胞质中的THUMPD1通过AKT-GSK3-Snail信号通路促进乳腺癌细胞的侵袭和转移。

Cytosolic THUMPD1 promotes breast cancer cells invasion and metastasis via the AKT-GSK3-Snail pathway.

作者信息

Zhang Xiupeng, Jiang Guiyang, Sun Mingfang, Zhou Haijing, Miao Yuan, Liang Mengyuan, Wang Enhua, Zhang Yong

机构信息

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Department of Pathology, Cancer Hospital of China Medical University, Shenyang, China.

出版信息

Oncotarget. 2017 Feb 21;8(8):13357-13366. doi: 10.18632/oncotarget.14528.

Human THUMP domain-containing protein 1 (THUMPD1) is a specific adaptor protein that modulates tRNA acetylation through interaction with NAT10. Immunohistochemical analysis of 146 breast cancer specimens (82 triple-negative and 64 non-triple-negative cases) indicated THUMPD1 expression is higher in breast cancer tissues (60.9%, 89/146) than normal breast tissues (28.3%, 15/53; p < 0.001). Overall and cytosolic, but not nuclear, THUMPD1 expression in breast cancer correlated with advanced TNM stage (p = 0.003 and p < 0.001, respectively), lymph node metastasis (p = 0.001 and p < 0.001, respectively), and poor patient prognosis (p = 0.001 and p < 0.001, respectively). THUMPD1 interacted and co-localized with YAP, but did not affect Hippo pathway activity. THUMPD1 overexpression enhanced breast cancer cells invasion and migration in vivo and in vitro, possibly through activation of AKT, GSK3β and Snail, and inhibition of E-cadherin. Treatment with the AKT inhibitor, LY294002, reduced the effects of THUMPD1 overexpression in breast cancer cells. These results indicate that THUMPD1 promotes breast cancer cells invasion and migration via the AKT-GSK3β-Snail pathway.

人类含THUMP结构域蛋白1（THUMPD1）是一种特异性衔接蛋白，通过与NAT10相互作用调节tRNA乙酰化。对146例乳腺癌标本（82例三阴性和64例非三阴性病例）的免疫组织化学分析表明，THUMPD1在乳腺癌组织中的表达（60.9%，89/146）高于正常乳腺组织（28.3%，15/53；p<0.001）。乳腺癌中THUMPD1的总体和胞质表达（而非核表达）与晚期TNM分期（分别为p = 0.003和p<0.001）、淋巴结转移（分别为p = 0.001和p<0.001）以及患者预后不良（分别为p = 0.001和p<0.001）相关。THUMPD1与YAP相互作用并共定位，但不影响Hippo信号通路活性。THUMPD1过表达在体内和体外均增强了乳腺癌细胞的侵袭和迁移能力，可能是通过激活AKT、GSK3β和Snail，并抑制E-钙黏蛋白实现的。用AKT抑制剂LY294002处理可降低THUMPD1过表达对乳腺癌细胞的影响。这些结果表明，THUMPD1通过AKT-GSK3β-Snail信号通路促进乳腺癌细胞的侵袭和迁移。