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.
Highlights
Prostate cancer (PCa) is the most frequently diagnosed cancer among men in Western countries and a major cause of cancer-related mortality [1, 2]
In line with previous reports that V-ets erythroblastosis virus E26 homolog (ERG) expression leads to downregulation of androgen receptor (AR) transcripts [18], both LNCaP-The most common fusion mRNA variant III (T/E III) and VI cell lines showed markedly decreased AR protein after ERG overexpression (Figure 1C), indicating that the cell lines faithfully reflect the in vivo situation
TGF-β-mediated AKT serine/threonine kinase 1 (AKT) activation has previously been proposed to overcome the growth-inhibitory effects of TGF-β in BPH1 tumorigenic sublines [23]. These findings provided evidence for increased TGF-β signaling in both T/E variants, as well as an activated AKT dependent survival network upon T/E III overexpression, that might act together to induce epithelial-to-mesenchymal transition (EMT) in this prostate cancer (PCa) cell model
Summary
Prostate cancer (PCa) is the most frequently diagnosed cancer among men in Western countries and a major cause of cancer-related mortality [1, 2]. The TMPRSS2:ERG (T/E) gene fusion, resulting from a chromosomal rearrangement of ERG (v-ets erythroblastosis virus E26 homolog (avian)) to the androgen responsive gene TMPRSS2 (transmembrane protease, serine 2), is the most frequent somatic alteration in PCa [3], and detectable in 50% of the tumors [4]. In those cases, ERG www.impactjournals.com/oncotarget overexpression is driven by the androgen-responsive promoter of TMPRSS2, resulting in upregulation of ERG protein and activation of downstream target genes [5]. The resulting protein includes the first five amino acids of TMPRSS2 and lacks the first 12 amino acids of the fulllength ERG protein
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