Roles of Autotaxin/Autotaxin-Lysophosphatidic Acid Axis in the Initiation and Progression of Liver Cancer

Abstract

Autotaxin (ATX) is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a growth factor-like signaling phospholipid. ATX has been abundantly detected in the culture medium of various cancer cells, tumor tissues, and serum or plasma of cancer patients. Biological actions of ATX are mediated by LPA. The ATX-LPA axis mediates a plethora of activities, such as cell proliferation, survival, migration, angiogenesis, and inflammation, and participates in the regulation of various physiological and pathological processes. In this review, we have summarized the physiological function of ATX and the ATX-LPA axis in liver cancer, analyzed the role of the ATX-LPA axis in tumorigenesis and metastasis, and discussed the therapeutic strategies targeting the ATX-LPA axis, paving the way for new therapeutic developments.

Keywords: autotaxin; liver cancer; lysophosphatidic acid; metastasis; tumorigenesis.

Figure 1

Overview of the autotaxin-lysophosphatidic acid signaling pathway. ATX produces the lipid mediator and GPCR agonist lysophosphatidic acid (LPA) from abundantly available extracellular lysophosphatidylcholine (LPC). LPA signal through its six homologous receptors (LPAR1-6) that is binds to G proteins to activate downstream signaling pathways, including those involving Ras/Raf, RhoA, phosphoinositide 3-kinases, mitogen-activated protein kinases, and protein kinase B/mammalian target of rapamycin. The activated LPA-LPAR pathway participates in wound healing, embryonic development, vascular homeostasis, lymphocyte trafficking, cancer biology, stem cell physiology, and therapy resistance, etc.

Figure 2

Role and Mechanisms of ATX/LPA in hepatocellular carcinoma. LPAR1 promoted the occurrence, proliferation, migration and angiogenesis of HCC by coupling with Gαi/0, Gαq/11, and Gα12/13, and activating downstream a-SMA, PI3K/AKT/mTOR, VEGF pathways. LPAR2 may regulate the proliferation of HCC cells through Src signaling pathway and HIF1α pathway. On the other hand, LPAR2 may interact with TRIP to inhibit apoptosis of HCC cells. LPAR3 promoted tumor cell motility in HCC through coupling to Gαi/0 and Gα11/q to mediate downstream activation of MAPK, PLC, and inactivation of AC. LPAR6 supported the tumorigenicity of HCC through a STAT3/pim-3-dependent mechanism. And LPAR6 increased microvascular invasion in HCC through mediating cAMP reduction, Rho-dependent morphological changes, MAPK and HGF activation.