Abstract
Six-transmembrane epithelial antigen of the prostate-2 (STEAP2) expression is increased in prostate cancer when compared to normal prostate, suggesting STEAP2 may drive prostate cancer progression. This study aimed to establish the functional role of STEAP2 in prostate tumourigenesis and evaluate if its knockdown resulted in reduced invasive potential of prostate cancer cells. PC3 and LNCaP cells were transfected with STEAP2 siRNA and proliferation, migration, invasion and gene expression analyses were performed. STEAP2 immunohistochemistry was applied to assess the protein expression and localisation according to Gleason score in 164 prostate cancer patients. Invasion significantly decreased in both cell lines following STEAP2 knockdown. PC3 proliferation and migration capacity significantly reduced, while LNCaP cell morphology and growth characteristics were altered. Additionally, STEAP2 downstream targets associated with driving invasion were identified as MMP3, MMP10, MMP13, FGFR4, IL1β, KiSS1 and SERPINE1 in PC3 cells and, MMP7 in LNCaP cells, with CD82 altered in both. In patient tissues, STEAP2 expression was significantly increased in prostate cancer samples and this significantly correlated with Gleason score. These data demonstrate that STEAP2 drives aggressive prostate cancer traits by promoting proliferation, migration and invasion and significantly influencing the transcriptional profile of ten genes underlying the metastatic cascade.
Highlights
An understanding of many of the key molecules in the invasion and metastasis cascade is currently being formed, substantial gaps in our knowledge remain[5,6,7,8]
To evaluate whether this effect on proliferation was due to cell cycle alterations in response to Six-transmembrane epithelial antigen of the prostate-2 (STEAP2) knockdown, cell cycle analysis was carried out on both PC3 and LNCaP cells treated with STEAP2 siRNA (Figure S1)
STEAP2 is elevated in PCa tissues, both in vitro and in clinical samples compared to normal prostate cells[12,14]
Summary
An understanding of many of the key molecules in the invasion and metastasis cascade is currently being formed, substantial gaps in our knowledge remain[5,6,7,8]. LNCaP cells appear to share common features with adenocarcinomas, the most common diagnosed form of PCa; whilst PC3 cells appear to be more characteristic of the more aggressive prostatic small cell neuroendocrine carcinoma[18] While both LNCaP and PC3 cells have been shown to possess similar expression of proliferation-associated markers, differences in angiogenic markers, pro-inflammatory cytokines, PCa markers and responses to environmental stresses have been observed[19]. These two cell lines were selected as a model to evaluate the functional role of STEAP2 in the development of aggressive cancer traits. The aim of the present study was to establish the functional role of STEAP2 in driving PCa progression and to determine whether reduction of protein expression, via siRNA treatment, could reverse the tumourigenic impact of this protein
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