title: Differences of molecular expression mechanisms among neural cell adhesion molecule 1, synaptophysin, and chromogranin A in lung cancer cells.
abstract: Neural cell adhesion molecule 1 (NCAM1), synaptophysin (SYPT), and chromogranin A (CGA) are immunohistochemical markers for diagnosing lung neuroendocrine tumors (LNETs). However, the precise expression mechanisms have not been studied in enough detail. The purpose of the present study is to define the molecular mechanisms of NCAM1, SYPT, and CGA gene expressions, using cultivated lung cancer cells and focusing upon NeuroD1 (ND1), achaete-scute homolog-like 1 (ASCL1), and known transcription factors, repressor element 1 (RE1)-silencing transcription factor (REST) and c-AMP responsive element-binding protein (CREB). Promoter assays, chromatin immunoprecipitation, and transfection experiments revealed that ND1 activated NCAM1, that ASCL1 weakly upregulated SYPT expression, and that CGA expression was not regulated by ND1 or ASCL1. REST expression was restricted in non-small cell lung cancer (NSCLC) cells, and knockdown of REST could cause as much SYPT expression as in SCLC cells and weak CGA expression in NSCLC cells. However, CGA gene upregulation via CREB activation was not found in REST-lacking NSCLC cells, indicating the requirement of some additional mechanism for sufficient expression. These results suggest that NCAM1, SYPT and CGA expressions are differently regulated by neuroendocrine phenotype-specific transcription factors and provide a reason why NCAM1 and SYPT are frequently expressed in LNETs, irrespective of malignancy grade.
authors.affiliation: Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Korehito
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Jun
authors.initials: J
authors.lastname: Ishii
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakaeda
authors.forename: Yuu
authors.initials: Y
authors.lastname: Arimasu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimoyamada
authors.forename: Hanako
authors.initials: H
authors.lastname: Sato
authors.forename: Chie
authors.initials: C
authors.lastname: Miyata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kamma
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aoki
authors.forename: Takuya
authors.initials: T
authors.lastname: Yazawa
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019002:CD56 Antigen / Q000235:genetics* / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D053379:Chromogranin A / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016708:Synaptophysin; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019002:CD56 Antigen; D053379:Chromogranin A; D017362:Cyclic AMP Response Element-Binding Protein; D009245:NADH Dehydrogenase; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D016708:Synaptophysin; D033921:Vesicular Transport Proteins; D000099229:RE1-Silencing Transcription Factor; C065500:ASCL1 protein, human; C115163:CREB1 protein, human; C522918:NCAM1 protein, human; C093970:NEUROD1 protein, human; C569014:SYP protein, human; C515075:NADH dehydrogenase subunit 1, human