Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p

Sudeepti S. Kuppa, Wei Jia, Shuying Liu, Ha Nguyen, Susan S. Smyth, Gordon B. Mills, Kevin K. Dobbin, William J. Hardman, Mandi M. Murph

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 languageEnglish
Pages (from-to)84-92
Number of pages9
JournalCancer Letters
Volume432
DOIs
StatePublished - Sep 28 2018

Bibliographical note

Publisher Copyright:
© 2018

Funding

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.

FundersFunder number
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer InstituteR15CA176653

    Keywords

    • Cancer
    • Lysophosphatidic acid
    • MAPK
    • Serum biomarkers
    • miRNA

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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