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LOXL2 serves as a prognostic biomarker for hepatocellular carcinoma by mediating immune infiltration and vasculogenic mimicry

  • Author Footnotes
    # These authors contributed equally to this study.
    Nan Zhao
    Footnotes
    # These authors contributed equally to this study.
    Affiliations
    Department of Pathology, Tianjin Medical University, Tianjin 300070, China

    Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this study.
    Chen Chen
    Footnotes
    # These authors contributed equally to this study.
    Affiliations
    Department of Pathology, Tianjin Medical University, Tianjin 300070, China
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  • Yuhong Guo
    Affiliations
    Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin 300060, China
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  • Tieju Liu
    Affiliations
    Department of Pathology, Tianjin Medical University, Tianjin 300070, China

    Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China
    Search for articles by this author
  • Na Che
    Affiliations
    Department of Pathology, Tianjin Medical University, Tianjin 300070, China

    Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China
    Search for articles by this author
  • Danfang Zhang
    Affiliations
    Department of Pathology, Tianjin Medical University, Tianjin 300070, China

    Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China
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  • Xiaohui Liang
    Affiliations
    Department of Pathology, Tianjin Medical University, Tianjin 300070, China

    Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China
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  • Yanhui Zhang
    Affiliations
    Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin 300060, China
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  • Xiulan Zhao
    Correspondence
    Corresponding author.
    Affiliations
    Department of Pathology, Tianjin Medical University, Tianjin 300070, China

    Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this study.
Published:October 01, 2022DOI:https://doi.org/10.1016/j.dld.2022.09.003

      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

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