We recently reported that 14-3-3sigma is frequently inactivated in small cell lung cancer (SCLC) and a part of large cell carcinomas. Subsequent studies revealed that the large cell carcinomas could be morphologically categorized as large cell neuroendocrine carcinomas (LCNEC). The present study therefore examines 14-3-3sigma expression in a spectrum of neuroendocrine lung tumors, which had varied p53 status, proliferative activity and clinical aggressiveness. The expression of 14-3-3sigma was decreased in all four categories of the spectrum, (5 out of 5 typical carcinoids, 2 out of 2 atypical carcinoids, 5 out of 7 LCNECs and 15 out of 18 SCLCs). In sharp contrast, the level of 14-3-3sigma expression in 75 non-small cell lung cancers (NSCLCs) was the same as that in normal lung tissue, with only one exception. The expression status of neuroendocrine tumors and NSCLCs was not affected by p53 status, but dense promoter hypermethylation of the 14-3-3sigma gene was specifically observed in neuroendocrine tumors, suggesting that methylation plays a regulatory role in 14-3-3sigma expression in vivo as well as in vitro. Furthermore, the expression was not only down-regulated in pulmonary neuroendocrine tumors, but also in neuroendocrine tumors arising from various other organs, through examination of 123 non-pulmonary tumors. Since various carcinogenic machineries are involved in the neuroendocrine tumors, a reduced expression of 14-3-3sigma might be required for the development of neuroendocrine tumors. Constitutive 14-3-3sigma expression was distributed exclusively in putative stem cells of the normal lung, namely the basal cells of the bronchus, and type II pneumocytes. Notably, 14-3-3sigma expression was up-regulated during the regeneration of type II pneumocytes, suggesting that 14-3-3sigma plays a biological role when a regenerative and/or differentiating drive is activated, facilitating exit from stem cells.