Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma.
Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma.
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睾丸孤儿受体 4 通过 AKT3 调节促进精原细胞瘤的肿瘤进展并暗示生存率低
DOI：
10.1111/cas.13461
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发表时间：
2018-03
期刊：
影响因子：
5.7
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Chen Y;Lu J;Xia L;Xue D;Yu X;Shen D;Xu L;Li G
精原细胞瘤是世界上最常见的睾丸生殖细胞肿瘤，主要发生在15 - 35岁的年轻男性。早期研究表明，首次从睾丸中克隆的睾丸核受体4 （TR4）参与了几种人类肿瘤的侵袭和转移；然而，对TR4在精原细胞瘤中的作用关注甚少。我们的免疫组化（IHC）染色结果显示，晚期肿瘤患者倾向于表达更高的TR4。重要的是，精原细胞瘤患者中TR4表达升高与总生存率降低之间存在显著关联。体外MTS、western blot和transwell实验显示，在调控Tcam‐2细胞中TR4的表达后，TR4诱导上皮向间充质转化（EMT），促进Tcam‐2细胞的增殖和侵袭。机制解剖表明，AKT3作为信号通路中的关键组分，在介导TR4促进的Tcam - 2细胞增殖和侵袭中发挥了关键作用。我们通过染色质免疫沉淀和荧光素酶分析进一步揭示了TR4在转录水平上调节AKT3。同时，AKT3 siRNA的加入阻断了TR4的功能。总的来说，这些发现首先阐明了TR4是一种新的预后标志物，并且通过EMT调节在Tcam‐2细胞的转移能力中起着关键作用，因此，靶向TR4‐AKT3途径可能作为精原细胞瘤的潜在治疗方法。
Seminoma is the most common testicular germ cell tumor worldwide and mainly occurs in 15‐35‐year‐old young men. Early studies have indicated that testicular nuclear receptor 4 (TR4) first cloned from testis is involved in the invasion and metastasis of several human tumors; however, little attention is paid to the function of TR4 in seminoma. Our immunohistochemical (IHC) staining results showed that patients with advanced stage tumors tended to have higher expression of TR4. Importantly, there was a significant association between elevated TR4 expression and reduced overall survival in seminoma patients. In vitro MTS, western blot and transwell assays, after manipulating TR4 expression in Tcam‐2 cells, revealed that TR4 induced epithelial‐to‐mesenchymal transition (EMT) and promoted Tcam‐2 cell proliferation and invasion. Mechanism dissection demonstrated that AKT3, a critical component in the signaling pathway, played a crucial role in mediating TR4‐promoted Tcam‐2 cell proliferation and invasion. We further revealed that TR4 modulated AKT3 at the transcriptional level via chromatin immunoprecipitation and luciferase assays. Meanwhile, addition of the AKT3 siRNA blocked the function of TR4. Overall, these findings first elucidate that TR4 is a novel prognostic marker and plays a critical role in the metastatic capacity of Tcam‐2 cells by EMT regulation and, consequently, targeting TR4‐AKT3 pathway may serve as a potential therapeutic approach for seminoma.
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影响因子：
3.9
作者：
Joy, Anna;Kapoor, Manisha;Georges, Joseph;Butler, Lacy;Chang, Yongchang;Li, Chaokun;Crouch, Acacia;Smirnov, Ivan;Nakada, Mitsitoshi;Hepler, James;Marty, Max;Feuerstein, Burt G.
通讯作者：
Feuerstein, Burt G.
影响因子：
6.4
作者：
Ding, Xianfan;Yang, Dong-Rong;Chang, Chawnshang
通讯作者：
Chang, Chawnshang
影响因子：
254.7
作者：
Siegel, Rebecca;Ma, Jiemin;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
影响因子：
2.1
作者：
Russell SM;Lechner MG;Mokashi A;Megiel C;Jang JK;Taylor CR;Looijenga LH;French CA;Epstein AL
通讯作者：
Epstein AL
DOI：
10.1073/pnas.91.13.6040
发表时间：
1994-06-21
影响因子：
11.1
作者：
CHANG, CS;DASILVA, SL;BURBACH, JPH
通讯作者：
BURBACH, JPH