N6-methyladenosine (m6A) plays an important role in post-transcriptional gene regulation. IGF2BP2, a key gene in the m6A signaling pathway, has recently been shown to play an important role in the development and progression of cancer[23]. IGF2BP2 is one of the members of the m6A reader family IGF2BPs, which can target thousands of mRNAs. Its K homology domain is necessary for them to recognize m6A and is essential for its oncogenic function[24]. In our study, we confirmed that gene amplification was the most common type of genetic alteration in IGF2BP2. However, additional gain- and loss-of-function studies are needed to further explore its function in different cellular context. In recent years, the research on the function of IGF2BP2 in diseases including cancer has been increasing, which partially revealed the potential carcinogenic mechanism of IGF2BP2.
Nevertheless, the carcinogenic mechanism of IGF2BP2 is still poorly understood. At present, the relationship between IGF2BP2 and tumorigenesis is mainly concentrated in the research of colorectal cancer, liver cancer, pancreatic cancer, thyroid cancer, cervical cancer, and so on, whereas the research in other types of tumors is relatively rare, so here we perform a pan-cancer analysis of IGF2BP2. Our comprehensive analysis method mainly includes exploring the gene expression of IGF2BP2 in thirty- three different tumors based on the TCGA database. At the same time, we systematically collected and integrated the data in the CPTAC and GEO databases and analyzed the location, molecular characteristics, drug treatment response, and possibly related interacting proteins of IGF2BP2 through a series of online data analysis websites.
In our results, we observed that the expression levels of IGF2BP2 in tumor tissues of CHOL, COAD, ESCA, GBM, HNSC, KICH, KIRP, LIHC, LUSC, STAD, and THCA were higher than the corresponding normal tissues, whereas in BRCA, KIRC, PCPG, and PRAD tissues, IGF2BP2 expression was significantly lower than the corresponding normal tissues. This difference in IGF2BP2 expression levels in different tumor types may reflect different underlying functions and mechanisms. We further found that overexpression of IGF2BP2 usually predicted poor OS in tumor patients, such as BLCA, HNSC, KIRC, LGG, LUAD, PAAD and SARC. These results suggest that IGF2BP2 is a potential biomarker for predicting prognosis in tumor patients.
According to our analysis, the expression level of IGF2BP2 was significantly higher in THCA than in normal thyroid tissue, and its expression in stage IV was higher than its expression in stage I, stage II, and stage III. In the analysis of the correlation between THCA and immune checkpoint gene, we could see that IGF2BP2 showed a significant positive correlation with the expression of CD200, NRP1, CD276, TNFRSF8, CD40, TNFSF15, and CD44, while the expression of LAG3, PDCD1, IDO2, and IDO1 showed a significant negative correlation with IGF2BP2.There was no significant difference in the promoter methylation levels of IGF2BP2 in THCA tissues and paracancerous tissues. Furthermore, in studying the relationship between IGF2BP2 and THCA, we found that reduced expression of IGF2BP2 inhibited the proliferation, migration and invasion of thyroid tumor cells, while inducing cell cycle arrest and apoptosis. Meanwhile, in thyroid tumor cells, IGF2BP2 was able to regulate the expression of LncRNA HAGLR in an m6A-dependent manner, and IGF2BP2 was positively correlated with the expression of LncRNA HAGLR[25]. Also, LncRNA MALAT1 could further upregulate IGF2BP2 expression by binding to miR-204, thus promoting the progression of thyroid cancer[26].
However, even though we performed a comprehensive analysis on IGF2BP2 and used different databases for cross-verification, there are some limitations to this study. First of all, there are some differences in sequencing data in different databases, and the analysis results of some websites are time-limited, which may lead to some deviations in the analysis results, but it does not affect the overall conclusion. Second, in recent years, IGF2BP2 has received increasing attention from researchers as an important regulatory protein in m6A modification, and this has been repeatedly mentioned in our paper, but whether IGF2BP2 mainly influences tumorigenesis through regulating m6A modification has not yet been analyzed by us. Third, although we concluded that IGF2BP2 expression is closely related to immune cell infiltration and prognosis of human cancers, we lacked direct evidence that IGF2BP2 affects prognosis by participating in immune cell infiltration. Fourth, we have not performed further in vivo/in vitro studies to confirm the results of this study regarding the potential function of IGF2BP2. Our study shows that low IGF2BP2 expression is associated with the clinical benefit of ICB therapy. Therefore, in the future, we can improve the prognosis of cancer patients from the perspective of lowering IGF2BP2 expression and using ICB, while also working to develop a new anti-tumor immunotherapy drug targeting IGF2BP2.
In conclusion, through a comprehensive analysis of IGF2BP2 pan-cancer, we determined the expression of IGF2BP2 in different cancers and its relationship with clinical prognosis, as well as the promoter methylation levels of IGF2BP2 in different tumors, and found correlations between IGF2BP2 and immune cell infiltration, sensitivity to treatment with ICIs, tumor mutational load, and microsatellite instability. It helps to elucidate the role of IGF2BP2 in tumorigenesis and development from multiple aspects, and also provides research directions to further explore the specific oncogenic mechanisms of IGF2BP2.