Abstract

<div>Abstract<p>Sunitinib resistance remains a serious challenge to the treatment of advanced and metastatic renal cell carcinoma (RCC), yet the mechanisms underlying this resistance are not fully understood. Here, we report that the long noncoding RNA <i>IGFL2-AS1</i> is a driver of therapy resistance in RCC. <i>IGFL2-AS1</i> was highly upregulated in sunitinib-resistant RCC cells and was associated with poor prognosis in patients with clear cell RCC (ccRCC) who received sunitinib therapy. <i>IGFL2-AS1</i> enhanced TP53INP2 expression by competitively binding to hnRNPC, a multifunctional RNA-binding protein that posttranscriptionally suppresses TP53INP2 expression through alternative splicing. Upregulated TP53INP2 enhanced autophagy and ultimately led to sunitinib resistance. Meanwhile, <i>IGFL2-AS1</i> was packaged into extracellular vesicles through hnRNPC, thus transmitting sunitinib resistance to other cells. N<sup>6</sup>-methyladenosine modification of <i>IGFL2-AS1</i> was critical for its interaction with hnRNPC. In a patient-derived xenograft model of sunitinib-resistant ccRCC, injection of chitosan-solid lipid nanoparticles containing antisense oligonucleotide-<i>IGFL2-AS1</i> successfully reversed sunitinib resistance. These findings indicate a novel molecular mechanism of sunitinib resistance in RCC and suggest that <i>IGFL2-AS1</i> may serve as a prognostic indicator and potential therapeutic target to overcome resistance.</p>Significance:<p>Extracellular vesicle-packaged <i>IGFL2-AS1</i> promotes sunitinib resistance by regulating TP53INP2-triggered autophagy, implicating this lncRNA as a potential therapeutic target in renal cell carcinoma.</p></div>

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