Association between Expression of Transcription Factor Sp1 and Increased Vascular Endothelial Growth Factor Expression, Advanced Stage, and Poor Survival in Patients with Resected Gastric Cancer

Abstract

The biological and clinical behaviors of cancer are affected by multiple molecular pathways that are under the control of transcription factors. Improved understanding of how transcription factors affect cancer biology may lead to improved ability to predict clinical outcome and discovery of novel therapeutic strategies. We evaluated the relationship between Sp1 and vascular endothelial growth factor (VEGF) expression, as well as their effect on survival in 86 cases of resected human gastric cancer. The degree of VEGF expression correlated highly with Sp1 expression (P < 0.01). Patients with high Sp1 expression were 98 times more likely to have high VEGF expression compared with those with negative Sp1 expression. Clinically, negative or weak Sp1 expression was associated with early stage (IA) in gastric cancer. Strong Sp1 expression was more frequently observed among patients with stage IB-IV disease (P ‫؍‬ 0.035). Similarly, whereas strong Sp1 expression was uncommonly observed among patients with N0 or N1 disease (19 and 16%), N2/N3 gastric cancer was associated with strong Sp1 expression (48%; P ‫؍‬ 0.034). Strong Sp1 expression was also associated with inferior survival. The median survival duration in patients who had a tumor with a negative, weak, and strong Sp1 expression was 44, 38, and 8 months (P ‫؍‬ 0.0075), respectively, whereas patients with strong VEGF expression had a shorter survival duration; the difference was not statistically significant. When Sp1 and VEGF expression, stage, completeness of resection, histology, and patient age were entered in a Cox proportional hazards model, strong Sp1 expression (P ‫؍‬ 0.021) and an advanced disease stage (P < 0.001) were independently prognostic of poor survival. Given the importance of Sp1 in the expression of VEGF, our data suggest that dysregulated Sp1 expression and activation play important roles in VEGF overexpression and, thus, gastric cancer development and progression.

The microRNA-27a: ZBTB10-specificity protein pathway is involved in follicle stimulating hormone-induced VEGF, Cox2 and survivin expression in ovarian epithelial cancer cells

“…Previous reports stated that Sp1 was overexpressed in several type of cancer tissues (29)(30)(31), moreover, it is a significant predictor of survival in human gastric cancer (30)(31)(32). In the current study, overexpression of Sp1 was observed in ovarian cancer cell lines, which indicates that Sp1 may be involved in OEC occurrence.…”

Transcriptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein-1 and its coactivator DRIP-130

“…Genes involved in cell cycle progression, cell growth and differentiation, apoptosis and capillary growth have all been shown to contain GC-rich Sp1 elements (Ryuto et al, 1996;Finkenzeller et al, 1997;Ji et al, 1997;Dong et al, 1999). Recent studies indicate Sp1 expression is directly correlated to severity of multiple forms of cancer, suggesting that Sp1 expression may also be a determining factor in tumor metastatic progression (Shi et al, 2001;Zhu et al, 2002;Wang et al, 2003;Abdelrahim et al, 2004;Jiang et al, 2004;Yao et al, 2004;Liu et al, 2005;Wang and Bannon, 2005). Another explanation for increased Sp1 in such cases, however, is that the normal ratio of Sp1 expression is altered such as in the overexpression of thrombin receptor protease-activated receptor (PAR-1).…”

Dynamic transcriptional regulatory complexes including BORIS, CTCF and Sp1 modulate NY-ESO-1 expression in lung cancer cells

“…Sp1 is a member of a family of transcription factors that bind GC/GT-rich promoter elements via three C 2 H 2 -type zinc fingers present within their C-terminal domains (Suske, 1999;Safe and Abdelrahim, 2005). There is growing evidence that Sp1 is overexpressed in human malignancies (Hosoi et al, 2004;Yao et al, 2004), and that Sp1 modulates growth and metastasis of cancer cells, in part, by regulating expression of a variety of cell-cycle-related genes, as well as vascular endothelial growth factor (Pore et al, 2004;Safe and Abdelrahim, 2005). Of particular interest in this regard, are recent data indicating that HDAC inhibitors such as DP induce p21 expression via activation of Sp1 (Nguyen et al, 2004).…”