GCT-22. PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT NON-GERMINOMATOUS CNS GERM CELL TUMORS
GCT-22. PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT NON-GERMINOMATOUS CNS GERM CELL TUMORS
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DOI：
10.1093/neuonc/noaa222.242
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发表时间：
2020-12-04
期刊：
影响因子：
15.9
通讯作者：
Ichimura K
中科院分区：
文献类型：
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作者：
Tomiyama A;Uchida E;Wada K;Ichimura K
摘要中枢神经系统生殖细胞肿瘤是一种罕见的颅内肿瘤，通常发生在青少年和青壮年。然而，在包括日本在内的东亚，与世界其他地区相比，cnsgct的发病率要高得多。虽然生殖细胞瘤通常对放化疗反应良好，但非生殖细胞瘤恶性亚型（NGGCT）是难治性的，迫切需要开发针对NGGCT的新疗法。为了开发针对侵袭性NGGCT的新治疗策略，我们研究了NGGCT治疗的新分子靶点。我们共筛选了120例已登记在颅内生殖细胞肿瘤协会（Intracranial Germ Cell tumor Consortium, iGCT）的CNSGCT肿瘤组织（其中包括55例NGGCT），在NGGCT病例（55例中有5例；1例未成熟畸胎瘤，3例混合gem细胞瘤，1例胚胎癌）中发现了特异性调节蛋白泛素化和降解的分子的多个突变。体外泛素化实验显示，在NGGCT病例中发现的这种分子突变是功能缺失突变。通过敲低已建立的人精原细胞瘤细胞系Tcam2或我们研究所最近建立的人卵黄囊肿瘤细胞系YST1，降低该分子的表达，导致增殖增强以及MEK-ERK激活上调。重要的是，用MEK抑制剂曲美替尼处理这两种GCT细胞系，降低该分子的表达，抑制了这些细胞的增殖增强。综上所述，这些结果表明蛋白质泛素化相关途径以及MEK-ERK级联可能作为nggct的新治疗靶点。
Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.