Extracellular Vesicle-Mediated Transfer of LncRNA IGFL2-AS1 Confers Sunitinib Resistance in Renal Cell Carcinoma.
Extracellular Vesicle-Mediated Transfer of LncRNA IGFL2-AS1 Confers Sunitinib Resistance in Renal Cell Carcinoma.
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细胞外囊泡介导的 lncRNA IGFL2-AS1 转移赋予肾细胞癌舒尼替尼耐药性
DOI：
10.1158/0008-5472.can-21-3432
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发表时间：
2023-01-04
期刊：
影响因子：
11.2
通讯作者：
Zhang, Jiaxing
中科院分区：
文献类型：
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作者：
Pan, Yihui;Lu, Xuanxuan;Shu, Guannan;Cen, Junjie;Lu, Jun;Zhou, Mi;Huang, Kangbo;Dong, Jiaqi;Li, Jiaying;Lin, Haishan;Song, Hongde;Xu, Quanhui;Han, Hui;Chen, Zhenhua;Chen, Wei;Luo, Junhang;Wei, Jinhuan;Zhang, Jiaxing
细胞外囊泡包装的 IGFL2-AS1 通过调节 TP53INP2 触发的自噬促进舒尼替尼耐药，表明该 lncRNA 作为肾细胞癌的潜在治疗靶点。舒尼替尼耐药仍然是晚期和转移性肾细胞癌（RCC）治疗的严峻挑战，但这种耐药的机制尚未完全了解。在此，我们报告长链非编码 RNA IGFL2-AS1 是 RCC 治疗耐药的驱动因素。 IGFL2-AS1 在舒尼替尼耐药的 RCC 细胞中高度上调，并且与接受舒尼替尼治疗的透明细胞 RCC (ccRCC) 患者的不良预后相关。 IGFL2-AS1 通过竞争性结合 hnRNPC 来增强 TP53INP2 表达，hnRNPC 是一种多功能 RNA 结合蛋白，可通过选择性剪接在转录后抑制 TP53INP2 表达。上调 TP53INP2 增强自噬并最终导致舒尼替尼耐药。同时，IGFL2-AS1通过hnRNPC被包装到细胞外囊泡中，从而将舒尼替尼耐药性传递给其他细胞。 IGFL2-AS1 的 N6-甲基腺苷修饰对于其与 hnRNPC 的相互作用至关重要。在源自患者的舒尼替尼耐药性ccRCC异种移植模型中，注射含有反义寡核苷酸-IGFL2-AS1的壳聚糖固体脂质纳米粒子成功逆转了舒尼替尼耐药性。这些发现表明了肾细胞癌中舒尼替尼耐药的新分子机制，并表明 IGFL2-AS1 可作为预后指标和克服耐药性的潜在治疗靶点。细胞外囊泡包装的 IGFL2-AS1 通过调节 TP53INP2 触发的自噬促进舒尼替尼耐药，表明该 lncRNA 作为肾细胞癌的潜在治疗靶点。
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. 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. 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.