TC2N, a novel oncogene, accelerates tumor progression by suppressing p53 signaling pathway in lung cancer.
TC2N, a novel oncogene, accelerates tumor progression by suppressing p53 signaling pathway in lung cancer.
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TC2N是一种新型癌基因，通过抑制肺癌中的p53信号通路加速肿瘤进展
DOI：
10.1038/s41418-018-0202-8
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发表时间：
2019-07
影响因子：
12.4
通讯作者：
Liu JY
中科院分区：
文献类型：
--
作者：
Hao XL;Han F;Zhang N;Chen HQ;Jiang X;Yin L;Liu WB;Wang DD;Chen JP;Cui ZH;Ao L;Cao J;Liu JY
含C2结构域的蛋白质因其在内吞作用、细胞代谢和癌症中的重要作用已有详尽记载。Tac2 - N（TC2N）是一种含串联C2结构域的蛋白质，但其功能，包括在肿瘤发生中的作用，仍不明确。在此，我们首先确定TC2N是肺癌中的一种新型癌基因。与相邻的正常肺组织相比，TC2N在肺癌组织中优先上调。TC2N高表达与肺癌患者的不良预后显著相关。在体外，敲低TC2N可显著诱导细胞凋亡和细胞周期阻滞，抑制细胞增殖，在体内可抑制肿瘤形成，而TC2N过表达在体外和体内均产生相反的效果。通过结合使用癌症基因组图谱（TCGA）数据库和生物信息学，我们证明TC2N参与p53信号通路的调节。从机制上讲，TC2N通过诱导细胞周期蛋白依赖性激酶5（Cdk5）降解或破坏Cdk5与p53之间的相互作用，抑制Cdk5诱导的p53磷酸化，从而减弱p53信号通路。此外，阻断p53会减弱敲低TC2N在调节细胞增殖和凋亡方面的功能。此外，下调的TC2N参与阿霉素诱导的肺癌细胞凋亡，导致p53通路激活。总体而言，这些发现揭示了p53抑制剂TC2N在调节肺癌细胞增殖和凋亡中的作用。我们目前的研究为肺癌肿瘤发生机制提供了新的见解。
The protein containing the C2 domain has been well documented for its essential roles in endocytosis, cellular metabolism and cancer. Tac2-N (TC2N) is a tandem C2 domain-containing protein, but its function, including its role in tumorigenesis, remains unknown. Here, we first identified TC2N as a novel oncogene in lung cancer. TC2N was preferentially upregulated in lung cancer tissues compared with adjacent normal lung tissues. High TC2N expression was significantly associated with poor outcome of lung cancer patients. Knockdown of TC2N markedly induces cell apoptosis and cell cycle arrest with repressing proliferation in vitro, and suppresses tumorigenicity in vivo, whereas overexpression of TC2N has the opposite effects both in vitro and in vivo. Using a combination of TCGA database and bioinformatics, we demonstrate that TC2N is involved in regulation of the p53 signaling pathway. Mechanistically, TC2N attenuates p53 signaling pathway through inhibiting Cdk5-induced phosphorylation of p53 via inducing Cdk5 degradation or disrupting the interaction between Cdk5 and p53. Moreover, the blockade of p53 attenuates the function of TC2N knockdown in the regulation of cell proliferation and apoptosis. In addition, downregulated TC2N is involved in the apoptosis of lung cancer cells induced by doxorubicin, leading to p53 pathway activation. Overall, these findings uncover a role for the p53 inactivator TC2N in regulating the proliferation and apoptosis of lung cancer cells. Our present study provides novel insights into the mechanism of tumorigenesis in lung cancer.
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影响因子：
8
作者：
Han F;Liu W;Jiang X;Shi X;Yin L;Ao L;Cui Z;Li Y;Huang C;Cao J;Liu J
通讯作者：
Liu J
影响因子：
4
作者：
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通讯作者：
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影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
6.4
作者：
Fahmy, Karim;Gonzalez, Arnaud;Peulen, Olivier
通讯作者：
Peulen, Olivier
影响因子：
4.8
作者：
Bernatchez, Pascal N.;Acevedo, Lisette;Sessa, William C.
通讯作者：
Sessa, William C.