Research advances in the association of the tyrosine kinase receptor Axl and its ligand Gas6 with hepatocellular carcinoma

Yu WU; Ping'an QIAN; Xingliang FAN; Junfeng ZHU

doi:10.3969/j.issn.1001-5256.2021.01.040

Volume 37 Issue 1

Jan. 2021

Turn off MathJax

Article Contents

Article Navigation > Journal of Clinical Hepatology > 2021 > 37(1): 184-187

PDF( 2047 KB)

Research advances in the association of the tyrosine kinase receptor Axl and its ligand Gas6 with hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2021.01.040

Department of Hepatology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

Received Date: 2020-06-07
Accepted Date: 2020-08-17
Published Date: 2021-01-20

Abstract

Abstract

As one of the tyrosine kinase receptors, Axl is an important downstream regulator of epithelial-mesenchymal transition (EMT) and can bind to its ligand Gas6 protein. By activating the downstream signal transduction pathways, Axl is closely associated with vascular invasion, tumor metastasis, recurrence, and low survival rate of hepatocellular carcinoma. Current studies on the Gas6/Axl signaling pathway have confirmed that Axl inhibitors play an important role in the treatment of liver cancer and the Gas6/Axl signaling pathway may be a potential therapeutic target for liver cancer. This article mainly introduces the association of Axl and its ligand Gas6 with the development and progression of liver cancer and their application in the diagnosis and treatment of liver cancer, in order to provide new ideas for the early diagnosis of liver cancer and clinical research on anti-cancer treatment.
- Carcinoma, Hepatocellular,
- Axl,
- Growth Arrest Specific-6

FullText(HTML)

References(44)

