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Increased Expression of Insulin-like Growth Factor-II Messenger RNA–Binding Protein 1 Is Associated with Tumor Progression in Patients with Lung Cancer

Authors' Affiliations: ¹ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Departments of ² Surgical Oncology and ³ Surgical Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and ⁴ Kanagawa Cancer Center Research Institute, Kanagawa, Japan

Requests for reprints: Yataro Daigo, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5457; Fax: 81-3-5449-5406; E-mail: ydaigo{at}ims.u-tokyo.ac.jp.

Purpose: To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in a large proportion of non–small cell lung cancers (NSCLC) using a cDNA microarray representing 27,648 genes.

Experimental Design: A gene encoding insulin-like growth factor-II mRNA-binding protein 1 (IMP-1) was selected as a candidate (3-fold expression than in normal lung tissue in about 70% of NSCLCs). Tumor tissue microarray was applied to examine expression of IMP-1 protein in archival lung cancer samples from 267 patients and investigated its clinicopathologic significance. A role of IMP-1 in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of IMP-1 on mammalian cells was examined using Matrigel assays. mRNAs associated with IMP-1 in cancer cells were also isolated by RNA immunoprecipitation followed by cDNA microarray analysis.

Results: Positive immunostaining of IMP-1 was correlated with male (P = 0.0001), tumor size (P = 0.0003), non-adenocarcinoma histology (P < 0.0001), smoking history (P = 0.0005), non–well-differentiated tumor grade (P = 0.0001), and poor prognosis (P = 0.0053). Suppression of IMP-1 expression with small interfering RNA effectively suppressed growth of NSCLC cells. In addition, we identified that exogenous expression of IMP-1 increased the migratory activity of mammalian cells. IMP-1 was able to bind to mRNAs encoding a variety of proteins involved in signal transduction, cell cycle progression, cell adhesion and cytoskeleton, and various types of enzymatic activities.

Conclusions: These results suggest that IMP-1 expression is likely to play important roles in lung cancer development and progression, and that IMP-1 is a prognostic biomarker and a promising therapeutic target for lung cancer.

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