Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer

Abstract

The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) plays essential roles in embryogenesis and carcinogenesis. IGF2BP1 serves as a post-transcriptional fine-tuner regulating the expression of some essential mRNA targets required for the control of tumor cell proliferation and growth, invasion, and chemo-resistance, associating with a poor overall survival and metastasis in various types of human cancers. Therefore, IGF2BP1 has been traditionally regarded as an oncogene and potential therapeutic target for cancers. Nevertheless, a few studies have also demonstrated its tumor-suppressive role. However, the details about the contradictory functions of IGF2BP1 are unclear. The growing numbers of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been identified as its direct regulators, during tumor cell proliferation, growth, and invasion in multiple cancers. Thus, the mechanisms of post-transcriptional modulation of gene expression mediated by IGF2BP1, miRNAs, and lncRNAs in determining the fate of the development of tissues and organs, as well as tumorigenesis, need to be elucidated. In this review, we summarized the tissue distribution, expression, and roles of IGF2BP1 in embryogenesis and tumorigenesis, and focused on modulation of the interconnectivity between IGF2BP1 and its targeted mRNAs or non-coding RNAs (ncRNAs). The potential use of inhibitors of IGF2BP1 and its related pathways in cancer therapy was also discussed.

Keywords: CRD-BP; Cancer; IGF2 mRNA-binding protein; IGF2BP; IMP; VICKZ.

Fig. 1

The KH domains of IGF2BP1 recognize and bind m⁶A-mRNAs, as well as the potential fate selection of IGF2BP1-targeted mRNAs. a Domain structure of human IGF2BP1. RNA-binding domains include two RNA recognition motifs (RRMs, blue) and four hnRNP-K homology domains (KH, red) [5]. b Schematic structures showing that mRNAs are methylated at the 3′-UTR by methyltransferase complex then recognized by IGF2BP1 under the co-effects of stabilizers such as ELAVL1, which finally inhibits the decay of m⁶A-RNAs [10]. c YT521-B homology (YTH) domain-containing proteins (YTHDFs) compete for the same m⁶A sites with IGF2BP1 and promote decay of m⁶A-RNAs. d The β-catenin physically binds to the element (CTTTG-TC) located in the promoter of IGF2BP1, which contributes to IGF2BP1 transcription activity (left) [–15]. The hypermethylation of element (CTTTG-TC) blocks β-catenin binding to the region and thus suppresses IGF2BP1 transcription activity (right), leading to increased proliferation and migration of metastatic breast cancer cells [54, 103]

Fig. 2

The roles of IGF2BP1 in promoting and suppressing tumor growth and invasion via regulating different mRNA targets, under the modulation of upstream non-coding RNAs. (1) Some miRNAs/lncRNAs upregulate or downregulate IGF2BP1 expression levels. (2) IGF2BP1 promotes the expression of c-MYC and MKI67 by stabilizing their transcripts and promotes tumor cell proliferation and growth (a, b). In addition, IGF2BP1 elevates CD44 and PTEN expression via preventing mRNA turnover. The enhancement of CD44 expression induces the formation of invadopodia and therefore may promote the tumor cell migration and invasiveness (f, j). Elevation of PTEN inhibits PIP3/PIP2 ratios and then interferes with the activation of RAC1, which enhances cell polarization and thus contributes to directed tumor cell migration as well as tumor invasion (e, j). IGF2BP1 suppresses the expression of MAPK4 and ACTB through interfering with mRNA translation (g, h). The inhibition of MAPK4 antagonizes MK5-directed phosphorylation of HSP27. PHSP27 at both residues induces the degradation of oligomers and increases the sequestering of actin monomers by the phosphorylated protein. The reduced ACTB also decreases G-actin levels. This shifts the cellular G-/F-actin equilibrium contributes to cell adhesion and actin dynamics and finally promotes cell migration velocity (I) [, –86, 101, 102]. Furthermore, IGF2BP1 promotes RGS4 expression and thus indirectly depresses tumor cell invasion (d). IGF2BP1 inhibits PTGS2 expression (c). The reduction of PTGS2 indirectly promotes tumor cell invasion and releases the suppression for cell apoptosis (C1, C2) [17]. C-Myc and IGF2BP1 constitute a potential feedback mechanism to reciprocally regulate expression of each other (k) [68]. The hypermethylation of promoter in IGF2BP1 leads to its expression silencing (m) [81, 82].The gray dotted lines show that the interaction of the depicted pathways needs to be explored. The part of Fig. 2 including pathway from (e, f, h, and g to i and j is adapted from the Figure 3 of the paper by Stohr et al. [102]