Abstract
Background
The development of human hepatocellular carcinoma (HCC) is a multistep process that
is accompanied by progressive changes in the liver microenvironment, including immune
evasion and angiogenesis. Lysyl oxidase-like 2 (LOXL2) has been suggested to contribute
to tumour progression and metastasis; however, the underlying mechanism remains unclear.
The purpose of the present study was to explore the relationship between LOXL2 and
immune infiltration and vasculogenic mimicry (VM) and to identify the role of LOXL2
in HCC diagnosis prognosis evaluation.
Methods
The Cancer Genome Atlas (TCGA), UALCAN, GEPIA and Kaplan–Meier plotter databases were
used to analyse LOXL2 expression and perform survival analysis. The Tumour Immune
Estimation Resource (TIMER) was used to analyse immune cell infiltration, immune cell
biomarkers and immune checkpoints. Immunohistochemistry (IHC) of 201 HCC samples was
used to confirm the expression of LOXL2 and its relationship with VM. Coimmunoprecipitation
(co-IP) and gain- and loss-of-function studies were performed to confirm the molecular
mechanism of LOXL2 in VM.
Results
The expression of LOXL2 in HCC was higher than that in normal tissues at both the
mRNA and protein levels. High expression of LOXL2 was associated with a poorer prognosis
of HCC. The genetic alteration rate of LOXL2 was 5%. LOXL2 was positively related
to immune cell infiltration and immune checkpoints (PD-1 and CTLA-4) in HCC. Co-IP
showed that LOXL2 can interact directly with IQGAP1. Both gain- and loss-of-function
studies showed that LOXL2 significantly induced cell migration, invasion and VM formation
when IQGAP1 was upregulated.
Conclusions
LOXL2 is involved in immune cell infiltration and promotes VM by upregulating IQGAP1.
LOXL2 can be used as a novel biomarker for HCC diagnosis and prognosis prediction.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Digestive and Liver DiseaseAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Hepatocellular carcinoma epidemiology.Best Pract Res Clin Gastroenterol. 2014; 28: 753-770
- Bcl-2 expression is a poor predictor for hepatocellular carcinoma prognosis of andropause-age patients.Cancer Biol Med. 2016; 13: 459-468
- Prognostic and therapeutic implications of microvascular invasion in hepatocellular carcinoma.Ann Surg Oncol. 2019; 26: 1474-1493
- From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma.J Exp Clin Cancer Res: CR. 2019; 38: 396
- Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma.Hepatology (Baltimore, Md.). 2014; 60: 1645-1658
- The human lysyl oxidase-like 2 protein functions as an amine oxidase toward collagen and elastin.Mol Biol Rep. 2011; 38: 145-149
- Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas.Cancer Res. 2008; 68: 4541-4550
- A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression.The EMBO J. 2005; 24: 3446-3458
- Regulation of heterochromatin transcription by Snail1/LOXL2 during epithelial-to-mesenchymal transition.Mol Cell. 2013; 52: 746-757
- Lysyl oxidase-like protein LOXL2 promotes lung metastasis of breast cancer.Cancer Res. 2017; 77: 5846-5859
- Lysyl oxidase-like 2 is a regulator of angiogenesis through modulation of endothelial-to-mesenchymal transition.J Cell Physiol. 2019; 234: 10260-10269
- Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane.Blood. 2011; 118: 3979-3989
- LOXL2 promotes vasculogenic mimicry and tumour aggressiveness in hepatocellular carcinoma.J Cell Mol Med. 2019; 23: 1363-1374
- IQGAP1 scaffold-MAP kinase interactions enhance multiple myeloma clonogenic growth and self-renewal.Mol Cancer Ther. 2016; 15: 2733-2739
- Role of IQGAP1 in carcinogenesis.Cancers (Basel). 2021; 13
- LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1-Rac1 pathway.J Biol Chem. 2017; 292: 14989-15001
- Single-molecule imaging of IQGAP1 regulating actin filament dynamics.Mol Biol Cell. 2022; 33: ar2
- IQGAP1 promotes pancreatic cancer progression and epithelial-mesenchymal transition (EMT) through Wnt/β-catenin signaling.Sci Rep-UK. 2019; 9: 7539
- IQGAP1: a key regulator of adhesion and migration.J Cell Sci. 2005; 118: 2085-2092
- LOXL2 in cancer: regulation, downstream effectors and novel roles.Biochim Biophys Acta. Rev Cancer. 2020; 1874188435
