Frequent Overexpression of HMGA1 and HMGA2 in Gastroenteropancreatic Neuroendocrine Tumors and Its Relationship to let-7 Down-Regulation
ZR Qian, MM Rahman, EL Wang, R Sultana, E Kudo, M Nakasono, T Hayashi, T Sano. Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan; Faculty of Medicine, Kagawa University, Takamatu, Kagawa, Japan
Background: The molecular pathogenesis of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) remain to be elucidated. High mobility group A (HMGA) proteins play important roles in the regulation of transcription, differentiation, and neoplastic transformation and expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that HMGA2 is negatively regulated by the let-7 microRNAs family in vitro. To our knowledge, there are no reports about any miRNA expression in GEP NETs and no investigation about the relation between HMGA1 and 2 proteins expression and the let-7 expression in GEP NETs.
Design: We performed immunohistochemistry and RT-PCR for HMGA1 and 2 expression in 55 GEP NETs from different sites and let-7 was also analysed by semiquantitative RT-PCR. Lasermicrodissection has been performed to take tissues from tumor and non-tumor area, respectively. The data were correlated with relevant clinical information and investigated possible associations between HMGA1, or 2 expression and let-7 expression.
Results: Overexpression of HMGA1 and 2 was frequently detected in GEP NETs compared with normal tissues. Nuclear immunostaining of HMGA1 and 2 were observed in GEP NETs (38 of 55, 69%; 40 of 55, 73%, respectively). HMGA2 expression increased from well-differentiated NET to well-differentiated NEC and poorly differentiated NEC (P < 0.005). In WNECs, the expression of HMGA1 and 2 was significantly higher in metastatic tumors than those without metastasis (P < 0.05). GEP NETs showed the highest level of HMGA1 and 2 expressions in foregut. MIB-1 labeling index correlated with HMGA1 and 2 overexpression (R = 0.28, P < 0.05; R = 0.434, P < 0.001; respectively) and progressively increased from WNETs to WNECs and PNECs (P < 0.001). Let-7 expression was addressed in 6 normal organs, 30 tumor samples and 24 tumor margin non-tumor tissues. Compared with normal tissues, let-7 down-regulation was frequent in NETs (19 of 30, 63%). Higher expression of HMGA1 and 2 was frequently observed in tumors with let-7 significant reduction (53%, 42%, respectively). The reverse correlation could be detected between HMGA1 and let-7 (P < 0.05).
Conclusions: Our findings suggested that HMGA1 and 2 overexpression and let-7 down-regulation may contribute to pathogenesis of GEP NETs.
Monday, March 9, 2009 1:00 PM
Poster Session II # 93, Monday Afternoon