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

Hassan Wael; Ryoji Yoshida; Shinji Kudoh; Kohki Hasegawa; Kanako Niimori-Kita; Takaaki Ito

doi:10.1016/j.lungcan.2014.05.001

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

Lung Cancer. 2014 Aug;85(2):131-40. doi: 10.1016/j.lungcan.2014.05.001. Epub 2014 May 13.

Authors

Hassan Wael¹, Ryoji Yoshida², Shinji Kudoh³, Kohki Hasegawa³, Kanako Niimori-Kita³, Takaaki Ito⁴

Affiliations

¹ Department of Pathology and Experimental Medicine, Kumamoto University, Graduate School of Medical Sciences, Japan; Department of Pathology, Faculty of Medicine, Suez Canal University, Egypt.
² Department of Oral and Maxillofacial Surgery, Kumamoto University, Graduate School of Medical Sciences, Japan.
³ Department of Pathology and Experimental Medicine, Kumamoto University, Graduate School of Medical Sciences, Japan.
⁴ Department of Pathology and Experimental Medicine, Kumamoto University, Graduate School of Medical Sciences, Japan. Electronic address: takaito@kumamoto-u.ac.jp.

PMID: 24888228
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.

Keywords: Apoptosis; Cell proliferation; Epithelial phenotype; Human lung carcinoma; Neuro-endocrine differentiation; Notch1 signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis* / genetics
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
Gene Expression
Gene Knockdown Techniques
Heterografts
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology*
Mice
Mice, Knockout
Neoplasm Grading
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism*
Signal Transduction*
Small Cell Lung Carcinoma / metabolism
Small Cell Lung Carcinoma / pathology

Substances

Receptor, Notch1