Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jun 13:12:922945.
doi: 10.3389/fonc.2022.922945. eCollection 2022.

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

Sha She  1 , Qian Zhang  1 , Jinzhi Shi  1 , Fan Yang  1 , Kai Dai  1
Affiliations
Review

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

Sha She et al. Front Oncol. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
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
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.
See this image and copyright information in PMC

References

    1. Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M. The Immunology of Hepatocellular Carcinoma. Nat Immunol (2018) 19(3):222–32. doi: 10.1038/s41590-018-0044-z - DOI - PubMed
    1. Ma C, Zhang Q, Greten TF. MDSCs in Liver Cancer: A Critical Tumor-Promoting Player and a Potential Therapeutic Target. Cell Immunol (2021) 361:104295. doi: 10.1016/j.cellimm.2021.104295 - DOI - PMC - PubMed
    1. Verslype C, Rosmorduc O, Rougier P, Group EGW. Hepatocellular Carcinoma: ESMO-ESDO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann Oncol (2012) 23 Suppl 7:vii41–8. doi: 10.1093/annonc/mds225 - DOI - PubMed
    1. Xia S, Pan Y, Liang Y, Xu J, Cai X. The Microenvironmental and Metabolic Aspects of Sorafenib Resistance in Hepatocellular Carcinoma. EBioMedicine (2020) 51:102610. doi: 10.1016/j.ebiom.2019.102610 - DOI - PMC - PubMed
    1. Zhang X, Li M, Yin N, Zhang J. The Expression Regulation and Biological Function of Autotaxin. Cells (2021) 10(4):939–52. doi: 10.3390/cells10040939 - DOI - PMC - PubMed