CBMS-11 PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT CNS NON-GERMINOMATOUS GERM CELL TUMORS
CBMS-11 PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT CNS NON-GERMINOMATOUS GERM CELL TUMORS
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CBMS-11蛋白去泛素化途径是治疗中枢神经系统恶性非生殖细胞肿瘤的新靶点
DOI：
10.1093/noajnl/vdaa143.018
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发表时间：
2020-11-28
期刊：
影响因子：
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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;Kawauchi D;Wada K;Ichimura K
中枢神经系统生殖细胞肿瘤是一种罕见的颅内肿瘤，通常发生于青少年和年轻人。然而，在包括日本在内的东亚地区，CNSGCT的发病率与世界其他地区相比要高得多。鉴于生殖细胞瘤通常对化疗-放疗反应良好，非生殖细胞瘤生殖细胞肿瘤（NGGCT）的恶性亚型是难治的，并且迫切需要开发针对NGGCT的新疗法。为了开发针对侵袭性NGGCT的新的治疗策略，我们已经研究了用于NGGCT治疗的新的分子靶点。我们共筛选了120例CNSGCT肿瘤组织（包括55例NGGCT），这些组织已在颅内生殖细胞肿瘤联盟（iGCT）注册，并发现了NGGCT病例中特异性调节蛋白泛素化和降解的分子的多个突变（55例中的5例; 1例未成熟畸胎瘤，3例混合性宝石细胞肿瘤和1例胚胎癌）。体外泛素化分析显示，在NGGCT病例中发现的该分子的突变是功能缺失突变。通过在已建立的人卵巢癌细胞系Tcam 2或最近在我们研究所建立的人卵黄囊肿瘤细胞系YST 1中敲减该分子的表达，导致增殖增强以及MEK-ERK活化上调。重要的是，用MEK抑制剂曲美替尼降低该分子表达的这两种GCT细胞系的处理抑制了这些细胞的增殖增加。总之，这些结果表明，蛋白质泛素化相关的途径以及MEK-ERK级联可能作为一个新的治疗靶点对NGGCT。
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.