Abstract
The stem cell factor SALL4 (Sal-like protein 4) plays important roles in the development and progression of cancer. SALL4 is critically involved in tumour growth, metastasis and therapy resistance. However, the underlying mechanisms responsible for the oncogenic roles of SALL4 have not been well characterized. In this study, we demonstrated that SALL4 knockdown by short hairpin RNA greatly inhibited the proliferation, migration and invasion of gastric cancer cells. We further confirmed the inhibitory effects of SALL4 knockdown on gastric cancer cells by using a tetracycline-inducible system. Mechanistically, SALL4 knockdown downregulated the expression of CD44. The results of luciferase assay and chromatin immunoprecipitation study showed that SALL4 bound to CD44 promoter region and transcriptionally activated CD44. The results of rescue study revealed that CD44 overexpression antagonized SALL4 knockdown-mediated inhibition of gastric cancer cell proliferation, migration, and invasion in vitro and gastric cancer growth in vivo. Collectively, our findings indicate that SALL4 promotes gastric cancer progression through directly activating CD44 expression, which suggests a novel mechanism for the oncogenic roles of SALL4 in gastric cancer and represents a new target for gastric cancer therapy.
Highlights
Cancer cells share common gene expression signature with stem cells
We reported that SALL4 bound to the promoter region of CD44 gene and transcriptionally activated CD44 expression
We found that stable and inducible knockdown of SALL4 upregulated the expression of E-cadherin (Supplementary Figure 4), which is in support of the finding that SALL4 promotes epithelial-mesenchymal transition (EMT) in gastric cancer cells
Summary
The studies on the key genes in the maintenance of stem cells have led to the identification of factors that are responsible for the malignant phenotype of cancer cells. SALL4 is first found to be aberrantly expressed in human acute myeloid leukemia (AML) and SALL4 transgenic mice have been shown to develop AML.[7] SALL4 is suggested as a key regulator of leukemic cell survival and SALL4 downregulation leads to significant cell apoptosis.[8] The roles of SALL4 in AML are associated with the regulation of β-catenin by protein–protein interaction,[7] the upregulation of Bmi-1 and HOXA9 by transcriptional activation,[7,9,10] and the inhibition of PTEN expression by epigenetic silencing.[11] SALL4 is involved in the maintenance of leukemic stem cells through the regulation of ABCA3.12. Our findings indicate that SALL4 promotes gastric cancer growth and metastasis through the activation of CD44, which represents a new mechanism responsible for the oncogenic roles of SALL4 in cancer
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