MicroRNA 520c and 373 (miR-520c and miR-373) have been characterized as oncogenes and play critical roles in
cancer cell
metastasis. However, the relationship between these two
microRNAs and
matrix metalloproteinases (
MMPs), which are important in
cancer cell
metastasis, remains unknown. Here, we report new evidence in which miR-520c and miR-373 effects in human
fibrosarcoma HT1080 cells are associated with MMP9 activity, and this upregulation of MMP9 is not only at the activity and
protein levels, but also at that of its
mRNA. Our experimental data demonstrate that these effects occur not by direct binding to the MMP9 promoter, but by miR-520c and miR-373 directly targeting the 3'-untranslational region (UTR) of mRNAs of mTOR and
SIRT1 (negative regulators of expression of MMP9 via inactivating the Ras/Raf/
MEK/Erk signaling pathway and
transcription factor NF-κB activity); and thus suppressing translation levels of
SIRT1 and mTOR. Moreover, inhibition of key
kinases of the Ras/Raf/
MEK/Erk signaling pathway and Western blots for selected
proteins further identified miR-520c and miR-373 as activating this signaling pathway and NF-κB. In conclusion, miR-520c and miR-373 increased the expression of MMP9 by directly targeting the 3'-UTRs of mRNAs of mTOR and
SIRT1 and suppressing their translation; resulting in activation of the Ras/Raf/
MEK/Erk signaling pathway and NF-κB; and, finally, increasing the
mRNA,
protein, and activity of MMP9 and enhancing cell migration and cell growth in 3D
type I collagen gels.