Endocrine Abstracts

Tobacco smoke (TS) is the major cause of lung cancer, including pulmonary neuroendocrine tumors such as small cell lung cancer and large cell neuroendocrine carcinoma. Unlike squamous cell carcinomas and adenocarcinomas, the precursor lesions for subtypes of pulmonary neuroendocrine tumors have not been historically defined, and theexpression of neuroendocrine markers has been served as critical indices for the identification of these tumors. Mitogen-activated protein kinases (MAPKs) pathways play central roles in the development of cancer. To date, the role and regulation of MAPK pathways in TS-induced abnormal pulmonary neuroendocrine differentiation has not been elucidated yet. By employing long-term TS exposure of normal human bronchial epithelial cells and 12-weeks mouse smoking model approaches, in the present study we demonstrated that long-term TS exposure induced abnormal differentiation of human bronchial epithelial cells towards a neuroendocrine-like phenotype, as shown by increased cell proliferation, colony formation ability, invasive capacity, morphological change (from epithelial round-shaped to a neuroendocrine-like phenotype manifested by cell elongation and the emission of filopodia), and upregulated expression of pulmonary neuroendocrine differentiation markers including CgA, NCAM, SYN, and NSE. TS-induced aberrant pulmonary neuroendocrine differentiation was associated with MAPKs/AP-1 activation. Inhibition of EKR1/2 and p38 pathwaysdiminished TS-induced neuroendocrine differentiation in human bronchial epithelial cells. Furthermore, in vivo studies also revealed TS-induced neuroendocrinedifferentiation and MAPKs/AP-1 activation in mice. These effects were attenuatedby inhibition of p38 activation, but rather EKR1/2 and JNK pathwaysinhibition. Collectively, we illustrated the distinct roles of MAPK pathways in TS-induced abnormal neuroendocrine differentiation, among which p38 pathway serves as the pivotal player in this process. Findings from our study could provideimportant information for TS-induced aberrant pulmonary neuroendocrine differentiation, shedding new light on the carcinogenic process of TS-associated neuroendocrine lung cancers and its target intervention.