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 Jackson Hardman, Mandi M. Murph

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

MicroRNAs
Neoplasms
alpha 1-Antitrypsin
Genetically Modified Animals
Phospholipases
Sequence Alignment
Phosphoric Diester Hydrolases
Serum
Liver
Enzymes
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kuppa, S. S., Jia, W., Liu, S., Nguyen, H., Smyth, S. S., Mills, G. B., ... 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

Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p. / Kuppa, Sudeepti S.; Jia, Wei; Liu, Shuying; Nguyen, Ha; Smyth, Susan S.; Mills, Gordon B.; Dobbin, Kevin K.; Hardman, William Jackson; Murph, Mandi M.

In: Cancer Letters, Vol. 432, 28.09.2018, p. 84-92.

Research output: Contribution to journalArticle

Kuppa, SS, Jia, W, Liu, S, Nguyen, H, Smyth, SS, Mills, GB, Dobbin, KK, Hardman, WJ & Murph, MM 2018, 'Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p', Cancer Letters, vol. 432, pp. 84-92. https://doi.org/10.1016/j.canlet.2018.05.037
Kuppa, Sudeepti S. ; Jia, Wei ; Liu, Shuying ; Nguyen, Ha ; Smyth, Susan S. ; Mills, Gordon B. ; Dobbin, Kevin K. ; Hardman, William Jackson ; Murph, Mandi M. / Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p. In: Cancer Letters. 2018 ; Vol. 432. pp. 84-92.
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