Pathobiology of Notch2 in lung cancer.

Notch signalling has been reported to be involved in initiation, progression, and suppression in various types of cancer. The pathological significance of Notch1 has been well studied in lung cancer, but that of Notch2 remains unclear. An immunohistochemical study was performed to clarify the expression of NOTCH2 in non-neoplastic lung tissues and lung cancers in comparison with Clara (Club) cell 10 kDa protein (CC10), and western blotting analysis was performed to detect NOTCH2 in human cancer cell lines. A Notch2 gene knockdown experiment was carried out to reveal the function of Notch2. Transient transfection of the intracellular domain of the Notch2 (N2ICD) gene was used. In addition, the relationship of the expressions of Notch1, 2, and 3 was studied. Immunohistochemical study of lung tissues revealed that NOTCH2 was detected in bronchiolar epithelial cells and was often colocalised with CC10, and that adenocarcinoma tissues were more positively stained than those of squamous cell carcinoma and small cell carcinoma. In human lung cancer cell lines, expression of NOTCH2 was similar to that of NOTCH1, and preferentially detected in non-small cell lung carcinoma (NSCLC) cell lines. Knockdown of the Notch2 gene in NSCLC cell lines showed no remarkable changes in expression of molecules associated with cell differentiation, proliferation, apoptosis, and motility, and the seemingly unvalued effects of Notch2 gene knockdown could be masked by concomitant Notch1 activation, as indicated by an increase in the intracellular domain of NOTCH1. Additionally, transient transfection of the N2ICD gene induced CC10 expression in an adenocarcinoma cell line. The present study revealed that Notch2 is important in Club cell differentiation in normal lungs and adenocarcinoma. Notch2 is regulated mutually with Notch1, and the balance of the expression of Notch receptors could determine the biological behaviours of lung cancer cells.