Phosphatase of regenerating liver‐3 promotes migration and invasion by upregulating matrix metalloproteinases‐7 in human colorectal cancer cells

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Abstract
Phosphatase of regenerating liver (PRL)‐3, a member of a subgroup of protein tyrosine phosphatases that can stimulate the degradation of the extracellular matrix, is over‐expressed in metastatic colorectal cancer (CRC) relative to primary tumors. To determine whether PRL‐3‐induced enhancement of migration and invasion is dependent on the expression of matrix metalloproteinases (MMPs), PRL‐3 was expressed in DLD‐1 human CRC cells. The motility, migration and invasion characteristics of the cells were examined, and metastasis to the lung was confirmed in a nude mouse using PRL‐3‐overexpressing DLD‐1 cells [DLD‐1 (PRL‐3)]. Migration and invasion of the cells were inhibited by phosphatase and farnesyltransferase inhibitors. Expression of MMPs was enhanced 3‐ to 10‐fold in comparison to control cells, and migration and invasion were partially inhibited by small interfering RNA (siRNA) knockdown of MMP‐2, ‐13 or ‐14. Importantly, siRNA knockdown of MMP‐7 completely inhibited the migration and invasion of DLD‐1 (PRL‐3) cells, whereas overexpression of MMP‐7 increased migration. The expression of MMP‐7 was also downregulated by phosphatase and farnesyltransferase inhibitors. It was found that PRL‐3 induced MMP‐7 through oncogenic pathways including PI3K/AKT and ERK and that there is a relationship between the expression of PRL‐3 and MMP‐7 in human tumor cell lines. The expression of MMP‐13 and ‐14 was very sensitive to the inhibition of farnesyltransferase; however, the migration and invasion of DLD‐1 (PRL‐3) cells did not strongly depend on the expression of MMP‐13 or ‐14. These results suggest that the migration and invasion of PRL‐3‐expressing CRC cells depends primarily on the expression of MMP‐7.

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