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. 2023 Jan 25:14:1071675.
doi: 10.3389/fimmu.2023.1071675. eCollection 2023.

Multi-omics analysis of N6-methyladenosine reader IGF2BP3 as a promising biomarker in pan-cancer

Pin Chen  1 , Jing Xu  2 , Zihan Cui  3   4 , Silin Wu  1 , Tao Xie  1   5 , Xiaobiao Zhang  1   5   6
Affiliations

Multi-omics analysis of N6-methyladenosine reader IGF2BP3 as a promising biomarker in pan-cancer

Pin Chen et al. Front Immunol. .

Abstract

Background: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has been reported to exhibit an oncogenic effect as an RNA-binding protein (RBP) by promoting tumor cell proliferation, migration and invasion in several tumor types. However, a pan-cancer analysis of IGF2BP3 is not currently available, and the exact roles of IGF2BP3 in prognosis and immunology in cancer patients remain enigmatic. The main aim of this study was to provide visualization of the systemic prognostic landscape of IGF2BP3 in pan-cancer and to uncover the potential relationship between IGF2BP3 expression in the tumor microenvironment and immune infiltration profile.

Methods: Raw data on IGF2BP3 expression were obtained from GTEx, CCLE, TCGA, and HPA data portals. We have investigated the expression patterns, diagnostic and prognostic significance, mutation landscapes, functional analysis, and functional states of IGF2BP3 utilizing multiple databases, including HPA, TISIDB, cBioPortal, GeneMANIA, GESA, and CancerSEA. Moreover, the relationship of IGF2BP3 expression with immune infiltrates, TMB, MSI and immune-related genes was evaluated in pan-cancer. IGF2BP3 with drug sensitivity analysis was performed from the CellMiner database. Furthermore, the expression of IGF2BP3 in different grades of glioma was detected by immunohistochemical staining and western blot.

Results: We found that IGF2BP3 was ubiquitously highly expressed in pan-cancer and significantly correlated with diagnosis, prognosis, TMB, MSI, and drug sensitivity in various types of cancer. Besides, IGF2BP3 was involved in many cancer pathways and varied in different immune and molecular subtypes of cancers. Additionally, IGF2BP3 is critically associated with genetic markers of immunomodulators in various cancers. Finally, we validated that IGF2BP3 protein expression was significantly higher in glioma than in normal tissue, especially in GBM.

Conclusions: IGF2BP3 may be a potential molecular biomarker for diagnosis and prognosis in pan-cancer, especially for glioma. It could become a novel therapeutic target for various cancers.

Keywords: genetic alteration; immune infiltration; insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3); pan-cancer analysis; prognosis; the Cancer Genome Atlas (TCGA).

