IGF2BP3 exhibits high expression in tumors
We selected normal as well as pan-cancer tissues from TIMER and analyzed IGF2BP3 expression. Compared to paired normal tissues, various tumors showed high IGF2BP3 expression (Fig. 1A). Additional analyses of cancers with unavailable data were then performed using GEPIA. IGF2BP3 mRNA expression in most cancer types was high, and IGF2BP3 mRNA was increased significantly in DLBC, OV, and UCS (Fig. 1B). As illustrated in Fig. 1C, endothelial cells showed the highest IGF2BP3 expression levels among all cell lines. Figure 1D shows IGF2BP3 expression in pan-cancer based on CCLE data. Additional table 1: Table S1 shows the details of IGF2BP3 expression in various cell lines. IGF2BP3 expression was compared between diverse cancer cell lines and normal tissues by using BioGPS. The IGF2BP3 expression level in 721 B lymphoblasts was the highest in normal tissues (Additional file 1: Fig. S1A), while IGF2BP3 showed a moderate level of expression in most cancer cell lines (Additional file 1: Fig. S1B). Additional file 1: Fig. S1 as well as Additional table 2: Table S2 provide detailed information regarding the expression levels of IGF2BP3. Taken together, cancer tissues demonstrated high IGF2BP3 expressed levels as compared to normal tissues.
IGF2BP3 is a prognostic biomarker for human cancers
We studied several databases for assessing IGF2BP3 expression’s correlation with pan-cancer prognosis. Based on GEPIA, high IGF2BP3 expression showed a relationship with poor OS (overall survival) as well as DFS (disease-free survival) in LGG, LIHC, KIRC, and MESO (LGG [Fig. 2A-B] - OS: n = 504, HR = 3, P = 3.4e-08; DFS: n = 504, HR = 1.7, P = 0.0015; LIHC [Fig. 2C-D] - OS: n = 361, HR = 1.4, P = 0.042; DFS: n = 361, HR = 1.4, P = 0.046; KIRC [Fig. 2E-F] - OS: n = 505, HR = 1.6, P = 0.0044; DFS: n = 505, HR = 2.1, P = 0.00017; and MESO [Fig. 2G-H] - OS: n = 82, HR = 2.7, P = 0.00018; DFS: n = 82, HR = 2.7, P = 0.0013). The TCGA database was used for this survival analysis. Similar outcomes were obtained for the PrognoScan database with the GEO data. High IGF2BP3 expression was related with low OS in glioma, LUAD, astrocytoma, AML, ovarian cancer, colorectal cancer, and SKCM. In summary, IGF2BP3 expression was correlated with pan-cancer prognosis.
Correlation of IGF2BP3 expression with various immune subtypes as well as immune molecular subtypes in pan-cancer
We investigated the correlation between various immune subtypes and immune molecule subtypes and IGF2BP3 expression in pan-cancer using online public websites (TISIDB). The following immune subtypes designated as C1 to C6, respectively, were included: wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immune quiet, and TGF-β dominant (20). IGF2BP3 expression showed an association with tumors of various immune subtypes, which included ACC, GBM, BRCA, UCEC, COAD, LGG, HNSC, and OV (Fig. 3A-H). Similarly, IGF2BP3 expression showed a clear correlation with human tumors of different molecular subtypes (Fig. 3I-P). Taken together, IGF2BP3 exhibits differential expression in tumors of diverse immune as well as molecular subtypes.
IGF2BP3 expression’s correlation with immune cell infiltration
TIICs are TME’s primary component and have a crucial effect on cancer initiation, metastasis, and progression [9, 10]. TIICs are critically involved in cancer malignancy and are an essential part of the TME. We investigated various immune cells for IGF2BP3 expression and obtained a boxplot of IGF2BP3 gene expression through the TIMER calculation method. The expression of IGF2BP3 differed among the immune cells (P < 0.05). A high level of IGF2BP3 expression showed a relationship with high immune cell enrichment, while a low expression of IGF2BP3 showed different results (Fig. 4). IGF2BP3 may also affect the treatment of cancer patients by influencing TIIC.