References

[1]	FERLAY J, SOERJOMATARAM I, DIKSHIT R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015, 136(5): e359-e386. DOI: 10.1002/ijc.29210
[2]	REICHL P, DENGLER M, van ZIJL F, et al. Axl activates autocrine transforming growth factor-β signaling in hepatocellular carcinoma[J]. Hepatology, 2015, 61(3): 930-941. DOI: 10.1002/hep.27492
[3]	HOLSTEIN E, BINDER M, MIKULITS W. Dynamics of Axl receptor shedding in hepatocellular carcinoma and its implication for theranostics[J]. Int J Mol Sci, 2018, 19(12): 4111. DOI: 10.3390/ijms19124111
[4]	LEMKE G. Biology of the TAM receptors[J]. Cold Spring Harb Perspect Biol, 2013, 5(11): a009076. DOI: 10.1101/cshperspect.a009076
[5]	PAOLINO M, PENNINGER JM. The role of TAM family receptors in immune cell function: Implications for cancer therapy[J]. Cancers (Basel), 2016, 8(10): 97. DOI: 10.3390/cancers8100097
[6]	GRAHAM DK, DERYCKERE D, DAVIES KD, et al. The TAM family: Phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer[J]. Nat Rev Cancer, 2014, 14(12): 769-785. DOI: 10.1038/nrc3847
[7]	LINGER RM, KEATING AK, EARP HS, et al. TAM receptor tyrosine kinases: Biologic functions, signaling, and potential therapeutic targeting in human cancer[J]. Adv Cancer Res, 2008, 100: 35-83. DOI: 10.1016/S0065-230X(08)00002-X
[8]	YTTERSIAN SLETTA K, TVEITARÅS MK, LU N, et al. Oxygen-dependent regulation of tumor growth and metastasis in human breast cancer xenografts[J]. PLoS One, 2017, 12(8): e0183254. DOI: 10.1371/journal.pone.0183254
[9]	RANKIN EB, FUH KC, CASTELLINI L, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET[J]. Proc Natl Acad Sci U S A, 2014, 111(37): 13373-13378. DOI: 10.1073/pnas.1404848111
[10]	WANG W, JIA WD, HU B, et al. RAB10 overexpression promotes tumor growth and indicates poor prognosis of hepatocellular carcinoma[J]. Oncotarget, 2017, 8(16): 26434-26447. DOI: 10.18632/oncotarget.15507
[11]	XU MZ, CHAN SW, LIU AM, et al. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma[J]. Oncogene, 2011, 30(10): 1229-1240. DOI: 10.1038/onc.2010.504
[12]	BEN-BATALLA I, SCHULTZE A, WROBLEWSKI M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma[J]. Blood, 2013, 122(14): 2443-2452. DOI: 10.1182/blood-2013-03-491431
[13]	RANKIN EB, GIACCIA AJ. The receptor tyrosine kinase AXL in cancer progression[J]. Cancers (Basel), 2016, 8(11): 103. DOI: 10.3390/cancers8110103
[14]	LEE HJ, JENG YM, CHEN YL, et al. Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma[J]. Carcinogenesis, 2014, 35(4): 769-775. DOI: 10.1093/carcin/bgt372
[15]	ANTONY J, HUANG RY. AXL-driven EMT state as a targetable conduit in cancer[J]. Cancer Res, 2017, 77(14): 3725-3732. DOI: 10.1158/0008-5472.CAN-17-0392
[16]	CICCHINI C, AMICONE L, ALONZI T, et al. Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte[J]. Liver Int, 2015, 35(2): 302-310. DOI: 10.1111/liv.12577
[17]	TAM WL, WEINBERG RA. The epigenetics of epithelial-mesenchymal plasticity in cancer[J]. Nat Med, 2013, 19(11): 1438-1449. DOI: 10.1038/nm.3336
[18]	PATTABIRAMAN DR, WEINBERG RA. Tackling the cancer stem cells - what challenges do they pose?[J]. Nat Rev Drug Discov, 2014, 13(7): 497-512.
[19]	FAN QM, JING YY, YU GF, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma[J]. Cancer Lett, 2014, 352(2): 160-168. DOI: 10.1016/j.canlet.2014.05.008
[20]	ZHOU JN, ZENG Q, WANG HY, et al. MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4[J]. Hepatology, 2015, 62(3): 801-815. DOI: 10.1002/hep.27887
[21]	GIANNELLI G, KOUDELKOVA P, DITURI F, et al. Role of epithelial to mesenchymal transition in hepatocellular carcinoma[J]. J Hepatol, 2016, 65(4): 798-808. DOI: 10.1016/j.jhep.2016.05.007
[22]	ZHU AX. Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: Current status and future perspectives[J]. Semin Oncol, 2012, 39(4): 493-502. DOI: 10.1053/j.seminoncol.2012.05.014
[23]	PRIETO AL, WEBER JL, LAI C. Expression of the receptor protein-tyrosine kinases Tyro-3, Axl, and mer in the developing rat central nervous system[J]. J Comp Neurol, 2000, 425(2): 295-314. DOI: 10.1002/1096-9861(20000918)425:2<295::AID-CNE11>3.0.CO;2-G
[24]	VERMA A, WARNER SL, VANKAYALAPATI H, et al. Targeting Axl and Mer kinases in cancer[J]. Mol Cancer Ther, 2011, 10(10): 1763-1773. DOI: 10.1158/1535-7163.MCT-11-0116
