SLC34A2 regulates miR-25-Gsk3β signaling pathway to affect tumor progression in gastric cancer stem cell-like cells.

A novel paradigm in tumor biology suggests that gastric cancer progression is driven by gastric cancer stem cell-like cells (GCSCs), but molecular mechanisms regulating tumorigenic and self-renewal potential of GCSCs are still unclear. Here, we aim to investigate biological function of SLC34A2 in regulating sphere formation and tumorigenicity (both are the hallmark of CSCs) of GCSCs and its underlying mechanisms. Our findings testified that CD44⁺ cells which were derived from fresh primary gastric cancer samples and cell lines displayed stem cell-like features. Significantly, SLC34A2 is increased in CD44⁺ GCSCs compared with those in adherent counterpart from CD44⁺ GCSCs. On clinic, SLC34A2 is overexpressed in primary tumor tissues compared with adjacent counterparts. We showed that SLC34A2 regulated sphere formation and self-renewal properties of CD44⁺ GCSCs in vitro and in vivo. Mechanistic investigations revealed that Gsk3β was the most strikingly up-regulated gene in response to SLC34A2 knockdown in GCSCs and Wnt/β-cantenin signaling was required for SLC34A2-mediated sphere formation. Furthermore, SLC34A2 directly binds specific sites in the miR-25 promoter region and that the promoter activity is decreased after the mutation of putative SLC34A2-binding sites, indicating that SLC34A2 is required for the transcriptional induction of miR-25. Meanwhile, luciferase assays showed that miR-25 directly targeted Gsk3β in CD44⁺ GCSCs. Overall, our findings define a SLC34A2-miR-25-Gsk3β pathway in the regulation of GCSCs features and gastric cancer progression, with potential therapeutic applications in blocking their progression.

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