Long Non‐Coding RNA IGFRIL Couples with PTBP1 to Destabilize IGFBP3 mRNA to Promote the IGF1R‐AKT‐mTOR Axis and Hepatocellular Carcinoma

Abstract The incomplete understanding of the IGFR pathway activation mechanism limits its clinical application in hepatocellular carcinoma (HCC). Here, a transcriptome‐wide screening is performed and a novel HCC‐associated lncRNA, named IGFR‐inducing lncRNA ( IGFRIL ) is identified. IGFRIL is frequently upregulated in HCC tissues and predicts poor clinical outcomes. It is revealed that IGFRIL plays an oncogenic role in the development of HCC. Mechanistically, IGFRIL serves as a scaffold to recruit PTBP1, destabilizing IGFBP3 mRNA and thereby overactivating the IGF1R‐AKT‐mTOR signaling in HCC cells. Furthermore, it is observed that the inhibitors against IGF1R or mTOR exhibit suppressive effects on patient‐derived tumor xenograft tumors with high IGFRIL expression, through simultaneous blocking of the IGF1R‐AKT‐mTOR signaling pathway. In summary, this study identifies IGFRIL as a novel non‐coding activator of the IGF1R pathway, providing a promising new therapeutic target for HCC patients.