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E2F1 Overexpression Correlates with Thymidylate Synthase and Survivin Gene Expressions and Tumor Proliferation in Non–Small-Cell Lung Cancer

Author's Affiliations: ¹ Departments of Second Surgery, ² Pathology and Host Defense, and ³ Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan; and ⁴ Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan

Requests for reprints: Cheng-long Huang, Department of Second Surgery, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Phone: 81-87-891-2191; Fax: 81-87-891-2192; E-mail: chuang{at}kms.ac.jp.

Purpose: We investigated the clinical significance of E2F1 gene expression in relation to its target genes, thymidylate synthase (TS) and Survivin, in case of non–small-cell lung cancer (NSCLC).

Experimental Design: One hundred twenty-seven cases of resected NSCLC were analyzed. Quantitative reverse transcription-PCR was done to evaluate the gene expression of E2F1, TS, and Survivin. Immunohistochemistry was done to investigate the protein expression of E2F1, TS, and Survivin. The Ki-67 proliferation index and the apoptotic index using the terminal deoxyribonucleotidyl transferase–mediated dUTP nick-end labeling method were also evaluated.

Results: E2F1 gene expression significantly correlated with the Ki-67 proliferation index (r = 0.487; P < 0.0001), although no correlation was observed between E2F1 gene expression and the apoptotic index. With regard to E2F1 target genes, E2F1 gene expression significantly correlated with TS gene expression (r = 0.709; P < 0.0001) and Survivin gene expression (r = 0.403; P < 0.0001). The overall survival rate was significantly lower in patients with high-E2F1 tumors than in those with low-E2F1 tumors (P = 0.0027), especially among patients with stage II to III NSCLCs (P = 0.0188). A Cox regression analysis showed that the E2F1 status was a significant prognostic factor for NSCLC patients (hazard ratio, 2.052; P = 0.0261).

Conclusions: The present study revealed that E2F1 gene expression correlates with TS and Survivin gene expressions and tumor proliferation. During the progression of NSCLC, E2F1 overexpression could produce more aggressive tumors with a high proliferation rate and chemoresistance.

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