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. 2021 Dec 1;21(6):712-723.
doi: 10.17305/bjbms.2021.5690.

Integrated profiling identifies ITGB3BP as prognostic biomarker for hepatocellular carcinoma

Qiuli Liang  1 , Chao Tan  2 , Feifei Xiao  3 , Fuqiang Yin  4 , Meiliang Liu  1 , Lei Lei  1 , Liuyu Wu  5 , Yu Yang  1 , Hui Juan Jennifer Tan  6 , Shun Liu  1 , Xiaoyun Zeng  7
Affiliations

Integrated profiling identifies ITGB3BP as prognostic biomarker for hepatocellular carcinoma

Qiuli Liang et al. Bosn J Basic Med Sci. .

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant tumor. In this study, we sought to identify a novel biomarker for HCC by analyzing transcriptome and clinical data. The R software was used to analyze the differentially expressed genes (DEGs) in the datasets GSE74656 and GSE84598 downloaded from the Gene Expression Omnibus database, followed by a functional annotation. A total of 138 shared DEGs were screened from two datasets. They were mainly enriched in the "Metabolic pathways" pathway (Padj = 8.21E-08) and involved in the carboxylic acid metabolic process (Padj = 0.0004). The top 10 hub genes were found by protein-protein interaction analysis and were upregulated in HCC tissues compared to normal tissues in The Cancer Genome Atlas database. Survival analysis distinguished 8 hub genes CENPE, SPDL1, Hyaluronan-mediated motility receptor, Rac GTPase activating protein 1, Thyroid hormone receptor interactor 13, cytoskeleton-associated protein (CKAP) 2, CKAP5, and Integrin subunit beta 3 binding protein (ITGB3BP) were considered as prognostic hub genes. Multivariate cox regression analysis indicated that all the prognostic hub genes were independent prognostic factors for HCC. Furthermore, the receiver operating characteristic curve revealed that the 8-hub genes model had better prediction performance for overall survival compared to the T stage (p = 0.008) and significantly improved the prediction value of the T stage (p = 0.002). The Human Protein Atlas showed that the protein expression of ITGB3BP was upregulated in HCC, so the expression of ITGB3BP was further verified in our cohort. The results showed that ITGB3BP was upregulated in HCC tissues and was significantly associated with lymph node metastasis.

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Conflict of interest statement

Conflict of interest statement: The authors declare no conflict of interests

Figures

FIGURE 1
FIGURE 1
Differentially expressed genes (DEGs) identified in GSE74656 and GSE84598. (A) Venn diagram of the overlapping DEGs between GSE74656 and GSE84598. (B) Protein-protein interactions network of 138 SDEGs. Orange nodes have the highest degree while blue nodes have the lowest degree. The smaller the edge, the lower the combined score. (C) The top 10 hub genes screened using the Cytohubbo module in Cytoscape. Darker node color indicates a higher score. (D) Heat map of the top 10 hub genes expression in GSE74656. (E) Heat map of the top 10 hub genes expression in GSE84598.
FIGURE 2
FIGURE 2
The expression level of hub genes of HCC patients in TCGA database. (A-J) Paired t-test showed that the 10 hub genes were upregulated in HCC tumor tissues. (K) ROC curve analysis showed that hub genes had good diagnostic efficacy for HCC.
FIGURE 3
FIGURE 3
The relationship between hub gene expression and overall survival of HCC patients in TCGA database. The expression levels of 8 hub genes CENPE (A), CKAP2 (B), CKAP5 (C), HMMR (D), ITGB3BP (E), RACGAP1 (F), SPDL1 (H), and TRIP13 (I) are associated with overall survival of HCC patients.
FIGURE 4
FIGURE 4
The relationship between hub gene expression and disease-free survival of HCC patients in TCGA database. The expression levels of 9 hub genes CENPE (A), CKAP2 (B), CKAP5 (C), HMMR (D), ITGB3BP (E), RACGAP1 (F), SMC2 (G), SPDL1 (H), and TRIP13(I) are associated with disease-free survival of HCC patients.
FIGURE 5
FIGURE 5
The expression levels of prognostic hub genes are related to some clinicopathological characteristics of HCC patients. (A) The expression of all prognostic hub genes is associated with histology grade of HCC. (B) The expression of all prognostic hub genes is associated with pathological stages of HCC. (C) The expression of all prognostic hub genes is associated with T stages of HCC. (D) The expression of CENPE, SPDL1, RACGAP1, HMMR, TRIP13, CKAP2, and CKAP5 is associated with AFP level of HCC patients. (E) The expression of CENPE, SPDL1, RACGAP1, HMMR, and TRIP13 is associated with vascular invasion of HCC. (*p < 0.05; **p < 0.01; ***p < 0.001; ns, not significant).
FIGURE 6
FIGURE 6
The predictive value of the 8-hub genes model for HCC survival. (A) The receiver operating characteristic (ROC) curves and area under the curves (AUCs) estimation for prediction of 1-year overall survival. (B) The ROC curves and AUCs estimation for predictive of 1-year disease-free survival.
FIGURE 7
FIGURE 7
The protein expression levels of prognostic hub genes in The Human Protein Atlas. Then results of immunohistochemical staining of CENPE (A), HMMR (B), ITGB3BP (C), RACGAP1 (D), SPDL1 (E), TRIP13 (F), CKAP2 (G), CKAP5 (H).
FIGURE 8
FIGURE 8
The expression level of ITGB3BP in HCC samples. (A) The mRNA expression level of ITGB3BP is up-regulated in HCC tissues. (B) Paired t-test of ITGB3BP expression in HCC tissues compared with para-carcinoma tissues. (C) ROC curve analysis of diagnostic efficacy of ITGB3BP expression for HCC.
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