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

2 Citations (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
Externally publishedYes

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
  • miRNA
  • Serum biomarkers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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; Dobbin, Kevin K.; Hardman, William J.; 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, G, 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 ; Dobbin, Kevin K. ; Hardman, William J. ; 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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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.",
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