hes1-protein--human and Adenocarcinoma-of-Lung

Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4

Topics: Adenocarcinoma of Lung; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Receptor, Notch4; Transcription Factor HES-1

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.

Topics: A549 Cells; AC133 Antigen; Adenocarcinoma of Lung; ATP Binding Cassette Transporter, Subfamily G, Member 2; Blotting, Western; Cigarette Smoking; Gene Expression Regulation, Neoplastic; Humans; Jagged-1 Protein; Ki-67 Antigen; Lung; Neoplasm Proteins; Real-Time Polymerase Chain Reaction; Receptor, Notch1; Signal Transduction; Smokers; Survivin; Transcription Factor HES-1; Up-Regulation

Our study aimed to investigate the function of GALNT2 in lung adenocarcinoma (LUAD).. We used network tools and tissue microarray immunohistochemistry to measure the expression levels of GALNT2 in LUAD. Kaplan-Meier curves and Cox regression methods were used in survival analysis. We detected the role of GALNT2 in cell lines by Cell Counting Kit-8, colony formation, transwell, and wound healing assays. We performed Western blotting to evaluate downstream protein levels.. GALNT2 was highly expressed in LUAD samples and indicated a poor prognosis. Knockdown of GALNT2 suppressed cell line proliferation, migration, and invasion abilities, while overexpression of GALNT2 enhanced those phenotypes. Moreover, GALNT2 activated Notch/Hes1-PTEN-PI3K/Akt signaling axis.. Our data confirmed the cancer-promoting effect of GALNT2, and might provide a new approach for LUAD therapy.

Topics: Adenocarcinoma of Lung; Aged; Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; N-Acetylgalactosaminyltransferases; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Polypeptide N-acetylgalactosaminyltransferase; Prognosis; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptor, Notch1; Survival Rate; Transcription Factor HES-1; Tumor Cells, Cultured

Tumor angiogenesis plays important roles in the pathogenesis and prognosis of lung cancer. Both vascular endothelial growth factor (VEGF) and Dll4/Notch pathways are critical for angiogenesis, whereas their relationship under hypoxia in lung cancer remains unknown. Thus, in the present study, we evaluated the expression of VEGF and Dll4/Notch signaling molecules, and assessed their association with the microvessel density (CD31) and hypoxia (HIF1a) in lung cancer and normal lung tissues using immunohistochemical and Real-time RT-PCR techniques. Then, we investigated the biological function of Dll4 by transfecting Dll4 into HUVECs. In lung cancer tissues, Notch pathway molecules (HES1) and VEGF pathway molecules (VEGFR1 and VEGFR2) were significantly up-regulated, while the ratio of VEGFR1/VEGFR2 was decreased. CD31 and HIF1a were also found to be elevated in lung cancer. VEGFR1 was negatively correlated with Notch1 while positively correlated with Dll4. CD31 was positively correlated with HIF1a but negatively correlated with VEGFR1. Moreover, HIF1a was nearly positively correlated with HES1 in lung cancer tissues. After transfection, Dll4, Notch1 and VEGFR1 were up-regulated while VEGF and VEGFR2 were down-regulated in Dll4-transfected HUVECs compared with controls. Also, our findings suggest that the expression of VEGF and VEGFR2 increased gradually with the disease progression of lung cancer. In summary, VEGF and Notch signaling pathway molecules were overexpressed in lung cancer, which positively correlates with hypoxia (HIF1a) and angiogenesis (CD31). There might be a negative feedback loop between VEGF and Dll4/Notch signaling pathway in lung tumor angiogenesis.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors; Calcium-Binding Proteins; Carcinoma, Squamous Cell; Cells, Cultured; Disease Progression; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Signaling Peptides and Proteins; Lung; Lung Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Notch; Retrospective Studies; Signal Transduction; Transcription Factor HES-1; Umbilical Veins; Up-Regulation; Vascular Endothelial Growth Factor A