Ashida Shingo, Furihata Mutsuo, Katagiri Toyomasa, Tamura Kenji, Anazawa Yoshio, Yoshioka Hiroki, Miki Tsuneharu, Fujioka Tomoaki, Shuin Taro, Nakamura Yusuke, Nakagawa Hidewaki
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Shirokanedai, Tokyo, Japan.
Clin Cancer Res. 2006 May 1;12(9):2767-73. doi: 10.1158/1078-0432.CCR-05-1995.
The aim of this study is to identify novel molecular targets for development of novel treatment or diagnostic markers of prostate cancer through genome-wide cDNA microarray analysis of prostate cancer cells purified by laser microdissection.
Here, we identified molecule interacting with CasL-2 prostate cancer variants (MICAL2-PV), novel splicing variants of MICAL2, showing overexpression in prostate cancer cells. Immunohistochemical analysis using an antibody generated specific to MICAL2-PV revealed that MICAL2-PV was expressed in the cytoplasm of cancer cells with various staining patterns and intensities, whereas it was not or hardly detectable in adjacent normal prostate epithelium or prostatic intraepithelial neoplasia. Interestingly, immunohistochemical analysis of 105 prostate cancer specimens on the tissue microarray indicated that MICAL2-PV expression status was strongly correlated with Gleason scores (P < 0.0001) or tumor classification (P < 0.0001). Furthermore, the expression levels of MICAL2-PVs were also concordant to those of c-Met, a marker of tumor progression, with statistical significance (P = 0.0018). To investigate its potential of molecular therapeutic target for prostate cancers, we knocked down endogenous MICAL2-PVs in prostate cancer cells by small interfering RNA, which resulted in the significant reduction of prostate cancer cell viability.
Our findings suggest that MICAL2-PV is likely to be involved in cancer progression of prostate cancer and could be a candidate as a novel molecular marker and/or target for treatment of prostate cancers with high Gleason score.
本研究旨在通过对经激光显微切割纯化的前列腺癌细胞进行全基因组cDNA微阵列分析，确定用于开发前列腺癌新治疗方法或诊断标志物的新型分子靶点。
在此，我们鉴定出与CasL-2前列腺癌变体相互作用的分子（MICAL2-PV），即MICAL2的新型剪接变体，其在前列腺癌细胞中过度表达。使用针对MICAL2-PV产生的特异性抗体进行免疫组织化学分析显示，MICAL2-PV在癌细胞的细胞质中表达，具有各种染色模式和强度，而在相邻的正常前列腺上皮或前列腺上皮内瘤变中未表达或几乎检测不到。有趣的是，对组织微阵列上的105个前列腺癌标本进行的免疫组织化学分析表明，MICAL2-PV的表达状态与Gleason评分（P < 0.0001）或肿瘤分级（P < 0.0001）密切相关。此外，MICAL2-PV的表达水平也与肿瘤进展标志物c-Met的表达水平一致，具有统计学意义（P = 0.0018）。为了研究其作为前列腺癌分子治疗靶点的潜力，我们通过小干扰RNA敲低前列腺癌细胞中的内源性MICAL2-PV，这导致前列腺癌细胞活力显著降低。
我们的研究结果表明，MICAL2-PV可能参与前列腺癌的癌症进展，并且可能作为高Gleason评分前列腺癌的新型分子标志物和/或治疗靶点的候选物。
