Abstract
Upregulated expression of autotaxin, a secreted phospholipase and phosphodiesterase enzyme, appears in malignant disease. The identification of a circulating miRNA signature should distinguish autotaxin-mediated disease and also elucidate unknown molecular mechanisms that rationalize its malignant potential. Using female transgenic ‘AT-ATX’ mice, whereby human wild-type autotaxin is expressed in liver under the control of the alpha-1 antitrypsin promoter, transgenic animals express augmented autotaxin in circulation and a percentage develop tumors. Serum collected at necropsy had circulating miRNAs analyzed for statistical significance. The ensuing autotaxin-mediated miRNome differentiated between groups: healthy FVB/N mice versus AT-ATX mice with and without tumors. Intriguingly, miR-489-3p was sharply increased in AT-ATX tumor-bearing mice. Tissue analysis showed a correlation between miR-489-3p expression in tumors and surrounding milieu with autotaxin concentration in circulation. Sequence alignment suggested miR-489-3p targets MEK1, which was confirmed through in vitro studies. Exogenously added miR-489-3p, which decreases MEK1 in normal cells, dramatically increased MEK1 expression in cells stably expressing autotaxin. Taken together, this suggests that autotaxin overrides the normal regulatory function of miR-489-3p to inhibit MEK1 via coordinately increased miR-489-3p appearing in serum.
Original language | English |
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Pages (from-to) | 84-92 |
Number of pages | 9 |
Journal | Cancer Letters |
Volume | 432 |
DOIs | |
State | Published - Sep 28 2018 |
Bibliographical note
Funding Information:The research was supported by a grant from the National Institutes of Health 1R15CA176653 (to MMM). We would like to thank Dr. Aaron M. Beedle for assistance with the transgenic animals.
Publisher Copyright:
© 2018
Keywords
- Cancer
- Lysophosphatidic acid
- MAPK
- Serum biomarkers
- miRNA
ASJC Scopus subject areas
- Oncology
- Cancer Research