Hes-1 gene and nuclear protein expression in A549. Immunofluorescence confirmed higher expression of nuclear Hes-1 in CSE-stimulated A549 cells. CSE increased both survivin and Ki-67 expression and this effect was reverted by inhibition of the Notch-1 pathway. In conclusion, these data show that cigarette smoke may promote adenocarcinoma progression by activating the Notch-1 pathway thus supporting its role as hallmark of lung cancer progression and as a new target for lung cancer treatment.

UI MeSH Term Description Entries
D008168 Lung Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood. Lungs
D009363 Neoplasm Proteins Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm. Proteins, Neoplasm
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000070997 ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-binding cassette transporter, sub-family G protein that functions as a high capacity UREA exporter, transporter of STEROLS, and in the absorption and efflux of many drugs. Its efflux activity for ANTINEOPLASTIC AGENTS contributes to DRUG RESISTANCE. It functions as a homodimer and is expressed by cells in a variety of organs, as well as by NEOPLASTIC STEM CELLS. ABCG2 Protein,ABCG2 Transporter,ATP Binding Cassette Transporter, Sub-Family G, Member 2,CD338 Antigen
D000071916 AC133 Antigen A member of the prominin family, AC133 Antigen is a 5-transmembrane antigen occurring as several isoforms produced by alternative splicing which are processed into mature forms. In humans, it is expressed as a subset of CD34 (bright) human hematopoietic stem cells and CD34 positive leukemias. Functionally, it is associated with roles in cell differentiation, proliferation, and apoptosis. Specifically, it regulates the organization of apical plasma membrane in epithelial cells, disk morphogenesis during early retinal development, MAPK and Akt signaling pathways, and in cholesterol metabolism. AC133-1 Antigen,AC133-2 Antigen,AC141 Antigen,CD133 Antigen,Fudenine,PROML1,Prominin,Prominin-1,Prominin-Like PROML1,AC133 1 Antigen,AC133 2 Antigen,Antigen, AC133,Antigen, AC133-1,Antigen, AC133-2,Antigen, AC141,Antigen, CD133,Prominin 1,Prominin Like PROML1
D000072056 Transcription Factor HES-1 A basic-helix-loop-helix transcription factor that functions as a transcriptional repressor for genes transcribed by bHLH proteins. For example, it may negatively regulate MYOGENESIS by inhibiting MyoD1 and ASH1 proteins. It is also required for the stability of FANCONI ANEMIA COMPLEMENTATION GROUP PROTEINS and their localization to the cell nucleus in response to DNA DAMAGE. Hairy and Enhancer of Split 1 Protein,Hairy-Like Transcription Factor,HES-1, Transcription Factor,Hairy Like Transcription Factor,Transcription Factor HES 1,Transcription Factor, Hairy-Like
D000072100 Jagged-1 Protein A serrate-jagged protein that functions as a ligand for NOTCH RECEPTORS. It may regulate CELL DIFFERENTIATION in HEMATOPOIESIS and PHYSIOLOGIC ANGIOGENESIS. Mutations in the Jagged-1 gene are associated with ALAGILLE SYNDROME 1. Alagille Syndrome Protein,CD339 Antigen,Jagged-1,Jagged1 Protein,Serrate-1 Protein,Serrate1 Protein,Antigen, CD339,Jagged 1,Jagged 1 Protein,Serrate 1 Protein
D000072283 A549 Cells An immortalized cell line derived from human ADENOCARCINOMA, ALVEOLAR basal epithelial cells isolated from the lungs of a male patient in 1972. The cell line is positive for KERATIN, can synthesize LECITHIN, and contains high levels of POLYUNSATURATED FATTY ACIDS in its PLASMA MEMBRANE. It is used as a model for PULMONARY ALVEOLI function and virus infections, as a TRANSFECTION host, and for PRECLINICAL DRUG EVALUATION. A549 Cell Line,A549 Cell,A549 Cell Lines,Cell Line, A549,Cell Lines, A549,Cell, A549,Cells, A549
D000073865 Cigarette Smoking The SMOKING of CIGARETTES. Smoking, Cigarette
D000074285 Smokers Persons with a history or habit of SMOKING. Smokers, Non-Tobacco Products,Smokers, Tobacco,Vapers,Non-Tobacco Products Smoker,Non-Tobacco Products Smokers,Smoker,Smoker, Non-Tobacco Products,Smoker, Tobacco,Smokers, Non Tobacco Products,Tobacco Smoker,Tobacco Smokers,Vaper

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