Abstract 2370: Epstein-Barr Virus-induced gene 3 as a novel serum and tissue biomarker and a therapeutic target for lung cancer.

Abstract

Abstract Lung cancer is the leading cause of cancer deaths in the world. The number of patients responding well to current standard therapies is still small, and no tumor marker has been entirely useful for screening curative stage cancers. To identify molecules which could be useful for the development of diagnostic biomarkers and novel drugs, we have established an effective screening strategy as follows; i) To identify up-regulated genes in 120 lung cancers by genome-wide screening using the cDNA microarray representing 27,648 genes and pure populations of tumor cells taken from cancer tissues by laser microdissection, ii) To verify the candidate genes for their very low level of expression in normal tissues by northern-blot analyses, iii) To validate the clinicopathological significance of its over-expression with tissue microarray containing hundreds of archived lung-cancers, iv) To verify whether the target gene is essential for the growth of cancer cells by RNAi and cell growth assays, v) To evaluate it for usefulness as a serum diagnostic biomarker by ELISA, if they are tumor-specific transmembrane or secretory proteins. As a result of this process, we identified 35 druggable oncoproteins. We further identified the Epstein-Barr virus-induced gene 3 (EBI3), which encodes a secretory glycoprotein. Immunohistochemical staining of EBI3 using tissue microarrays revealed that strong EBI3 expression was associated with a poor prognosis (P = 0.0014), and multivariate analysis confirmed it to be an independent prognostic factor (P = 0.0439; N=414). In addition, we established an ELISA to measure serum EBI3 and found that the proportion of serum EBI3-positive cases was 47.1% (73 of 155) for lung adenocarcinoma, 54.5% (24 of 44) for lung squamous cell carcinoma, and 41.3% (31 of 75) for small cell lung cancer, while 3 (2.4%) of 126 healthy volunteers were falsely diagnosed. The sensitivity of serum EBI3 for cancer detection was 44.4% for stage I-II lung adenocarcinoma, 50.0% for stage I-II lung squamous cell carcinoma, and 35.2% for small cell lung cancer with limited disease (LD) stage, thereby proving it was superior to conventional tumor markers of CEA and CYFRA21-1 in terms of both sensitivity and specificity. Validation analysis using another independent set of serum samples (132 lung cancers and 41 healthy volunteers) confirmed significant elevation of EBI3 in the sera of lung cancer patients. Furthermore, reduction in EBI3 expression by siRNA suppressed cancer cell proliferation, while induction of EBI3 conferred growth-promoting activity. EBI3 should be a biomarker for early cancer detection and for the prediction of prognosis, as well as being a suitable therapeutic target. Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Epstein-Barr Virus-induced gene 3 as a novel serum and tissue biomarker and a therapeutic target for lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2370. doi:10.1158/1538-7445.AM2013-2370 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.