High expression of the POU factor Brn3a in aggressive neuroendocrine tumors.
A new family of POU transcription factors called Brn plays a role in development of the brain and some neuroendocrine structure. Because a member of this family, Brn3a, is present in the ACTH-producing mouse pituitary tumor AtT-20, binds to POMC promoter, and stimulates its activity, we studied its human homolog in ACTH-secreting or nonsecreting tumors of pituitary and bronchial origins. A specific and quantitative reverse transcription-PCR assay was developed to assess Brn3a transcripts in tumor ribonucleic acid. Brn3a transcript levels were invariably low (< 5 x 10(-6) arbitrary units) in four GH-, two PRL-, three gonadotropin-, and seven of eight ACTH-producing pituitary adenomas. A single highly invasive ACTH-secreting pituitary adenoma in a patient who ultimately died with liver metastases, and the mouse corticotroph tumor cell line AtT-20 had high Brn3a transcripts levels at 3 x 10(-5) and 4 x 10(-4) arbitrary units, respectively. Five typical bronchial carcinoids had barely detectable levels (< 5 x 10(-6) arbitrary units), whereas seven of eight small cell carcinomas of the lung (SCCLs) had extremely high levels (between 10(-3)-10(-1) arbitrary units); six of seven atypical bronchial carcinoids had intermediate values, between 10(-6) and 5 x 10(-3) arbitrary units. Although nine bronchial tumors produced POMC, there was no association between Brn3a levels and POMC gene expression; the two tumors with the highest POMC messenger ribonucleic acid contents were two bronchial carcinoids with barely detectable Brn3a levels. A gel mobility shift assay was performed with a rat CRH promoter probe that binds Brn3a; extracts of the POMC-producing human SCCL line DMS-79, which contained high levels of Brn3a transcripts, generated the same specific complex as did AtT-20 cell extracts. These data show that Brn3a gene expression in neuroendocrine tumors is not correlated with POMC gene expression; rather, it is strikingly elevated in the highly aggressive tumors, independently of their POMC status and their pituitary or nonpituitary origin.
Leblond-Francillard
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Groupe d'Etude en Physiopathologie Endocrinienne, INSERM CJF 9208, Institut Cochin de Génétique Moléculaire, Université René Descartes, Paris, France.
Picon
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Bertagna
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de Keyzer
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D000236:Adenoma / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001984:Bronchial Neoplasms / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018358:Neuroendocrine Tumors / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics; D015175:Prolactinoma / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494188:POU4F1 protein, human; C494189:Pou4f1 protein, mouse; D012333:RNA, Messenger; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors; D019382:Human Growth Hormone; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D004247:DNA