TMPRSS2:ERGgene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells

Abstract

TMPRSS2:ERG (T/E) gene fusions are present in approximately 50% of all prostate cancer (PCa) cases. The expression of fusion mRNAs from distinct T/E variants is associated with clinicopathological parameters, while the underlying molecular processes remain unclear. We characterized the molecular mechanisms and functional implications caused by doxycycline (Dox)-inducible overexpression of the frequent T/E III and VI fusion variants in LNCaP cells. Induction of T/E expression resulted in increased cellular migratory and invasive potential, and reduced proliferation and accumulation in G1 phase. T/E overexpressing cells showed epithelial-to-mesenchymal transition (EMT), as demonstrated by upregulation of TGF-β and WNT pathway genes, mesenchymal markers, and increased phosphorylation of the p38 MAPK. Augmented secretion of TGF-β1 and –β2, and T/E-mediated regulation of ALK1, a member of the TGF-β receptor family, was detected. ALK1 inhibition in T/E overexpressing cells blocked p38 phosphorylation and reduced the expression of the TGF-β target genes VIM, MMP1, CDH2, and SNAI2. We found a T/E variant VI-specific induction of miR-503 associated with reduced expression of SMAD7 and CDH1. Overexpression of miR-503 led to increased levels of VIM and MMP1. Our findings indicate that TGF-β signaling is a major determinant of EMT in T/E overexpressing LNCaP cells. We provide evidence that T/E VI-specific transcriptional modulation by miR-503 accounts for differences in the activation of EMT pathway genes, promoting the aggressive phenotype of tumors expressing T/E variant VI. We suggest that ALK1-mediated TGF-β signaling is a novel oncogenic mechanism in T/E positive PCa.

Overexpression of lncRNA ANRIL promoted the proliferation and migration of prostate cancer cells via regulating let-7a/TGF-β1/ Smad signaling pathway

“…TGF- /Smad signaling pathway plays the important roles in the regulation of proliferation, migration and epithelial-mesenchymal transition (EMT) of prostate cancer [ 9 , 10 , 11 ]. Therefore, we investigated whether lncRNA ANRIL could regulate the TGF- /Smad signaling pathway in prostate cancer.…”

“…In prostate cancer, TFG- could promote PI3K/AKT signaling and cell migration through the TRAF6-mediated ubiquatylation of p85 [ 11 ]. TMPRSS2:ERG gene fusion activated the TFG- signaling via increasing VIM, MMP1, CDH2 and SNAI2, and induced the epithelial to mesenchymal transition in human prostate cancer cells [ 10 ]. The smad7 was commonly regulated by ubiquitin-mediated degradation via Smurf2 and ITCH, however, how its phosphorylation was regulated was still needed to explore.…”

High expression of hnRNPA1 promotes cell invasion by inducing EMT in gastric cancer

“…EMT is a crucial phenotypic conversion during cancer progression ( 27 , 28 ) and is a process by which cancer cells lose their polarized epithelial structures and acquire plastic and high motile mesenchymal properties ( 29 , 30 ). Clinicopathological studies revealed that EMT strongly correlated with poor histological differentiation, destruction of tissue integrity and metastasis ( 31 , 32 ). Therefore, EMT is considered to be an exclusive phenotypic switch for the invasion and metastasis of cancers including GC ( 33 ).…”

Genome-Based Classification and Therapy of Prostate Cancer

“…Despite the recurrent nature of this genomic alteration, ETS gene fusions alone are not sufficient to initiate tumorigenesis; other events such as PTEN loss or phosphatidylinositol 3-kinase ( PI3K ) /AKT activation must concomitantly be present for cellular transformation to occur [ 25 , 26 ]. ERG is a master transcription factor that interacts with several other cofactors to regulate the expression of target genes and modulate multiple biological processes that favor oncogenic transformation [ 27 , 28 , 29 , 30 ]. ERG induces the expression of the metalloproteinase MMP3 and the plasminogen activator genes PLAT and PLAU , facilitating invasion of the T2E-positive PCa cell line VCaP [ 30 ].…”

“…ERG induces the expression of the metalloproteinase MMP3 and the plasminogen activator genes PLAT and PLAU , facilitating invasion of the T2E-positive PCa cell line VCaP [ 30 ]. In LNCaP T2E cell models, overexpression of the fusion resulted in the activation of the TGF-β signaling pathway and induction of epithelial to mesenchymal transition [ 29 ]. Moreover, by binding to the AR promoter region, ERG hinders AR-mediated, cell-specific differentiation of prostate cells [ 28 ].…”