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-15/107
miRNAs. 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.