MicroRNA-454 regulates stromal cell derived factor-1 in the control of the growth of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant carcinoma with an extremely high lethality. We recently reported that hypoxia-inducible factor 1 (HIF-1) targets quiescin sulfhydryl oxidase 1 to facilitate PDAC cell growth and invasion. Here, we analyzed the control of another HIF-1 target, stromal cell derived factor-1 (SDF-1), in PDAC cells. We detected significantly more CD68+ macrophages in the PDAC, compared to normal human pancreas (NT). Since macrophages are recruited to the tissue through their expression of CXCR4 in response to SDF-1, we thus examined the SDF-1 levels in the PDAC specimens. Surprisingly, the SDF-1 protein but not mRNA significantly increased in PDAC, compared to NT. Moreover, a SDF-1-targeting microRNA, miR-454, was found to decrease in PDAC. Promoter luciferase assay confirmed that bindings of miR-454 to 3'-UTR of SDF-1 mRNAs inhibited SDF-1 protein translation. Co-culture of bone marrow derived macrophages and miR-454-modified PDAC cells in a transwell migration experiment showed that macrophages migrated less towards miR-454-overexpressing PDAC cells, and migrated more towards miR-454-depleted cells. Implanted miR-454-depleted PDAC cells grew significantly faster than control, while implanted miR-454-overexpressing PDAC cells grew significantly slower than control. Together, our data suggest that miR-454 may regulate SDF-1 in the control of the growth of PDAC.