Abstract
Past studies have shown that the Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) is commonly downregulated in gastric cancer, which contributes to elevated activation of PI3K/Akt signaling, proliferation and tumorigenesis of gastric cancer cells. However, the mechanisms underlying the reduced expression of SHIP2 in gastric cancer remain unclear. While gene copy number variation analysis and exon sequencing indicated the absence of genomic alterations of SHIP2, bisulfite genomic sequencing (BGS) showed promoter hypomethylation of SHIP2 in gastric cancer cells. Analysis of transcriptional activity of SHIP2 promoter revealed Specificity protein 1 (Sp1) was responsible for the regulation of SHIP2 expression in gastric cancer cells. Furthermore, Sp1 expression, but not Sp3, was frequently downregulated in gastric cancer compared with normal gastric mucosa, which was associated with a paralleled reduction in SHIP2 levels in gastric cancer. Moreover, overexpression of Sp1 inhibited cell proliferation, induced apoptosis, suppressed cell motility and invasion in gastric cancer cells in vitro, which was, at least in part, due to transcriptional activation of SHIP2 mediated by Sp1, thereby inactivating Akt. Collectively, these results indicate that decreased expression of transcription factor Sp1 contributes to suppression of SHIP2 in gastric cancer cells.
Highlights
Gastric cancer (GC) is the fourth most common cancer and second leading cause of cancer death worldwide [1]
We found that genetic and epigenetic alternations are not responsible for downregulation of Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) in GC cells, while transcriptional suppression of SHIP2 mediated by downregulation of the transcription factor Specificity protein 1 (Sp1) appears to be a commonly involved mechanism, suggesting that reduced expression of SHIP2 and Sp1 may directly contribute to GC development and progression
By use of qPCR analysis of genomic DNA in a panel of GC cell lines and the human immortalized normal gastric mucosal epithelial cell line GES-1, we found there was no significant reduction of INPPL1 copy number in five GC cell lines; INPPL1 copy number was increased in MKN-45 (Figure 1A)
Summary
Gastric cancer (GC) is the fourth most common cancer and second leading cause of cancer death worldwide [1]. Specificity protein 1 (Sp1) is a member of the Sp transcription factor family containing C2H2-type zinc fingers, and other members include Sp2, Sp3, and Sp4 They play important roles in regulation of cell survival, growth, and tumor development and progression through binding to GC-rich sequences of many cellular and viral genes [18,19]. We found that genetic and epigenetic alternations are not responsible for downregulation of SHIP2 in GC cells, while transcriptional suppression of SHIP2 mediated by downregulation of the transcription factor Sp1 appears to be a commonly involved mechanism, suggesting that reduced expression of SHIP2 and Sp1 may directly contribute to GC development and progression
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