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ORIGINAL RESEARCH ARTICLE

The Proangiogenic Factor Ephrin-A1 Is Up-Regulated in Radioresistant Murine Tumor by Irradiation

Kazunori Nojiri^*,, Mayumi Iwakawa^*,1, Yasushi Ichikawa, Kaori Imadome^*, Minako Sakai^*, Miyako Nakawatari^*, Ken-Ichi Ishikawa^*, Atsuko Ishikawa^*, Shinji Togo, Hirohiko Tsujii^*, Hiroshi Shimada and Takashi Imai^*

^* Research Center for Charged Particle Therapy, National Institute of Radiological Sciences (NIRS), Chiba 263-8555, Japan; and Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Yokohama 236-0004, Japan

To whom requests for reprints should be addressed at ¹ Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan. E-mail: mayumii{at}nirs.go.jp

While the pre-treatment status of cancer is generally correlated with outcome, little is known about microenvironmental change caused by anti-cancer treatment and how it may affect outcome. For example, treatment may lead to induction of gene expression that promotes resistance to therapy. In the present study, we attempted to find a gene that was both induced by irradiation and associated with radioresistance in tumors. Using single-color oligo-microarrays, we analyzed the gene expression profiles of two murine squamous cell carcinomas, NR-S1, which is highly radioresistant, and SCCVII, which is radiosensitive, after irradiation with 137-Cs gamma rays or carbon ions. Candidate genes were those differentially regulated between NR-S1 and SCCVII after any kind of irradiation. Four genes, Efna1 (Ephrin-A1), Sprr1a (small proline-rich protein 1A), Srgap3 (SLIT-ROBO Rho GTPase activating protein 3) and Xrra1 [RIKEN 2 days neonate thymus thymic cells (NOD) cDNA clone E430023D08 3'], were selected as candidate genes associated with radiotherapy-induced radioresistance. We focused on Efna1, which encodes a ligand for the Eph receptor tyrosine kinase known to be involved in the vascular endothelial growth factor (VEGF) pathway. We used immunohistochemical methods to detect expression of Ephrin-A1, VEGF, and the microvascular marker CD31 in radioresistant NR-S1 tumor cells. Ephrin-A1 was detected in the cytoplasm of NR-S1 tumor cells after irradiation, but not in SCCVII tumor cells. Irradiation of NR-S1 tumor cells also led to significant increases in microvascular density, and up-regulation of VEGF expression. Our results suggest that radiotherapy-induced changes in gene expression related with angiogenesis might also modulate microenvironment and influence responsiveness of tumors.

Key Words: Ephrin-A1 • radioresistancy • irradiation • mouse tumor model • microarray