title: 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.
authors.affiliation: Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, ZAMED, Heinrich-Damerow-Str.1, 06120 Halle, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Busch
authors.affiliation: Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, ZAMED, Heinrich-Damerow-Str.1, 06120 Halle, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bley
authors.affiliation: Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, ZAMED, Heinrich-Damerow-Str.1, 06120 Halle, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, ZAMED, Heinrich-Damerow-Str.1, 06120 Halle, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glaß
authors.affiliation: Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, ZAMED, Heinrich-Damerow-Str.1, 06120 Halle, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Misiak
authors.affiliation: Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, ZAMED, Heinrich-Damerow-Str.1, 06120 Halle, Germany.
authors.forename: Marcell
authors.initials: M
authors.lastname: Lederer
authors.affiliation: Clinic of Gynecology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Vetter
authors.affiliation: Clinic of Gynecology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Strauß
authors.affiliation: Clinic of Gynecology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomssen
authors.affiliation: Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, ZAMED, Heinrich-Damerow-Str.1, 06120 Halle, Germany stefan.huettelmaier@medizin.uni-halle.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hüttelmaier
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D025743:HMGA2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D059368:RNA Isoforms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism
chemical_list: D025743:HMGA2 Protein; C406144:IGF2BP1 protein, human; C516326:LIN28B protein, human; D035683:MicroRNAs; D015513:Oncogene Proteins; D059368:RNA Isoforms; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C026452:messenger ribonucleoprotein; C487931:mirnlet7 microRNA, human