CircHMGB2 Acts as a Molecular Decoy for IGF2BP1 to Promote Cisplatin Resistance via Grb10/Akt Signaling in Chondrosarcoma

Abstract

Chondrosarcoma is a common bone sarcoma in adults with limited therapeutic options due to frequent chemoresistance. Cisplatin (CDDP) is a key chemotherapeutic agent, but resistance often develops. This study investigated the role and mechanism of circular RNA HMGB2 (circHMGB2) in cisplatin resistance of chondrosarcoma. Clinically, circHMGB2 was upregulated in chondrosarcoma tumors and associated with cisplatin resistance and poor patient survival. Functionally, exogenous overexpression of circHMGB2 elevated cisplatin resistance in chondrosarcoma cells (SW1353, OUMS-27) in vitro, while its silencing re-sensitized resistant cells. Mechanistically, circHMGB2 did not function as a miRNA sponge but acted as a competitive molecular decoy for the RNA-binding protein IGF2BP1. We demonstrated that circHMGB2 directly binds IGF2BP1, competitively impairing IGF2BP1’s binding to and stabilization of Grb10 mRNA, leading to its destabilization and subsequent downregulation of Grb10 protein. This suppression of Grb10, a known negative regulator of the PI3K/Akt pathway, resulted in constitutive Akt phosphorylation, driving resistance. Crucially, co-overexpression of IGF2BP1 rescued circHMGB2-induced Grb10 downregulation, Akt activation, and cisplatin resistance, validating the decoy mechanism. Furthermore, in a cisplatin-resistant xenograft model, silencing circHMGB2 synergized with cisplatin to significantly inhibit tumor growth, improve host survival, and upregulate intratumoral Grb10 while suppressing Akt phosphorylation. Our results delineate a novel circHMGB2/IGF2BP1/Grb10/Akt axis that drives cisplatin resistance in chondrosarcoma. Targeting circHMGB2 could therefore serve as a promising therapeutic strategy to overcome chemoresistance and enhance treatment efficacy.