Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma

Abstract

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.

Peer Review #1 of "SPANXN2 functions a cell migration inhibitor in testicular germ cell tumor cells (v0.1)"

“…A previous study showed that activation of AKT expression drives the EMT phenotype and enhances the proliferation and invasion of seminoma (Chen et al, 2018). The AKT pathway is involved in cellular processes, particularly in cell proliferation and migration, and has a pivotal role in human tumorigenesis (Chen et al, 2018;Minna et al, 2016). In our study, the AKT proteins were downregulated in the TGCT cells overexpressing SPANXN2.…”

“…The AKT signaling pathway is activated in many cancers, such as thyroid carcinomas (Chen et al, 2018). A previous study showed that activation of AKT expression drives the EMT phenotype and enhances the proliferation and invasion of seminoma (Chen et al, 2018). The AKT pathway is involved in cellular processes, particularly in cell proliferation and migration, and has a pivotal role in human tumorigenesis (Chen et al, 2018;Minna et al, 2016).…”

<p>LncRNA EMX2OS Induces Proliferation, Invasion and Sphere Formation of Ovarian Cancer Cells via Regulating the miR-654-3p/AKT3/PD-L1 Axis</p>

“…Previous studies showed that AKT3 promotes tumor proliferation and invasion in seminoma, thyroid cancer, and liver cancer. [23][24][25] In prostate cancer cells lacking the tumor suppressor PTEN, the basal enzymatic activity of AKT3 was constitutively elevated and represented the major active AKT in these cells. 26 The same study also showed that the expression levels of AKT3 were significantly higher in the estrogen receptor-negative tumors in comparison to the estrogen receptor-positive tumors, indicating that AKT3 may contribute to the more aggressive clinical phenotype of prostate cancer.…”

SPANXN2 functions a cell migration inhibitor in testicular germ cell tumor cells

“…The AKT signaling pathway is activated in many cancers, such as thyroid carcinomas (Chen et al, 2018). A previous study showed that activation of AKT expression drives the EMT phenotype and enhances the proliferation and invasion of seminoma (Chen et al, 2018).…”

“…The AKT signaling pathway is activated in many cancers, such as thyroid carcinomas (Chen et al, 2018). A previous study showed that activation of AKT expression drives the EMT phenotype and enhances the proliferation and invasion of seminoma (Chen et al, 2018). The AKT pathway is involved in cellular processes, particularly in cell proliferation and migration, and has a pivotal role in human tumorigenesis (Chen et al, 2018;Minna , 2016).…”