Dysregulation of the mitogen granulin in human cancer through the miR-15/107 microRNA gene group

Granulin (GRN) is a potent mitogen and growth factor implicated in many human cancers, but its regulation is poorly understood. Recent findings indicate that GRN is regulated strongly by the microRNA miR-107, which functionally overlaps with miR-15, miR-16, and miR-195 due to a common 5′ sequence critical for target specificity. In this study, we queried whether miR-107 and paralogs regulated GRN in human cancers. In cultured cells, anti-argonaute RNA coimmunoprecipitation with downstream microarray analyses indicates that GRN mRNA is directly targeted by numerous miR-15/107miRNAs. We further tested this association in human tumors. MiR-15 and miR-16 are known to be downregulated in chronic lymphocytic leukemia (CLL). Using pre-existing microarray datasets, we found that GRN expression is higher in CLL relative to nonneoplastic lymphocytes (P < 0.00001). By contrast, other prospective miR-15/miR-16 targets in the dataset (BCL-2 and cyclin D1) were not upregulated in CLL. Unlike in CLL, GRN was not upregulated in chronic myelogenous leukemia (CML) where miR-107 paralogs are not known to be dysregulated. Prior studies have shown that GRN is also upregulated, and miR-107 downregulated, in prostate carcinoma. Our results indicate that multiple members of the miR-107 gene group indeed repress GRN protein levels when transfected into prostate cancer cells. At least a dozen distinct types of cancer have the pattern of increased GRN and decreased miR-107 expression. These findings indicate for the first time that the mitogen and growth factor GRN is dysregulated via the miR-15/107 gene group in multiple human cancers, which may provide a potential common therapeutic target.