Notch1 signaling controls cell proliferation, apoptosis and differentiation in lung carcinoma

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 85; no. 2; pp. 131 - 140
• Main Authors: Wael, Hassan, Yoshida, Ryoji, Kudoh, Shinji, Hasegawa, Kohki, Niimori-Kita, Kanako, Ito, Takaaki
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ireland Ltd 01.08.2014; Elsevier
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Biological and medical sciences; Carcinoma, Neuroendocrine - genetics; Carcinoma, Neuroendocrine - metabolism; Carcinoma, Neuroendocrine - pathology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Epithelial phenotype; Gene Expression; Gene Knockdown Techniques; Hematology, Oncology and Palliative Medicine; Heterografts; Human lung carcinoma; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Knockout; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Grading; Neuro-endocrine differentiation; Notch1 signaling; Pneumology; Pulmonary/Respiratory; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Signal Transduction; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Tumors; Tumors of the respiratory system and mediastinum; Cell proliferation; Human lung carcinoma; Epithelial phenotype; Notch1 signaling; Neuro-endocrine differentiation; Apoptosis; Human; Lung disease; Respiratory disease; Lung cancer; Check; Malignant tumor; Bronchopulmonary carcinoma; Cell differentiation; Epithelium; Control; Phenotype; Regulation(control); Surveillance; Bronchus disease; Differentiation; Cancer
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2014.05.001

Abstract Objectives The role of Notch signaling in human lung cancer still remains unclear, and there has been and stills a debate, on the extent to which Notch ligands and receptors are involved in lung cancer development. This study was carried out to investigate the role of Notch1 signaling in the proliferation and differentiation of human lung cancer cells. Methods We used small interfering RNA (siRNA) technology to down-regulate the expression of Notch1 in small cell lung carcinoma (SCLC) cells; H69AR and SBC-3, as well as in non-small cell lung carcinoma (NSCLC) cells; A549 adenocarcinoma (ADC) and H2170 squamous cell carcinoma (SCC). Also, we transfected venus Notch1 intracellular domain (v.NICD) plasmid into the human SCLC line H69 and H1688. In addition, H1688 cells with activated Notch1 were injected into immune-compromised Rag2(−/−) Jak3(−/−) mice for analysis of ex vivo tumor growth and differentiation phenotype. Results Notch1 controls cell proliferation and apoptosis in both SCLC and A549; but not in H2170 cell line. Overexpression of Notch1 in SCLC markedly decreased cell proliferation via apoptosis. The subcutaneous tumors arising from xenotransplaned SCLC cells transfected with Notch1 showed “epithelial-like glandular” arrangement, with positive Alcian blue staining and reduction in neuroendocrine markers. Conclusion Notch1 up regulation has an inhibitory effect on cell growth and NE differentiation in SCLC, with induction of an epithelial-like morphology of cells in tissue samples. In NSCLC, Notch1 expression has a tumor inhibitory effect on ADC cells, but not SCC cells.