[25]	ASIEDU MK, BEAUCHAMP-PEREZ FD, INGLE JN, et al. AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells[J]. Oncogene, 2014, 33(10): 1316-1324. DOI: 10.1038/onc.2013.57
[26]	ZHANG Z, LEE JC, LIN L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer[J]. Nat Genet, 2012, 44(8): 852-860. DOI: 10.1038/ng.2330
[27]	WILSON C, YE X, PHAM T, et al. AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs[J]. Cancer Res, 2014, 74(20): 5878-5890. DOI: 10.1158/0008-5472.CAN-14-1009
[28]	CICHON' MA, SZENTPETERY Z, CALEY MP, et al. The receptor tyrosine kinase Axl regulates cell-cell adhesion and stemness in cutaneous squamous cell carcinoma[J]. Oncogene, 2014, 33(32): 4185-4192. DOI: 10.1038/onc.2013.388
[29]	BROWN M, BLACK JR, SHARMA R, et al. Gene of the month: Axl[J]. J Clin Pathol, 2016, 69(5): 391-397. DOI: 10.1136/jclinpath-2016-203629
[30]	GIANNELLI G, VILLA E, LAHN M. Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma[J]. Cancer Res, 2014, 74(7): 1890-1894. DOI: 10.1158/0008-5472.CAN-14-0243
[31]	van der MEER JH, van der POLL T, van't VEER C. TAM receptors, Gas6, and protein S: Roles in inflammation and hemostasis[J]. Blood, 2014, 123(16): 2460-2469. DOI: 10.1182/blood-2013-09-528752
[32]	AITKEN A. Post-translational modification of 14-3-3 isoforms and regulation of cellular function[J]. Semin Cell Dev Biol, 2011, 22(7): 673-680. DOI: 10.1016/j.semcdb.2011.08.003
[33]	CHOI JE, HUR W, JUNG CK, et al. Silencing of 14-3-3ζ over-expression in hepatocellular carcinoma inhibits tumor growth and enhances chemosensitivity to cis-diammined dichloridoplatium[J]. Cancer Lett, 2011, 303(2): 99-107. DOI: 10.1016/j.canlet.2011.01.015
[34]	HUANG XY, KE AW, SHI GM, et al. αB-crystallin complexes with 14-3-3ζ to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma[J]. Hepatology, 2013, 57(6): 2235-2247. DOI: 10.1002/hep.26255
[35]	LI Y, JIA L, REN D, et al. Axl mediates tumor invasion and chemosensitivity through PI3K/Akt signaling pathway and is transcriptionally regulated by slug in breast carcinoma[J]. IUBMB Life, 2014, 66(7): 507-518. DOI: 10.1002/iub.1285
[36]	STENHOFF J, DAHLBÄCK B, HAFIZI S. Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts[J]. Biochem Biophys Res Commun, 2004, 319(3): 871-878. DOI: 10.1016/j.bbrc.2004.05.070
[37]	HECTOR A, MONTGOMERY EA, KARIKARI C, et al. The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma[J]. Cancer Biol Ther, 2010, 10(10): 1009-1018. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025816/
[38]	REICHL P, MIKULITS W. Accuracy of novel diagnostic biomarkers for hepatocellular carcinoma: An update for clinicians (Review)[J]. Oncol Rep, 2016, 36(2): 613-625.
[39]	HU B, TIAN X, SUN J, et al. Evaluation of individual and combined applications of serum biomarkers for diagnosis of hepatocellular carcinoma: A meta-analysis[J]. Int J Mol Sci, 2013, 14(12): 23559-23580.
[40]	EKMAN C, STENHOFF J, DAHLBÄCK B. Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood[J]. J Thromb Haemost, 2010, 8(4): 838-844. DOI: 10.1111/j.1538-7836.2010.03752.x/full
[41]	REICHL P, FANG M, STARLINGER P, et al. Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma[J]. Int J Cancer, 2015, 137(2): 385-394.
[42]	SHEN Y, CHEN X, HE J, et al. Axl inhibitors as novel cancer therapeutic agents[J]. Life Sci, 2018, 198: 99-111.
[43]	PINATO DJ, BROWN MW, TROUSIL S, et al. Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma[J]. Br J Cancer, 2019, 120(5): 512-521.
[44]	WU X, LIU X, KOUL S, et al. AXL kinase as a novel target for cancer therapy[J]. Oncotarget, 2014, 5(20): 9546-9563. http://europepmc.org/articles/pmc4259419/

Relative Articles

Supplements(0)

Cited By

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Get Citation

PDF

XML

Article Metrics

Article views (761) PDF downloads(35)

Research advances in the association of the tyrosine kinase receptor Axl and its ligand Gas6 with hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2021.01.040

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

Research advances in the association of the tyrosine kinase receptor Axl and its ligand Gas6 with hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2021.01.040

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

About Journal

Submission Guideline

Journal Online

Hepatobiliary College

Guidelines

Export File

Citation

Format

Content