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 Mills, Kevin K. Dobbin, William J. Hardman, Mandi M. Murph

Research output: Contribution to journalArticle

5 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 (US)
Pages (from-to)84-92
Number of pages9
JournalCancer Letters
Volume432
DOIs
StatePublished - Sep 28 2018
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kuppa, S. S., Jia, W., Liu, S., Nguyen, H., Smyth, S. S., Mills, G., Dobbin, K. K., Hardman, W. J., & Murph, M. M. (2018). Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p. Cancer Letters, 432, 84-92. https://doi.org/10.1016/j.canlet.2018.05.037