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Originally published online as doi:10.2353/ajpath.2009.081004 on August 13, 2009

Published online before print August 13, 2009
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(American Journal of Pathology. 2009;175:976-987.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081004

Neuroendocrine Cancer-Specific Up-Regulating Mechanism of Insulin-Like Growth Factor Binding Protein-2 in Small Cell Lung Cancer

Takuya Yazawa*, Hanako Sato*{dagger}, Hiroaki Shimoyamada*, Koji Okudela*, Tetsukan Woo{ddagger}§, Michihiko Tajiri§, Takashi Ogura, Nobuo Ogawa§, Takehisa Suzuki*, Hideaki Mitsui*, Jun Ishii*, Chie Miyata*, Masashi Sakaeda*, Kazuya Goto*, Korehito Kashiwagi*, Munetaka Masuda{ddagger}, Takashi Takahashi|| and Hitoshi Kitamura*

From the Departments of Pathology,* and Surgery,{ddagger} Yokohama City University Graduate School of Medicine, Yokohama; the Department of Anatomy,{dagger} St. Marianna University School of Medicine, Kawasaki; the Divisions of Thoracic Surgery,§ and Internal Medicine, Kanagawa Prefectural Cardiovascular and Respiratory Disease Center Hospital, Yokohama; and the Division of Molecular Carcinogenesis,|| Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Japan

Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivo lung cancers, whereas in vitro growth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2 promoter assays all revealed that NeuroD binds to the E-box in the 5'-untranslated region of IGFBP-2. A NeuroD transgene in both airway epithelial and NSCLC cells up-regulated the transcription of IGFBP-2 and retarded cell growth. Recombinant IGFBP-2 repressed the growth of both airway epithelial and NSCLC cells in a dose-dependent manner. A NeuroD-specific small interfering RNA repressed IGFBP-2 expression in SCLC, and neutralization of IGFBP-2 and an IGFBP-2-specific small interfering RNA increased SCLC cell growth. Pathological samples of SCLC also expressed IGFBP-2 abundantly, as compared with NSCLC, and showed only rare (8%) IGFBP-2 promoter methylation, whereas the IGFBP-2 promoter was methylated in 71% of adenocarcinomas and 29% of squamous cell carcinomas. These findings suggest that 1) SCLC has an IGFBP-2 overexpression mechanism distinct from NSCLC, 2) secreted IGFBP-2 contributes to the slow growth of SCLC in vitro, and 3) the epigenetic alterations in the IGFBP-2 promoter contribute to the striking differences in IGFBP-2 expression between SCLC and NSCLC in vivo.






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