Iiizumi Megumi, Hosokawa Masayo, Takehara Akio, Chung Suyoun, Nakamura Toru, Katagiri Toyomasa, Eguchi Hidetoshi, Ohigashi Hiroaki, Ishikawa Osamu, Nakamura Yusuke, Nakagawa Hidewaki
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.
Cancer Sci. 2006 Nov;97(11):1211-6. doi: 10.1111/j.1349-7006.2006.00313.x. Epub 2006 Sep 5.
To isolate novel diagnostic markers and drug targets for pancreatic ductal adenocarcinoma (PDAC), we previously performed expression profile analysis of PDAC cells using a genome-wide cDNA microarray combined with laser microdissection. Among dozens of up-regulated genes identified in PDAC cells, we herein focused on one tyrosine kinase receptor, Eph receptor A4 (EphA4), as a molecular target for PDAC therapy. Immunohistochemical analysis validated EphA4 overexpression in approximately half of the PDAC tissues. To investigate its biological function in PDAC cells, we knocked down EphA4 expression by siRNA, which drastically attenuated PDAC cell viability. In concordance with the siRNA experiment, PDAC-derivative cells that were designed to constitutively express exogenous EphA4 showed a more rapid growth rate than cells transfected with mock vector, suggesting a growth-promoting effect of EphA4 on PDAC cells. Furthermore, the expression analysis for ephrin ligand family members indicated the coexistence of ephrinA3 ligand in PDAC cells with EphA4 receptor, and knockdown of ephrinA3 by siRNA also attenuated PDAC cell viability. These results suggest that the EphA4-ephrinA3 pathway is likely to be a promising molecular target for pancreatic cancer therapy.
为了分离胰腺导管腺癌（PDAC）的新型诊断标志物和药物靶点，我们之前使用全基因组cDNA微阵列结合激光显微切割技术对PDAC细胞进行了表达谱分析。在PDAC细胞中鉴定出的数十个上调基因中，我们在此将重点放在一种酪氨酸激酶受体——Eph受体A4（EphA4）上，将其作为PDAC治疗的分子靶点。免疫组织化学分析证实约一半的PDAC组织中存在EphA4过表达。为了研究其在PDAC细胞中的生物学功能，我们通过小干扰RNA（siRNA）敲低EphA4的表达，这显著减弱了PDAC细胞的活力。与siRNA实验结果一致，设计用于组成性表达外源性EphA4的PDAC衍生细胞比转染空载体的细胞显示出更快的生长速度，这表明EphA4对PDAC细胞具有促生长作用。此外，对ephrin配体家族成员的表达分析表明，在PDAC细胞中ephrinA3配体与EphA4受体共存，并且通过siRNA敲低ephrinA3也减弱了PDAC细胞的活力。这些结果表明，EphA4-ephrinA3通路可能是胰腺癌治疗的一个有前景的分子靶点。
