Analysis of IGFBP7 expression characteristics in pan-cancer and its clinical relevance to stomach adenocarcinoma

Abstract

Background: Insulin-like growth factor (IGF) binding proteins (IGFBPs) are involved in tumorigenesis and cancer progression. IGFBP7 has been shown to act as either a tumor suppressive gene or an oncogene in many tumors, including stomach adenocarcinoma (STAD). To provide a more systematic and comprehensive understanding of IGFBP7 gene, we performed an integrative pan-cancer analysis and explored further with the case of STAD.

Methods: We compared the expression data of IGFBP7 in various cancer and normal tissues obtained from The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database. The TISIDB web portal was used to analyze the associations of IGFBP7 with cancer molecular subtypes and immune subtypes. We also analyzed the predictive ability and prognostic values of IGFBP7 in pan-cancer, as well as explored its targeted binding proteins and their biological functions. Additionally, we examined the relationship between IGFBP7 and the clinical characteristics of STAD, investigated the co-expression genes and biological functions of differentially expressed genes (DEGs), and validated the mRNA and protein expression levels of IGFBP7 using gastric cancer (GC) and adjacent normal tissues in a small self-case-control study.

Results: IGFBP7 was found to be overexpressed in STAD and downregulated in many other cancers. The mRNA and protein expression levels of IGFBP7 were also significantly higher in the collected GC tissues compared with adjacent tissues. Expression of IGFBP7 varied significantly across molecular subtypes of nine different cancer types and immune subtypes of eight types, with the highest expression observed in the genomically stable molecular subtype and C3 inflammatory immune subtype in STAD. IGFBP7 demonstrated an area under the curve (AUC) >0.7 for predicting 16 cancer types, and an AUC >0.9 for seven types. Patients in the higher IGFBP7 expression group showed a poorer prognosis for adrenal cortical carcinoma (ACC) and low-grade glioma (LGG), while demonstrating a more favorable prognosis for kidney renal clear cell carcinoma (KIRC). IGFBP7 expression in STAD was significantly associated with T stage, pathological stage, histologic grade, and Helicobacter pylori infection.

Conclusions: IGFBP7 showed promise as a biomarker for prediction and prognosis in pan-cancer. IGFBP7 was found to be overexpressed in STAD, and its expression was closely associated with the clinical characteristics of STAD.

Keywords: IGFBP7; pan-cancer analysis; stomach adenocarcinoma (STAD).

Figure 1

The expression levels of IGFBP7 in tumors and normal tissues obtained from TCGA (A) and the GTEx database (B). ns, not significant, P≥0.05; *, P<0.05; **, P<0.01; ***, P<0.001. TPM, transcripts per million; TCGA, The Cancer Genome Atlas; GTEx, Genotype-Tissue Expression.

Figure 2

The correlations between the expression of IGFBP7 and molecular subtypes across TCGA tumors. TCGA, The Cancer Genome Atlas; G-CIMP, CpG island methylator phenotype; PA, pilocytic astrocytoma; CIN, chromosomal instability; EBV, Epstein-Barr virus; GS, genomically stable; HM, hypermutation; SNV, single nucleotide variants; CN, copy number; MSI, microsatellite instability; POLE, DNA polymerase epsilon.

Figure 3

The correlations between the expression of IGFBP7 and immune subtypes across TCGA tumors. TCGA, The Cancer Genome Atlas.

Figure 4

The PPI network (A), as well as the GO (B) and KEGG analyses (C) of the 50 targeted binding proteins of IGFBP7. PPI, protein-protein interaction; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; BP, biological process; CC, cellular component; MF, molecular function.

Figure 5

The ROC curve for IGFBP7 expression in various pan-cancer cases. ROC, receiver operating characteristic; FPR, false positive rate; TPR, true positive rate; AUC, area under the curve; CI, confidence interval.

Figure 6

The correlations between the expression of IGFBP7 and the prognosis (OS, DSS, and PFI) of four cancer types: ACC (A-C), KIRC (D-F), LGG (G-I), and STAD (J-L). OS, overall survival; DSS, disease-specific survival; PFI, progression-free interval; HR, hazard ratio.

Figure 7

The different expression levels of IGFBP7 among four types of clinical characteristics in patients with STAD. ns, not significant, P≥0.05; *, P<0.05; **, P<0.01; ***, P<0.001. TPM, transcripts per million; STAD, stomach adenocarcinoma.

Figure 8

The analyses of DEGs based on the high and low expression groups of IGFBP7 in STAD. (A) shows the Volcano map, where red points represent upregulation and blue points represent downregulation. (B) displays the GO and KEGG enrichment analyses. (C) presents the top 50 hub genes, while (D) illustrates the top 10 hub genes. DEGs, differentially expressed genes; STAD, stomach adenocarcinoma; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; BP, biological process; CC, cellular component; MF, molecular function.

Figure 9

The expression levels of IGFBP7 mRNA and protein in collected GC and adjacent normal tissues by hematoxylin-eosin staining. (A) shows the qRT-PCR analysis of IGFBP7 mRNA expression, while (B) presents representative micrographs of IGFBP7 protein expression. GC, gastric cancer; qRT-PCR, quantitative reverse transcriptase polymerase chain reaction.