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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
IGF2BP3 mRNA expression levels in pan-cancer. (A) IGF2BP3 expression levels in normal tissues from GTEx database. (B) IGF2BP3 expression levels in tumor cell lines from CCLE database. (C) IGF2BP3 expression levels in tumor tissues from TCGA database. (D) IGF2BP3 expression difference between tumor tissues from TCGA database and normal tissues from the GTEx database; ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.
Figure 2
Figure 2
Representative immunohistochemical staining (IHC) in multiple normal (left) and tumor (right) tissues. The protein expression of IGF2BP3 in (A) glioma, GBMLGG; (B) lung adenocarcinoma, LUAD;(C) lung squamous cell carcinoma, LUSC; (D) pancreatic adenocarcinoma, PAAD; (E) colon adenocarcinoma, COAD; (F) cervical squamous cell carcinoma and endocervical adenocarcinoma, CESC; (G) head and neck squamous cell carcinoma, HNSC; (H) ovarian serous cystadenocarcinoma, OV.
Figure 3
Figure 3
Associations between IGF2BP3 expression and different clinical characteristics in GBMLGG. (A) WHO grade; (B) Histological type; (C) IDH status; (D) p/19q codeletion; (E) Age; (F) Primary therapy outcome. ns, p ≥ 0.05; *p < 0.05; ***p < 0.001.
Figure 4
Figure 4
Receiver operating characteristic (ROC) curve for IGF2BP3 expression in pan-cancer.(A) LAML; (B) GBM; (C) UCS; (D) LUSC; (E) STAD; (F) OV; (G) CHOL; (H) ESCA.
Figure 5
Figure 5
Relationship of IGF2BP3 expression with patient Overall Survival (OS). (A) Forest map shows the univariate Cox regression analysis results for IGF2BP3 in TCGA pan-cancer samples. (B–N) Kaplan–Meier analysis of the association between IGF2BP3 expression and OS.
Figure 6
Figure 6
Associations between IGF2BP3 expression and the OS in different clinical subgroups of GBMLGG. (A) WHO grade (G3); (B) 1p/19q codeletion (non−codel); (C) IDH status (WT); (D) IDH status (Mut); (E) Primary therapy outcome (PD); (F) Primary therapy outcome (SD); (G) Gender (Female); (H) Gender (Male); (I) Race (Black or African American) (J) Race (White); (K) Age ≤ 60; (L) Age>60; (M) Histological type (Astrocytoma); (N) Histological type (Oligoastrocytoma).
Figure 7
Figure 7
Correlations between IGF2BP3 expression and immune subtypes across TCGA tumors. (A) CESC; (B) LUAD; (C) LUSC; (D) LGG; (E) COAD; (F) STAD; (G) BLCA; (H) OV; (I) BRCA.
Figure 8
Figure 8
Correlations between IGF2BP3 expression and molecular subtypes across TCGA tumors. (A) LGG; (B) GBM; (C) LUSC; (D) HNSC; (E) ACC; (F) BRCA; (G) UCEC; (H) COAD; (I) KIRP.
Figure 9
Figure 9
Relationship of IGF2BP3 expression with Immune cell infiltration analysis. (A) The relationship between IGF2BP3 expression levels and the levels of infiltration of six immune-related cells based on TIMER database. (B) Analysis of immune-associated cells infiltration with IGF2BP3 expression in pan-cancer. p ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 10
Figure 10
Co-expression of IGF2BP3 and immune-related genes in pan-cancer. Heatmaps indicating the co-expression of IGF2BP3 with immune-relevant genes in pan-cancer, including chemokine genes (A), chemokine-receptor genes (B), MHC molecules (C), immunoinhibitors (D), and immunostimulators (E). *p-value < 0.05, **p-value < 0.01, ***p-value < 0.001, and ****p-value < 0.0001.
Figure 11
Figure 11
PPI network for IGF2BP3 was constructed via GeneMANIA. Different colors of the network edge indicate the bioinformatics methods applied: physical interaction, coexpression, predicted, colocalization, pathway, genetic interaction, and shared protein domains. PPI, protein–protein interaction.
Figure 12
Figure 12
GSEA for samples with high IGF2BP3 expression and low expression. (A) The enriched gene sets in KEGG collection by the high IGF2BP3 expression sample. (B) The enriched gene sets in KEGG by samples with low IGF2BP3 expression. (C) Enriched gene sets in HALLMARK collection, the immunologic gene sets, by samples of high IGF2BP3 expression. (D) Enriched gene sets in HALLMARK by the low IGF2BP3 expression. Each line represented one particular gene set with unique color, and up-regulated genes located in the left approaching the origin of the coordinates, by contrast the down-regulated lay on the right of x-axis. Only gene sets with NOM p < 0.05 and FDR q < 0.25 were considered statistically significant. And only the leading-edge genes were displayed.
Figure 13
Figure 13
Drug sensitivity analysis of IGF2BP3. The expression of IGF2BP3 was associated with the sensitivity of ARRY-704 (A), RO-4987655 (B), Trametinib (C), TAK-733 (D), PD-0325901 (E), Cobimetinib (isomer1) (F), RO-5126766 (G), Ulixertinib (H), ARRY-162 (I), Selumetinib (J), GDC-0810 (K), AZD-9496 (L), BAY-876 (M), VT-464 (N), and Acetalax sensitivity (O).
Figure 14
Figure 14
Validation of IGF2BP3 Expression in Glioma. (A) Representative immunohistochemical staining of IGF2BP3 expression in clinical glioma tissue and normal peritumor tissues. Scale bar=50 μm. (B) Western blot analysis of IGF2BP3 protein level in human glioma patient samples (grade 2 (n = 3), grade 3 (n = 6), grade GBM (n = 13)) and normal peritumor brain tissues (n = 3). β-actin was used as a loading control. All data are shown as the mean ± SD (at least three independent experiments). ns, no significance, *P <0.05, ***P < 0.001.
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