Association between the ICP genes and IGF2BP3 expression
ICPs participate as a critical immunomodulatory component in maintaining immune homeostasis and preventing autoimmunity, and they are also essential for immunotherapy [11]. We further investigated whether IGF2BP3 has immunotherapeutic potential by analyzing the association of IGF2BP3 expression with the ICP genes. Eight ICP genes, namely PDCD1, CTLA4, LAG3, PDCD1LG2, SIGLEC15, TIGIT, CD274, and HAVCR2, were selected. IGF2BP3 expression was related closely with these genes in several cancers, including LIHC, PRAD, LGG, BRCA, THCA, KIRP, BLCA, and KIRC (Fig. 5). This indicates IGF2BP3 could potentially be an ideal target for immunotherapy. Thus, IGF2BP3 could function as a novel biomarker with the potential to predict immunotherapeutic responses to human cancers or as a target for immunotherapy.
IGF2BP3’s potential for predicting immunotherapeutic response of pan-cancer
To understand IGF2BP3’s relevance in predicting the immunotherapy response of human cancers, we examined how IGF2BP3 expression is related to MSI, TMB, and NEO. The expression of IGF2BP3 correlated positively with NEO for 8 tumors, including GBM, OV, COAD, LUAD, PRAD, BRCA, HNSC, and LGG (Fig. 6A), and with TMB for BRCA, BLCA, LGG, GBM, LUAD, PAAD, LUSC, PRAD, COAD, HNSC, SARC, KIRC, SKCM, THYM, and THCA (Fig. 6B). We further analyzed IGF2BP3 expression’s association with MSI. A positive correlation was noted between the expression of IGF2BP3 and MSI in BLCA, COAD, ESCA, SARC, TGCT, as well as LUSC (Fig. 6C). Mutations and MMRs are known to be important carcinogenic factors. By investigating the relationship between IGF2BP3 expression and mutations and MMRs in different human cancers, we determined how IGF2BP3 expression influences tumorigenesis. Among IGF2BP3 mutations in various tumors, UCEC showed the highest mutation rate, accounting for 3.77%, and the mutations were mainly missense mutations. Additional file 2: Fig. S2A shows the necessary details. The heat map also shows how IGF2BP3 expression is related with DNA MMR genes. As shown in Additional file2: Fig. S2B, IGF2BP3 expression was positively correlated with 5 MMR genes in BLCA, READ, STAD, TGCT, UCEC, LGG, HNSC, LUAD, OV, LUSC, and PAAD. Thus, we found that IGF2BP3 may regulate antitumor immunity by affecting the tumor immune microenvironment.
IGF2BP3 co-expression network shows an association with immune response
The above-mentioned findings indicate a significant association between IGF2BP3 expression and the immunity and prognosis of cancers. By summarizing these conclusions, we found that IGF2BP3 has a remarkable association with cancer immunity and prognosis. We also determined IGF2BP3 expression’s correlation with the ICP genes. A positive correlation was noted for various tumors, including KICH, ACC, BRCA, BLCA, COAD, LIHC, LAML, PRAD, LGG, KIRC, OV, UVM, and THYM; in particular, 36/47 ICP genes were related to IGF2BP3 expression in UVM (refer to Additional file 3: Fig. S3 for details). We examined IGF2BP3’s co-expression network in tumors by considering UVM as an example, and the data were obtained from the LinkedOmics database. In UVM, 4176 genes showed a positive association with IGF2BP3 expression, while 1424 genes showed a negative association with it (Fig. 7A). The heatmap of IGF2BP3 with the top 50 associated genes was plotted (Fig. 7B- C). Gene expression profiles are provided in Additional table 3: Table S3. SAR1B, ABL2, and CEBPG genes were most closely correlated with IGF2BP3 expression (r = 0.676, 0.660, and 0.645; P = 5.81E-12, 2.67E-11, and 1.10E-10, respectively). We also assessed GO terms of the IGF2BP3 co-expressed genes. IGF2BP3 and its co-expressed genes are primarily enriched in B-cell activation, adaptive immune responses, and T-cell activation (Fig. 7D). Next, as shown in Fig. 7E, we performed KEGG pathway enrichment analysis, and the co-expressed genes participated in Autoimmune thyroid disease, Allograft rejection, Graft-versus-host disease, and Type I diabetes mellitus. Thus, IGF2BP3 expression may mediate tumor biological processes through immune regulation. Finally, the relationship of IGF2BP3 expression with potential ICB [immune checkpoint blockade] response was evaluated using the TIDE algorithm. TIDE determines the function of tumor immunity regulating genes [12]. For BLCA, LUAD, LGG, and PAAD, the high IGF2BP3 expression group showed better ICB treatment response than the low IGF2BP3 expression group (Fig. 8).