Cho Jung-Hyun, Lee Su-Jin, Oh Ah-Young, Yoon Min-Ho, Woo Tae-Geun, Park Bum-Joon
Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan.
Oncotarget. 2015 Apr 30;6(12):10073-85. doi: 10.18632/oncotarget.3543.
Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM.
尽管石棉会引发恶性胸膜间皮瘤（MPM），起源于肺间皮，但迄今为止其分子机制尚未明确。经典肿瘤抑制基因（如p53和pRb）和癌基因（包括Ras或myc）的极低突变率表明，MPM存在特定的致癌途径。为了探究这一点，我们用二氧化硅处理间皮瘤和非小细胞肺癌细胞系（NSCLC）以模拟间皮瘤致癌过程。二氧化硅处理通过降低RKIP诱导p-Erk和Snail。此外，二氧化硅处理使p53和E-钙黏蛋白减少。消除Snail可恢复p53表达。我们发现NF2（在MPM中经常缺失）抑制Snail介导的p53抑制，并被RKIP稳定。重要的是，p53-Snail相互作用抑制剂GN25可诱导p53和细胞凋亡。这些结果表明，RKIP/NF2的减少可诱导MPM，其通过Snail抑制p53。因此，诸如GN25这样的p53-Snail结合抑制剂是MPM的候选药物。
