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TDRG1 functions in testicular seminoma are dependent on the PI3K/Akt/mTOR signaling pathway

Authors Wang Y, Gan Y, Tan Z, Zhou J, Riko K, Jiang X, Tang Y, Yang J

Received 28 September 2015

Accepted for publication 1 December 2015

Published 20 January 2016 Volume 2016:9 Pages 409—420


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Manfred Beleut

Peer reviewer comments 3

Editor who approved publication: Professor Jianmin Xu

Yong Wang,1 Yu Gan,1 Zhengyu Tan,1 Jun Zhou,1 Riko Kitazawa,2 Xianzhen Jiang,1 Yuxin Tang,1 Jianfu Yang1

1Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2Department of Diagnostic Pathology, Ehime University Hospital, Shitsukawa, Tōon, Ehime Perfecture, Japan

Abstract: Human testis development-related gene 1 (TDRG1) is a recently identified gene that is expressed exclusively in the testes and promotes the development of testicular germ cell tumors. In this study, the role of TDRG1 in the development of testicular seminoma, which is the most common testicular germ cell tumor, was further investigated. Based on polymerase chain reaction, Western blotting, and immunohistochemistry tests, both gene and protein expression levels of TDRG1 were significantly upregulated in testicular seminoma tissues compared with normal testicular tissues. Additionally, the levels of phosphoinositide-3 kinase (PI3K)/p110 and Akt phosphorylation were dramatically upregulated in testicular seminoma tissues. Accordingly, in our cell experiment, seminoma TCam-2 cells were subjected to different treatments: the TDRG1 knockout, TDRG1 overexpression, PI3K inhibition (LY294002 administration), or PI3K activation (insulin-like growth factor-1 administration). Cell proliferation, the proliferation index, apoptosis rate, cell adhesive capacity, and cell invasion capability were assessed. Cells with both TDRG1 knockout and PI3K inhibition exhibited decreased cell proliferation, proliferation indexes, cell adhesion capacity, and cell invasion capability and increased apoptosis rates. Most of these effects were reversed by TDRG1 overexpression or PI3K activation, indicating that both TDRG1- and PI3K-mediated signaling promote proliferation and invasion of testicular seminoma cells. The knockout of TDRG1 significantly decreased the phosphorylation levels of PI3K/p85, PI3K/p110, Akt, and mammalian target of rapamycin (mTOR; Ser2448). Except for PI3K/p110, TDRG1 overexpression had the opposite effects on phosphorylation levels. Phosphorylated mTOR at Ser2481 and Thr2446 was not affected by TDRG1 or PI3K in our tests. Thus, these results indicate that TDRG1 promotes the development and migration of seminoma cells via the regulation of the PI3K/Akt/mTOR signaling pathway; this contributes to an understanding of the precise mechanisms underlying the development and migration of seminomas and lays a theoretical foundation for the development of appropriate therapies.

TDRG1, testicular seminoma, PI3K, Akt, mTOR

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