SLC39A1 promotes pancreatic cancer metastasis by elevating intracellular zinc and activating the Src/FAK signaling pathway

Pancreatic Cancer (PC) is a highly aggressive malignancy, and zinc ion homeostasis is closely linked to its metastatic potential, though the underlying regulatory mechanisms remain unclear. To investigate this, single-cell RNA Sequencing data from primary and metastatic PC were downloaded from the GEO database to analyze differences in zinc ion levels and identify key zinc-regulating proteins. A PC mouse model was further established, and experiments including immunofluorescence, immunohistochemistry, and zinc ion level detection were conducted to comprehensively evaluate the impact of zinc ions and their regulatory proteins on PC metastasis and the associated mechanisms. PC cell models with SLC39A1 knockdown or overexpression were also constructed; Western blot was used to measure protein expression levels, while cell scratch assay, Transwell invasion assay, and 3D cell sphere formation assay were employed to assess cell migration, invasion, and sphere-forming capabilities, respectively. Single-cell Sequencing analysis demonstrated that zinc ions and SLC39A1 were significantly enriched in PC metastases, with higher enrichment levels in epithelial cells compared to Other cell types. Overexpression of SLC39A1 increased intracellular zinc levels and enhanced the migration and invasion of PC cells, whereas application of zinc chelators or Src/FAK inhibitors effectively suppressed Cancer cell migration and invasion induced by elevated zinc levels. Animal model experiments further showed that knockdown of SLC39A1 in PC cells inhibited their liver metastasis capability. Collectively, these findings indicated that SLC39A1 was highly expressed in PC metastases, where its elevated expression increased intracellular zinc levels and activated the Src/FAK signaling pathway, thereby promoting the migration and invasion of PC cells.