Growth factor independence-1 is expressed in primary human neuroendocrine lung carcinomas and mediates the differentiation of murine pulmonary neuroendocrine cells.
Human small cell lung cancers might be derived from pulmonary cells with a neuroendocrine phenotype. They are driven to proliferate by autocrine and paracrine neuropeptide growth factor stimulation. The molecular basis of the neuroendocrine phenotype of lung carcinomas is relatively unknown. The Achaete-Scute Homologue-1 (ASH1) transcription factor is critically required for the formation of pulmonary neuroendocrine cells and is a marker for human small cell lung cancers. The Drosophila orthologues of ASH1 (Achaete and Scute) and the growth factor independence-1 (GFI1) oncoprotein (Senseless) genetically interact to inhibit Notch signaling and specify fly sensory organ development. Here, we show that GFI1, as with ASH1, is expressed in neuroendocrine lung cancer cell lines and that GFI1 in lung cancer cell lines functions as a DNA-binding transcriptional repressor protein. Forced expression of GFI1 potentiates tumor formation of small-cell lung carcinoma cells. In primary human lung cancer specimens, GFI1 expression strongly correlates with expression of ASH1, the neuroendocrine growth factor gastrin-releasing peptide, and neuroendocrine markers synaptophysin and chromogranin A (P < 0.0000001). GFI1 colocalizes with chromogranin A and calcitonin-gene-related peptide in embryonic and adult murine pulmonary neuroendocrine cells. In addition, mice with a mutation in GFI1 display abnormal development of pulmonary neuroendocrine cells, indicating that GFI1 is important for neuroendocrine differentiation.
Institute for Cellular Therapeutics and Departments of Surgery, Biochemistry, and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Avedis
A
Kazanjian
Deeann
D
Wallis
Nicholas
N
Au
Rupesh
R
Nigam
Koen J T
KJ
Venken
Philip T
PT
Cagle
Burton F
BF
Dickey
Hugo J
HJ
Bellen
C Blake
CB
Gilks
H Leighton
HL
Grimes
D000818:Animals; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism*; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002457:Cell Extracts / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D009490:Neurosecretory Systems / Q000166:cytology* / Q000187:drug effects; D011247:Pregnancy; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous
D002457:Cell Extracts; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; C079873:Gfi1 protein, mouse; D014157:Transcription Factors