MicroRNA Regulation of the Autotaxin-Lysophosphatidic Acid Signaling Axis

Abstract

The revelation that microRNAs (miRNAs) exist within the human genome uncovered an underappreciated mechanism of gene expression. For cells to regulate expression of their genes, miRNA molecules and argonaute proteins bind to mRNAs and interfere with efficient translation of the RNA transcript. Although miRNAs have important roles in normal tissues, miRNAs may adopt aberrant functions in malignant cells depending on their classification as either a tumor suppressor or oncogenic miRNA. Within this review, the current status of miRNA regulation is described in the context of signaling through the lysophosphatidic acid receptors, including the lysophosphatidic acid-producing enzyme, autotaxin. Thus far, research has revealed miRNAs that increase in response to lysophosphatidic acid stimulation, such as miR-21, miR-30c-2-3p, and miR-122. Other miRNAs inhibit the translation of lysophosphatidic acid receptors, such as miR-15b, miR-23a, and miR200c, or proteins that are downstream of lysophosphatidic acid signaling, such as miR-146 and miR-21. With thousands of miRNAs still uncharacterized, it is anticipated that the complex regulation of lysophosphatidic acid signaling by miRNAs will continue to be elucidated. RNA-based therapeutics have entered the clinic with enormous potential in precision medicine. This exciting field is rapidly emerging and it will be fascinating to witness its expansion in scope.

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…ATX upregulation also correlates to dysregulated microRNA regulation, favoring a pro-tumorigenic state [75,76]. A thorough review on the micoRNA regulation of the ATX-LPA signaling axis has recently been published [77].…”

Relative expression and regulation by short‐term fasting of lysophosphatidic acid receptors and autotaxin in white and brown adipose tissue depots

“…Thus, together with our data, this suggests that allosteric regulation may predominate in controlling ATX activity, although other mechanisms of post‐transcriptional regulation may also play a role. Recent studies have found that Atx is a known or predicted target of micro RNA that can inhibit mRNA translation, including MiR‐29a/b/c, MiR‐489‐3p, and MiR‐101‐3p (reviewed in (Murph, )). Future work investigating whether these MiR are induced by fasting will provide additional insight into mechanisms underlying nutritional regulation of ATX activity.…”

Long-Term Decrease of Intraocular Pressure in Rats by Viral Delivery of miR-146a

“…Specifically, it plays a key role in the regulation of autotaxin, a major producer of lisophosphatidic acid (LPA). 50 , 51 Both, autotaxin and LPA are known to be increased in the aqueous humor of open-angle glaucoma patients. Inhibition of autotaxin has been shown to increase aqueous outflow ex vivo.…”