- Gene expression markers of tumor infiltrating leukocytes.J Immunother Cancer. 2017; 5: 18
- Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies.J Hepatol. 2012; 56: 267-275
- Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal.GUT. 2017; 66: 1697-1708
- The effect of LOXL2 in hepatocellular carcinoma.Mol Med Rep. 2016; 14: 1923-1932
- Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification.J Hepatol. 2017; 67: 727-738
- Immunotherapy for hepatocellular carcinoma: A 2021 update.Cancers (Basel). 2020; : 12
- Myeloid cells in hepatocellular carcinoma.Hepatology. 2015; 62: 1304-1312
- Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis.J Hepatol. 2021; 75: 1271-1283
- Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC).J Immunother Cancer. 2018; 6: 39
- Tumor cell vascular mimicry: Novel targeting opportunity in melanoma.Pharmacol Ther. 2016; 159: 83-92
- Tumour angiogenesis-Origin of blood vessels.Int J Cancer. 2016; 139: 729-735
- Practical application of angiogenesis and vasculogenic mimicry in prostatic adenocarcinoma.Arch Iran Med. 2010; 13: 498-503
- Evaluation of the correlation of vasculogenic mimicry, ALDH1, KiSS-1, and MACC1 in the prediction of metastasis and prognosis in ovarian carcinoma.Diagn Pathol. 2017; 12: 23
- Vasculogenic mimicry and expression of slug and vimentin correlate with metastasis and prognosis in non-small cell lung cancer.Int J Clin Exp Pathol. 2018; 11: 2749-2758
- Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry.Hepatology (Baltimore, Md.). 2010; 51: 545-556
- Hsp90β promotes aggressive vasculogenic mimicry via epithelial-mesenchymal transition in hepatocellular carcinoma.Oncogene. 2019; 38: 228-243
- Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1: a study of hepatocellular carcinoma.Hepatology (Baltimore, Md.). 2011; 54: 1690-1706
- The expression and functional significance of runx2 in hepatocellular carcinoma: its role in vasculogenic mimicry and epithelial-mesenchymal transition.Int J Mol Sci. 2017; 18
- The EMT transcription factor, Twist1, as a novel therapeutic target for pulmonary sarcomatoid carcinomas.Int J Oncol. 2020; 56: 750-760
- Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments.Mol Cancer. 2021; 20: 7
- Downregulation of IQGAP1 inhibits epithelial-mesenchymal transition via the HIF1α/VEGF-A signaling pathway in gastric cancer.J Cell Biochem. 2019; 120: 15790-15799
- Overexpression of IQGAP1 promotes the angiogenesis of esophageal squamous cell carcinoma through the AKT and ERK‑mediated VEGF‑VEGFR2 signaling pathway.Oncol Rep. 2018; 40: 1795-1802
- IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration.Plos One. 2010; 5: e13440
- IQGAP1: insights into the function of a molecular puppeteer.Mol Immunol. 2015; 65: 336-349
- The cytoskeletal adaptor protein IQGAP1 regulates TCR-mediated signaling and filamentous actin dynamics.J Immunol. 2012; 188: 6135-6144
- IQGAP1 is important for activation of caspase-1 in macrophages and is targeted by Yersinia pestis type III effector YopM.MBIO. 2014; 5: e01402-e01414
- Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation.The J Cell Biol. 2007; 178: 193-200
- IQ domain-containing GTPase-activating protein 1 regulates cytoskeletal reorganization and facilitates NKG2D-mediated mechanistic target of rapamycin complex 1 activation and cytokine gene translation in natural killer cells.Front Immunol. 2018; 9: 1168
- IQGAP1 involvement in MTOC and granule polarization in NK-cell cytotoxicity.Eur J Immunol. 2011; 41: 2763-2773
- The Rap1-cofilin-1 pathway coordinates actin reorganization and MTOC polarization at the B cell immune synapse.J Cell Sci. 2017; 130: 1094-1109
- Over-expression of IQGAP1 indicates poor prognosis in head and neck squamous cell carcinoma.J Mol Histol. 2018; 49: 389-398
- Antibody-validated proteins in inflamed islets of fulminant type 1 diabetes profiled by laser-capture microdissection followed by mass spectrometry.Plos One. 2014; 9e107664
- IQGAP1 is positively correlated with PD-L1 and regulates its expression via mediating STAT proteins phosphorylation.Int Immunopharmacol. 2022; 108108897
Article info
Publication history
Published online: October 01, 2022
Accepted:
September 7,
2022
Received:
July 1,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.