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. 2023 Aug 18;102(33):e34765.
doi: 10.1097/MD.0000000000034765.

Prognostic value and potential molecular mechanism of ITGB superfamily members in hepatocellular carcinoma

Haixiang Xie  1 , Chongjiu Qin, Xin Zhou, Junqi Liu, Kejian Yang, Jusen Nong, Jianzhu Luo, Tao Peng
Affiliations

Prognostic value and potential molecular mechanism of ITGB superfamily members in hepatocellular carcinoma

Haixiang Xie et al. Medicine (Baltimore). .

Abstract

We analyzed the prognostic value and potential molecular mechanisms of the members of integrin β (ITGB)superfamily in hepatocellular carcinoma (HCC) using data from The Cancer Genome Atlas (TCGA), cBioPortal, Gene Expression Profiling Interactive Analysis (GEPIA), Human Protein Atlas (HPA) HPA, Search Tool for the Retrieval of Interacting Genes/Proteins, GeneMANIA, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), TIMER and Gene set enrichment analysis (GSEA) databases. ITGB4/5 mRNA was upregulated in HCC tissues in contrast to the normal liver tissues, whereas ITGB2/3/8 levels were lower in the former. ITGB4 was the most frequently mutated ITGB gene in HCC. Receiver operating characteristic curve (ROC) analysis showed that the expression levels of ITGB2/3/4/5/7/8 had significant diagnostic value in distinguishing HCC tissues from healthy liver tissues, ITGB8 had the highest diagnostic efficacy. The ITGB1/3/6/8 were also upregulated in the HCC tissues in contrast to healthy liver tissues. The expression of ITGB8 was verified by immunohistochemistry (IHC). Furthermore, ITGB6 and ITGB7 expression levels were strongly associated with the overall survival (OS) of HCC patients. The ITGB superfamily members exhibited homology and interactions in protein structure. In addition, ITGB6 together with ITGB7 were negatively related to the infiltration of multiple immune cell populations. GSEA results showed that ITGB6 was enriched in HCC migration and recurrence, whereas ITGB7 was significantly enriched in HIPPO, TOLL and JAK-STAT signaling pathways. In conclusion, ITGB6 and ITGB7 genes are possible to be prognostic biomarkers for HCC.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.How to cite this article: Xie H, Qin C, Zhou X, Liu J, Yang K, Nong J, Luo J, Peng T. Prognostic value and potential molecular mechanism of ITGB superfamily members in hepatocellular carcinoma. Medicine 2023;102:33(e34765).

Figures

Figure 1.
Figure 1.
Differential mRNA expression of (A) ITGB1, (B) ITGB2, (C) ITGB3, (D) ITGB4, (E) ITGB5, (F) ITGB6, (G) ITGB7, and (H) ITGB8 between HCC tissues and normal liver tissues based on TCGA database. (I) Mutation rate of the ITGB1-8 gene in HCC based on cBioPortal data. HCC = hepatocellular carcinoma, ITGB = integrin β, TCGA = The Cancer Genome Atlas.
Figure 2.
Figure 2.
ROC curves of (A) ITGB1, (B) ITGB2, (C) ITGB3, (D) ITGB4, (E) ITGB5, (F) ITGB6, (G) ITGB7, and (H) ITGB8 in TGCA cohort, AUC was used to predict the diagnostic efficiency of genes. (I) Pearson correlation analysis matrix plots of ITGB1-8 gene. AUC = area under curve, ITGB = integrin β, ROC = receiver operating characteristic curve.
Figure 3.
Figure 3.
Association of (A) ITGB1, (B) ITGB2, (C) ITGB3, (D) ITGB4, (E) ITGB5, (F) ITGB6, (G) ITGB7 and (H) ITGB8 with the tumor stage of HCC patients based on GEPIA. GEPIA = gene expression profiling interactive analysis, HCC = hepatocellular carcinoma, ITGB = integrin β.
Figure 4.
Figure 4.
Representative immunohistochemical images showing in situ expression of ITGB1, ITGB2, ITGB3, ITGB4, ITGB5, ITGB6, and ITGB8 proteins in HCC and normal liver tissues. IHC images were obtained from Human Protein Atlas. HCC = hepatocellular carcinoma, IHC = immunohistochemistry, ITGB = integrin β.
Figure 5.
Figure 5.
Kaplan–Meier survival curves showing overall survival (OS) of HCC patients in TCGA database demarcated on the basis of (A) ITGB1, (B) ITGB2, (C) ITGB3, (D) ITGB4, (E) ITGB5, (F) ITGB6, (G) ITGB7 and (H) ITGB8 expression. HCC = hepatocellular carcinoma, ITGB = integrin β, TCGA = The Cancer Genome Atlas.
Figure 6.
Figure 6.
Prognostic ability of ITGB6 and ITGB7 for HCC in the TCGA database. (A) Kaplan–Meier survival curves of HCC patients based on ITGB6 and ITGB7 expression. (B) Nomogram based on clinical characteristics and ITGB6/ITGB7 gene expression. (C–E) Calibration plots for (C) 1-yr, (D) 3-yr, and (E) 5-yr OS prediction. HCC = hepatocellular carcinoma, ITGB = integrin β, OS = overall survival, TCGA = The Cancer Genome Atlas.
Figure 7.
Figure 7.
STRING Protein Interaction Network and GeneMANIA Gene Interaction Network. (A) Protein-Protein interaction network (PPI) of ITGB proteins based on the STRING database. (B) Interaction network between ITGB genes and 20 potential target genes based on the GeneMANIA database. ITGB = integrin β, STRING = search tool for the retrieval of interacting genes/proteins.
Figure 8.
Figure 8.
Functional analysis of ITGB genes in HCC. (A–C) Bubble diagrams showing the significantly enriched (A) BP, (B) CC, and (C) MF terms in GO analysis. (D) Bubble diagram of KEGG pathways. (E–F) Scatter plots showing the tumor-infiltrating cells corresponding to (E) ITGB6 and (F) ITGB7 expression. GO = gene ontology, HCC = hepatocellular carcinoma, ITGB = integrin β, KEGG = Kyoto encyclopedia of genes and genomes.
Figure 9.
Figure 9.
GSEA results of ITGB genes: (A–F) GSEA results of ITGB6 in the HCC and (G–L) GSEA results of ITGB7 in the HCC. ES, enrichment score. FDR = false discovery rate, GSEA = gene set enrichment analysis, HCC = hepatocellular carcinoma, ITGB = integrin β.
Figure 10.
Figure 10.
Results of immunohistochemistry for ITGB8. (A) Typical immunohistochemical images of hepatocellular carcinoma and paracancerous tissue in a case of HCC. (B) Histogram of the IHC scores. IHC = immunohistochemistry, ITGB = integrin β.
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