Critical role of CCDC6 in the neoplastic growth of testicular germ cell tumors.
Critical role of CCDC6 in the neoplastic growth of testicular germ cell tumors.
复制标题
DOI：
10.1186/1471-2407-13-433
复制
发表时间：
2013-09-24
期刊：
影响因子：
3.8
通讯作者：
Celetti A
中科院分区：
文献类型：
--
作者：
Staibano S;Ilardi G;Leone V;Luise C;Merolla F;Esposito F;Morra F;Siano M;Franco R;Fusco A;Chieffi P;Celetti A
DNA损伤反应已被明确描述为人类肿瘤发生早期的抗癌屏障。此外，有趣的是，据报道睾丸生殖细胞肿瘤（TGCT）缺乏DNA损伤反应（DDR）途径激活。CCDC 6是激酶共济失调毛细血管扩张突变（ATM）的促凋亡磷蛋白底物，能够维持DNA损伤检查点以响应遗传毒性应激，并且通常在与不同伴侣融合后在恶性肿瘤中重排。在我们的研究中，我们试图确定CCDC 6是否在睾丸生殖细胞肿瘤的病理发生中起作用。为了实现这一目标，CCDC 6表达的分析已经通过免疫组织化学在小鼠睾丸的连续切片上和通过蛋白质印迹在小鼠睾丸细胞的单独群体上进行了评价。接下来，在来源于永生化B型鼠生殖细胞的GC 1细胞中研究了CCDC 6沉默后对DNA损伤诱导的细胞凋亡和活性氧产生的抗性。最后，通过免疫组织化学和蛋白质印迹分析评估了正常人睾丸细胞、未分类小管内生殖细胞瘤（IGCNU）、大量男性生殖细胞肿瘤和独特的人睾丸腺瘤TCam 2细胞系中的CCDC 6表达。CCDC 6表达的分析显示其存在于支持细胞和精原细胞中。CCDC 6丢失是原发性肿瘤和TCam 2细胞中最一致的特征。有趣的是，用低剂量的H2 O2处理后，GC 1细胞中CCDC 6的沉默导致细胞色素c的氧化形式减少，Bad、PARP-1和Caspase 3蛋白的检测降低。此外，在沉默的细胞中，在氧化损伤后，细胞活力受到保护，γ H2 AX活化受到损害，活性氧（ROS）释放减少。因此，我们的研究结果表明，CCDC 6的损失可以帮助精原细胞成为促生存途径的一部分，有助于逃避内源性氧化剂的毒性作用，并有助于睾丸肿瘤生长。
DNA damage response has been clearly described as an anti-cancer barrier in early human tumorigenesis. Moreover, interestingly, testicular germ cell tumors (TGCTs) have been reported to lack the DNA Damage Response (DDR) pathway activation. CCDC6 is a pro-apoptotic phosphoprotein substrate of the kinase ataxia telangectasia mutated (ATM) able to sustain DNA damage checkpoint in response to genotoxic stress and is commonly rearranged in malignancies upon fusion with different partners. In our study we sought to determine whether CCDC6 could have a role in the patho-genesis of testicular germ cell tumors. To achieve this aim, analysis for CCDC6 expression has been evaluated on serial sections of the mouse testis by immunohistochemistry and on separate populations of murine testicular cells by western blot. Next, the resistance to DNA damage-induced apoptosis and the production of reactive oxygen species has been investigated in GC1 cells, derived from immortalized type B murine germ cells, following CCDC6 silencing. Finally, the CCDC6 expression in normal human testicular cells, in Intratubular Germ Cell Neoplasia Unclassified (IGCNU), in a large series of male germ cell tumours and in the unique human seminoma TCam2 cell line has been evaluated by immunohistochemistry and by Western Blot analyses. The analysis of the CCDC6 expression revealed its presence in Sertoli cells and in spermatogonial cells. CCDC6 loss was the most consistent feature among the primary tumours and TCam2 cells. Interestingly, following treatment with low doses of H2O2, the silencing of CCDC6 in GC1 cells caused a decrease in the oxidized form of cytochrome c and low detection of Bad, PARP-1 and Caspase 3 proteins. Moreover, in the silenced cells, upon oxidative damage, the cell viability was protected, the γH2AX activation was impaired and the Reactive Oxygen Species (ROS) release was decreased. Therefore, our results suggest that the loss of CCDC6 could aid the spermatogonial cells to be part of a pro-survival pathway that helps to evade the toxic effects of endogenous oxidants and contributes to testicular neoplastic growth.
登录
查看更多内容
影响因子：
5.4
作者：
Maheshwari, Ankur;Misro, Man M.;Nandan, Deoki
通讯作者：
Nandan, Deoki
影响因子：
2.8
作者：
Andrews, PW
通讯作者：
Andrews, PW
影响因子：
7.3
作者：
Fedele, M.;Franco, R.;Chieffi, P.
通讯作者：
Chieffi, P.
影响因子：
82.9
作者：
Kononen, J;Bubendorf, L;Kallioniemi, OP
通讯作者：
Kallioniemi, OP
影响因子：
11.2
作者：
De Martino, Ivana;Visone, Rosa;Fusco, Alfredo
通讯作者：
Fusco, Alfredo