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Published on: September 23, 2021
Extracellular Vesicle-Mediated Transfer of LncRNA IGFL2-AS1 Confers Sunitinib Resistance in Renal Cell Carcinoma
Yihui Pan1, Xuanxuan Lu2, Guannan Shu1
1Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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.
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.
Insights
The long noncoding RNA IGFL2-AS1 drives sunitinib resistance in renal cell carcinoma (RCC) by enhancing autophagy. Targeting IGFL2-AS1 offers a new strategy to overcome treatment resistance in RCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Sunitinib resistance is a major obstacle in treating advanced renal cell carcinoma (RCC).
- Mechanisms driving sunitinib resistance in RCC are not fully elucidated.
- Identifying novel therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of long noncoding RNA IGFL2-AS1 in sunitinib resistance in RCC.
- To elucidate the molecular mechanisms by which IGFL2-AS1 contributes to therapy resistance.
- To evaluate IGFL2-AS1 as a potential therapeutic target and prognostic biomarker.
Main Methods:
- Analysis of IGFL2-AS1 expression in sunitinib-resistant RCC cells and patient samples.
- Investigated the interaction between IGFL2-AS1, hnRNPC, and TP53INP2.
- Assessed the role of IGFL2-AS1 in autophagy and extracellular vesicle packaging.
- Utilized a patient-derived xenograft model with antisense oligonucleotide therapy.
Main Results:
- IGFL2-AS1 was significantly upregulated in sunitinib-resistant RCC and correlated with poor prognosis.
- IGFL2-AS1 enhances TP53INP2 expression, promoting autophagy and sunitinib resistance.
- IGFL2-AS1 is packaged into extracellular vesicles, mediating intercellular resistance.
- Antisense oligonucleotide targeting IGFL2-AS1 reversed sunitinib resistance in vivo.
Conclusions:
- IGFL2-AS1 is a key driver of sunitinib resistance in RCC through TP53INP2-mediated autophagy.
- Extracellular vesicle-mediated transfer of IGFL2-AS1 contributes to resistance.
- IGFL2-AS1 represents a promising prognostic marker and therapeutic target for overcoming sunitinib resistance in RCC.
