Abstract
Sp1 transcription factor regulates genes involved in various phenomena of tumor progression. Vasculogenic mimicry (VM) is the alternative neovascularization by aggressive tumor cells. However, there is no evidence of the relationship between Sp1 and VM. This study investigated whether and how Sp1 plays a crucial role in the process of VM in human prostate cancer (PCa) cell lines, PC-3 and DU145. A cell viability assay and three-dimensional culture VM tube formation assay were performed. Protein and mRNA expression levels were detected by Western blot and reverse transcriptase-polymerase chain reaction, respectively. The nuclear twist expression was observed by immunofluorescence assay. A co-immunoprecipitation assay was performed. Mithramycin A (MiA) and Sp1 siRNA significantly decreased serum-induced VM, whereas Sp1 overexpression caused a significant induction of VM. Serum-upregulated vascular endothelial cadherin (VE-cadherin) protein and mRNA expression levels were decreased after MiA treatment or Sp1 silencing. The protein expression and the nuclear localization of twist were increased by serum, which was effectively inhibited after MiA treatment or Sp1 silencing. The interaction between Sp1 and twist was reduced by MiA. On the contrary, Sp1 overexpression enhanced VE-cadherin and twist expressions. Serum phosphorylated AKT and raised matrix metalloproteinase-2 (MMP-2) and laminin subunit 5 gamma-2 (LAMC2) expressions. MiA or Sp1 silencing impaired these effects. However, Sp1 overexpression upregulated phosphor-AKT, MMP-2 and LAMC2 expressions. Serum-upregulated Sp1 was significantly reduced by an AKT inhibitor, wortmannin. These results demonstrate that Sp1 mediates VM formation through interacting with the twist/VE-cadherin/AKT pathway in human PCa cells.
Highlights
Prostate cancer (PCa) is a common cancer among men around the world [1]
PC-3 cells were treated with an increasing concentration of serum for 24 h and the expression level of Sp1 was checked by Western blot
To determine whether Sp1 is associated with Vasculogenic mimicry (VM) formation, 3D culture VM formation assay was performed in PC-3 cells after Mithramycin A (MiA) treatment or transfection with Sp1 Small Interfering RNA (siRNA)
Summary
Prostate cancer (PCa) is a common cancer among men around the world [1]. PCa spread to nearby organs, tissues and other parts of the body including lymph nodes and bones [2]. A quarter of men with PCa in the world have a metastatic disease and the 5-year survival rate of patients with metastasis to distant sites is 29% [4]. PCa cells are known to have largely aggressive properties [5]. Since these tumors need a blood supply to grow and spread through blood circulation [6], it is important to shut off the blood supply to prevent tumor growth and metastasis in PCa
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