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Extracellular Vesicle-Mediated Transfer of LncRNA IGFL2-AS1 Confers Sunitinib Resistance in Renal Cell Carcinoma.
- Source :
-
Cancer research [Cancer Res] 2023 Jan 04; Vol. 83 (1), pp. 103-116. - Publication Year :
- 2023
-
Abstract
- 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 IGFL2-AS1 is a driver of therapy resistance in RCC. IGFL2-AS1 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. IGFL2-AS1 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, IGFL2-AS1 was packaged into extracellular vesicles through hnRNPC, thus transmitting sunitinib resistance to other cells. N6-methyladenosine modification of IGFL2-AS1 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-IGFL2-AS1 successfully reversed sunitinib resistance. These findings indicate a novel molecular mechanism of sunitinib resistance in RCC and suggest that IGFL2-AS1 may serve as a prognostic indicator and potential therapeutic target to overcome resistance.<br />Significance: Extracellular vesicle-packaged IGFL2-AS1 promotes sunitinib resistance by regulating TP53INP2-triggered autophagy, implicating this lncRNA as a potential therapeutic target in renal cell carcinoma.<br /> (©2022 The Authors; Published by the American Association for Cancer Research.)
- Subjects :
- Humans
Sunitinib pharmacology
Sunitinib therapeutic use
Cell Line, Tumor
Drug Resistance, Neoplasm genetics
Cell Proliferation
Gene Expression Regulation, Neoplastic
Nuclear Proteins metabolism
Carcinoma, Renal Cell drug therapy
Carcinoma, Renal Cell genetics
Carcinoma, Renal Cell pathology
RNA, Long Noncoding genetics
RNA, Long Noncoding metabolism
Kidney Neoplasms drug therapy
Kidney Neoplasms genetics
Kidney Neoplasms pathology
Extracellular Vesicles metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 83
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 36264173
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-21-3432