IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors

Abstract

The oncofetal IGF2 mRNA binding proteins (IGF2BPs) are upregulated in most cancers but their paralogue-specific roles in tumor cells remain poorly understood. In a panel of five cancer-derived cell lines, IGF2BP1 shows highly conserved oncogenic potential. Consistently, the deletion of IGF2BP1 impairs the growth and metastasis of ovarian cancer-derived cells in nude mice. Gene expression analyses in ovarian cancer-derived cells reveal that the knockdown of IGF2BPs is associated with the downregulation of mRNAs that are prone to miRNA regulation. All three IGF2BPs preferentially associate upstream of miRNA binding sites (MBSs) in the 3′UTR of mRNAs. The downregulation of mRNAs co-regulated by miRNAs and IGF2BP1 is abrogated at low miRNA abundance or when miRNAs are depleted. IGF2BP1 associates with these target mRNAs in RISC-free complexes and its deletion enhances their association with AGO2. The knockdown of most miRNA-regulated target mRNAs of IGF2BP1 impairs tumor cell properties. In four primary cancers, elevated synthesis of these target mRNAs is largely associated with upregulated IGF2BP1 mRNA levels. In ovarian cancer, the enhanced expression of IGF2BP1 and most of its miRNA-controlled target mRNAs is associated with poor prognosis. In conclusion, these findings indicate that IGF2BP1 enhances an aggressive tumor cell phenotype by antagonizing miRNA-impaired gene expression.

Functions of N6-methyladenosine and its role in cancer

“…IGF2BP1 promotes tumor cell malignant phenotype by preferentially associating upstream of miRNA binding sites in the 3′ UTR of target mRNAs and then antagonizing miRNA-impaired gene expression [100]. Serum response factor (SRF) controls expression of oncogenes like FOXK1 and PDLIM7.…”

“…SRF contributes to tumor cell proliferation and metastasis, and transcription of oncogenes like FOXK1 and PDLIM7 [131,132]. IGF2BP1 enhances expression of SRF through inhibiting the miRNA-mediated degradation of it in an m6A-dependent way, resulting in increased expression of SRF, FOXK1 and PDLIM7 [78,100]. METTL3 stimulates AXL mRNA translation and epithelial-mesenchymal transition, thereby promoting growth and invasion of ovarian tumors [126,133].…”

Combinatorial recognition of clustered RNA elements by a multidomain RNA-binding protein, IMP3

“…The currently best-understood IMP-mediated mechanism of modulating mRNA fate comprises the so-called safe-housing of specific transcripts in mRNP granules 4 . This "caging" of mRNAs ranges in its functional spectrum from packaging for cytoplasmic transport 5 , delayed translation within stable mRNPs [6][7][8] , cytoplasmic storage, and protection against pre-mature miRNA-directed mRNA regulation 3,[9][10][11][12] . Several target mRNAs have been suggested 3,13 , with IMP1 associating with the ACTB mRNA zipcode element and all three IMPs regulating HMGA2 stability via the 3´-UTR as the currently best-studied examples [9][10][11][12][14][15][16] .…”

Comprehensive characterization of cancer‐testis genes in testicular germ cell tumor

“…Recently, increasing evidence suggested that the development of cancer cells involves the acquisition of stem‐cell‐like phenotypes and loss of differential features, which may lead to the progression and distant metastasis of cancer cells . Interestingly, we identified that LIN28A and IGF2BP1 , the essential members in stem cell maintenance, were also associated with advanced tumor stages in addition to the oncogenic effect in tumorigenesis . Thus, we proposed that the dysregulation of stemness‐related CT genes in TGCT may not only lead to the initiation of tumorigenesis and oncogenic de‐differentiation, but also contribute to the progression of testicular germ cells.…”

“…[23][24][25] Interestingly, we identified that LIN28A and IGF2BP1, the essential members in stem cell maintenance, were also associated with advanced tumor stages in addition to the oncogenic effect in tumorigenesis. 26,27 Thus, we proposed that the dysregulation of stemness-related CT genes in TGCT may not only lead to the initiation of tumorigenesis and oncogenic de-differentiation, but also contribute to the progression of testicular germ cells.…”