The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family

Abstract

The tumor-suppressive let-7 microRNA family targets various oncogene-encoding mRNAs. We identify the let-7 targets HMGA2, LIN28B and IGF2BP1 to form a let-7 antagonizing self-promoting oncogenic triangle. Surprisingly, 3′-end processing of IGF2BP1 mRNAs is unaltered in aggressive cancers and tumor-derived cells although IGF2BP1 synthesis was proposed to escape let-7 attack by APA-dependent (alternative polyadenylation) 3′ UTR shortening. However, the expression of the triangle factors is inversely correlated with let-7 levels and promoted by LIN28B impairing let-7 biogenesis. Moreover, IGF2BP1 enhances the expression of all triangle factors by recruiting the respective mRNAs in mRNPs lacking AGO proteins and let-7 miRNAs. This indicates that the downregulation of let-7, largely facilitated by LIN28B upregulation, and the protection of let-7 target mRNAs by IGF2BP1-directed shielding in mRNPs synergize in enhancing the expression of triangle factors. The oncogenic potential of this triangle was confirmed in ovarian cancer (OC)-derived ES-2 cells transduced with let-7 targeting decoys. In these, the depletion of HMGA2 only diminishes tumor cell growth under permissive conditions. The depletion of LIN28B and more prominently IGF2BP1 severely impairs tumor cell viability, self-renewal and 2D as well as 3D migration. In conclusion, this suggests the targeting of the HMGA2-LIN28B-IGF2BP1 triangle as a promising strategy in cancer treatment.

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

“…IMP family members are commonly re-expressed in tumor cells that contain one or both of the LIN28 paralogs (Busch et al 2016;our unpublished observations). In ovarian cancer cell lines, LIN28B and IMP1 appear to display synergistic protection of let-7 target transcripts, including HMGA2, as well as mutual protection, as they are both let-7 targets (Busch et al 2016).…”

“…Several recent studies have shown that one mechanism by which IMPs promote mRNA stability is by preventing miRNA-mediated silencing (Elcheva et al 2009;Goswami et al 2010;Nishino et al 2013;Busch et al 2016;Degrauwe et al 2016). IMP1 was notably observed to promote the expression of the self-renewal factor and let-7 miRNA family target HMGA2 (for review, see Fusco and Fedele 2007), which raised the possibility that IMP1 may counteract let-7 miRNA action during development and thereby contribute to stem cell maintenance (Nishino et al 2013).…”

“…Sequestration of miRNA target mRNAs in mRNP granules that are free of Ago/RISC (Weidensdorfer et al 2009;Busch et al 2016) is proposed to be one mechanism by which IMP1 protects mRNAs from let-7-mediated silencing (Fig. 2).…”

IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts

“…The mRNA and protein expression patterns of BCL11A and HMGA2 suggest that IGF2BP1 is a posttranscriptional regulator of both proteins. The posttranscriptional up-regulation of HMGA2 was expected because IGF2BP1 is a known competitor of let-7 for HMGA2 mRNA binding (31).…”

“…Also an oncofetal protein, IGF2BP1 is commonly detected in several tumors. Its effects upon growth are variable with speculation of both oncogenic as well as tumorsuppressive functionality (31,(44)(45)(46) based upon the cellular context of its expression. As shown here, overexpression of IGF2BP1 in the committed erythroblasts did not prevent their maturation or enucleation in ex vivo cultures.…”