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. 2022 Mar 4:12:843880.
doi: 10.3389/fonc.2022.843880. eCollection 2022.

Diagnostic Value, Prognostic Value, and Immune Infiltration of LOX Family Members in Liver Cancer: Bioinformatic Analysis

Chenyu Sun  1 , Shaodi Ma  2 , Yue Chen  3 , Na Hyun Kim  1 , Sujatha Kailas  4 , Yichen Wang  5 , Wenchao Gu  6 , Yisheng Chen  7 , John Pocholo W Tuason  1 , Chandur Bhan  1 , Nikitha Manem  1 , Yuting Huang  8 , Ce Cheng  9   10 , Zhen Zhou  11 , Qin Zhou  12 , Yanzhe Zhu  13
Affiliations

Diagnostic Value, Prognostic Value, and Immune Infiltration of LOX Family Members in Liver Cancer: Bioinformatic Analysis

Chenyu Sun et al. Front Oncol. .

Abstract

Background: Liver cancer (LC) is well known for its prevalence as well as its poor prognosis. The aberrant expression of lysyl oxidase (LOX) family is associated with liver cancer, but their function and prognostic value in LC remain largely unclear. This study aimed to explore the function and prognostic value of LOX family in LC through bioinformatics analysis and meta-analysis.

Results: The expression levels of all LOX family members were significantly increased in LC. Area under the receiver operating characteristic curve (AUC) of LOXL2 was 0.946 with positive predictive value (PPV) of 0.994. LOX and LOXL3 were correlated with worse prognosis. Meta-analysis also validated effect of LOX on prognosis. Nomogram of these two genes and other predictors was also plotted. There was insufficient data from original studies to conduct meta-analysis on LOXL3. The functions of LOX family members in LC were mostly involved in extracellular and functions and structures. The expressions of LOX family members strongly correlated with various immune infiltrating cells and immunomodulators in LC.

Conclusions: For LC patients, LOXL2 may be a potential diagnostic biomarker, while LOX and LOXL3 have potential prognostic and therapeutic values. Positive correlation between LOX family and infiltration of various immune cells and immunomodulators suggests the need for exploration of their roles in the tumor microenvironment and for potential immunotherapeutic to target LOX family proteins.

Keywords: bioinformatic analysis; immune infiltration; liver cancer; lysyl oxidase; nomogram; prognostic value; receiver operating curve.

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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
Expression level of LOX family members between normal tissue and tumor tissue in liver cancer. (A) analysis via R software, (B) analysis via ULCAN. ** means P < 0.01, *** means P < 0.001.
Figure 2
Figure 2
ROC curve analysis for LOX family members in liver cancer.
Figure 3
Figure 3
Survival analysis of LOX family members in liver cancer. (A) analysis via R software, (B) analysis via ULCAN.
Figure 4
Figure 4
Nomogram for liver cancer based on overexpressed LOX and LOXL3. The nomogram was developed in the cohort, with pathologic stage, histologic grade, AFP (ng/ml), Child-Pugh grade, albumin (g/dl), adjacent hepatic tissue inflammation, vascular invasion, Ishak Fibrosis score, prothrombin time, age, gender, weight. (C-index: 0.738, 95% CI, 0.697-0.778).
Figure 5
Figure 5
Gene mutation and expression analysis of LOX family members in patients with liver cancer: (A) Genetic alterations of LOX family members in different histopathologic types of liver cancer; (B) Summary of genetic alterations in different expressed LOX family members in liver cancer; (C) Correction between different LOX family members in in liver cancer (cBioPortal); (D) Correction between different LOX family members in in liver cancer (TIMER).
Figure 6
Figure 6
Network of association between LOX and LOXL3 and different drugs in liver neoplasm via Coremine Medical.
Figure 7
Figure 7
Protein-protein interaction (PPI) network analysis of LOX family members in patients with liver cancer. (A) PPI network of LOX family members and their interactors visualized by STRING; (B) PPI network of LOX family members and their interactors visualized by GeneMANIA.
Figure 8
Figure 8
Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of LOX family members and their interactors. GO enrichment analysis of target genes based on (A) biological process, (B) cellular component, and (C) molecular function. (D) KEGG pathway enrichment analysis of target genes.
Figure 9
Figure 9
Correlations between differentially expressed LOX family members and immune cell infiltration in liver cancer (TIMER).
Figure 10
Figure 10
Associations of the LOX and LOXL3 expression level with immunomodulators in LC from TISIDB database. (A) Immunomodulators that are highly correlated with LOX; (B) Immunomodulators that are highly correlated with LOXL3.
Figure 11
Figure 11
The co‐expression genes with LOX family members in LC from the LinkedOmics database. (A) The whole significantly associated genes with LOX family member distinguished by Pearson test in LC cohort. (B) Top 50 genes positively related to LOX family member in LC showed by heat maps. (C) Top 50 genes negatively related to LOX family member in LC showed by heat maps. Red represents positively linked genes and blue represents negatively linked genes.
Figure 12
Figure 12
GO annotations and KEGG pathways of LOX family and their associated genes in LC cohort: (A) results of LOX; (B) results of LOXL1; (C) results of LOXL2; (D) results of LOXL3; (E) results of LOXL4.
Figure 13
Figure 13
Forest plot of the prognosis of LOX, LOXL2 and LOXL4 for LC patients: (A) Forest plot of overexpressed LOX; (B) Forest plot of overexpressed LOXL2; (C) Forest plot of overexpressed LOXL4.
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