Reduced GFI1 Transcription Factor Expression in Small Intestinal Neuroendocrine Tumor Metastases

Abstract

Introduction: Neuroendocrine (NE), or carcinoid, tumors of the small intestine frequently metastasize and produce hormones, such as serotonin, causing significant morbidity and mortality. The molecular events underlying NE tumor progression and hormone production remain largely unknown. The growth factor-independent 1 (GFI1) zinc finger transcription factor is a transcriptional repressor implicated in normal development and cancer. The intestines of Gfi (-/-) mice have increased numbers of endocrine cells. This led us to investigate GFI1 expression in human small intestinal NE tumors in which serotonin contributes to tumor growth and causes debilitating symptoms, such as diarrhea, flushing, wheezing, and abdominal pain (carcinoid syndrome). Methods: GFI1 expression levels were evaluated in matched small intestinal NE primary tumors (n=10), NE lymph node metastases (n=6), NE liver metastases (n=12), and normal small intestine (n=12) by real-time TaqMan RT-PCR. Differences in expression levels were compared using the Wilcoxon rank-sum test. Preoperatively, serotonin elaboration by small intestinal NE tumors was determined by measuring urinary 24-hour 5-hydroxyindoleacetic acid (5-HIAA) levels and/or documenting the presence of the carcinoid syndrome. Results: GFI1 expression levels in human small intestinal NE primary tumors and matched normal small intestine were not significantly different (P=0.11). However, GFI1 expression levels were significantly reduced in NE lymph node metastases (33-fold, P=0.0475), and NE liver metastases (25-fold, P<0.0002) compared to those in matched normal small intestine. GFI1 expression levels in NE lymph node metastases were not significantly different from those in NE liver metastases (P=1.00). Increased serotonin elaboration was observed in all patients as evidenced by elevated urinary 24-hour 5-HIAA levels (11 of 11 patients; median=27.2, range=7.9 to 520.6, normal<6.0 mg/24 h) and/or presence of the carcinoid syndrome (9 of 12 patients). Conclusions: GFI1 expression is reduced in small intestinal NE lymph node and liver metastases compared to normal small intestine. These data suggest a role for GFI1 in small intestinal NET progression. Moreover, these data also suggest that findings from the development of small intestinal endocrine cells may provide insight into small intestinal NET biology. Future studies of GFI1 function in small intestinal NE tumors may improve our understanding of hormone production by NE tumors and NE tumor progression.