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Aberrant Expression of Human Achaete-Scute Homologue Gene 1 in the Gastrointestinal Neuroendocrine Carcinomas

Departments of ¹ Molecular Pathology, ² General Surgery, and ³ Clinical Pathology, Chiba University Graduate School of Medicine, Chiba, Japan and ⁴ Department of Pathology, Jikei University School of Medicine, Tokyo, Japan

Requests for reprints: Mitsuko Furuya, Department of Molecular Pathology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba 260-8670, Japan. Phone: 81-43-226-2061; Fax: 81-43-226-2063. E-mail: furuya{at}faculty.chiba-u.jp.

Purpose: Gastrointestinal neuroendocrine carcinoma (NEC) is extremely aggressive, but its pathophysiologic features remain poorly understood. There have been no biologically specific markers for this disease. In this study, distinctive up-regulation of human achaete-scute homologue 1 (hASH1) in gastrointestinal NECs was clarified.

Experimental Design: Expression of hASH1 in NECs (n=10), carcinoid tumors (n = 10), other tumors (10adenocarcinomas, 2 squamous cell carcinomas and 1 malignant lymphoma), and the corresponding normal mucosa were investigated by in situ hybridization, reverse transcription-PCR (RT-PCR), real-time RT-PCR, and immunohistochemistry.

Results: By in situ hybridization, mild to intense signals of hASH1 mRNA were detected in 9 of 10 NECs, but not in other tumors or normal mucosa, except for focally weak signals in one carcinoid tumor. RT-PCR showed strong expression of hASH1 in a small cell NEC, followed by a moderately differentiated NEC, and a carcinoid tumor, whereas it is undetectable in adenocarcinomas or normal mucosa. By real-time RT-PCR, the amounts of hASH1 mRNA in a small cell NEC were 16,600 times higher than those in adenocarcinomas and 110 times higher than those in a carcinoid tumor. Immunohistochemically, mammalian homologue of hASH1 was positive in 7 of 10 NECs but was negative in the other tumors. Pan-endocrine markers chromogranin A and synaptophysin were positive in almost all carcinoid tumors, in 4 and 7 of the 10 NECs, respectively.

Conclusions: These findings revealed that hASH1 is distinctly up-regulated in gastrointestinal NECs. hASH1 may be used as a more sensitive and specific marker than conventional pan-endocrine markers for clinical diagnosis of gastrointestinal NECs.

Key Words: basic helix-loop-helix family • transcription factor • neuroendocrine tumor • in situ hybridization

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