This study demonstrates, for the first time, that SHIP2 is frequently downregulated in gastric cancer, and reduced SHIP2 expression promotes tumorigenesis and proliferation of gastric cancer via activation of the PI3K/Akt signaling.

Purpose: Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein overexpressed in various malignancies, including esophageal squamous cell carcinoma (ESCC), and is involved in tumor development and progression. This study was initially designed to investigate the biological roles of SPARC in ESCC cell lines by silencing SPARC expression.Methods: The expression of SPARC was examined in eight human ESCC cell lines. Eca109 and HKESC cell lines with high SPARC expression were selected and transiently transfected with SPARC-targeted small interfering RNAs (siRNAs) and subsequently evaluated its impact on cell proliferation, migration and invasion in vitro, as well as the underlying mechanism.Results: Knockdown of SPARC by the specified siRNAs in Eca109 and HKESC cell lines resulted in dramatically downregulation of SPARC expression, and significantly decreased cell migration and invasion involving epithelial-mesenchymal transition (EMT) in vitro. Moreover, SPARC-targeted siRNA reduced the activation of phosphorylated focal adhesion kinase (p-FAK) and extracellular regulated protein kinase (p-ERK). Furthermore, downregulation of either FAK or SPARC expression with specified siRNAs inhibited the phosphorylation of ERK and inhibited cell migration and invasion. However, decreased SPARC expression showed no impact on cell proliferation, survival or apoptosis of Eca109 and HKESC cells when comparing to control transfected groups.Conclusions: These results demonstrated that downregulation of SPARC could decrease cell migration and invasion involving EMT via the p-FAK/p-ERK pathway that might serve as a novel therapeutic target against ESCC.

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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.

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