Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma
Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma
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长非编码RNA SNHG12通过上调肾细胞癌中的CDCA3促进肿瘤进展和舒尼替尼耐药
DOI：
10.1038/s41419-020-2713-8
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发表时间：
2020-07-08
影响因子：
9
通讯作者：
Zhang, Xiaoping
中科院分区：
文献类型：
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作者：
Liu, Yuenan;Cheng, Gong;Zhang, Xiaoping
肾细胞癌（RCC）是泌尿系统最常见的恶性肿瘤之一，其靶向耐药现象十分普遍。长链非编码RNA SNHG 12（lncRNA SNHG 12）已成为许多人类癌症的关键分子，但其在肾细胞癌（RCC）舒尼替尼耐药中的功能尚不清楚。在本研究中，我们发现SNHG 12在肾细胞癌组织和舒尼替尼耐药细胞中高表达，并且与不良的临床预后相关。SNHG 12通过CDCA 3在体外促进RCC增殖、迁移、侵袭和舒尼替尼耐药。SNHG 12与SP1结合，阻止了SP1的泛素化依赖性蛋白水解。稳定的SP1与CDCA 3启动子中的特定区域结合并增加CDCA 3表达。此外，体内实验表明SNHG 12增加了肿瘤生长，并且敲低SNHG 12可以逆转RCC舒尼替尼耐药性。我们的研究发现lncRNA SNHG 12/SP1/CDCA 3轴促进了肾癌的进展和舒尼替尼耐药，这可能为舒尼替尼耐药的肾癌提供新的治疗靶点。
Renal cell carcinoma (RCC) is one of the most frequently observed malignant tumours in the urinary system and targeted drug resistance is quite common in RCC. Long noncoding RNA SNHG12 (lncRNA SNHG12) has emerged as a key molecule in numerous human cancers, but its functions in renal cell carcinoma (RCC) sunitinib resistance remain unclear. In this study, we found SNHG12 was highly expressed in RCC tissues and in sunitinib-resistant RCC cells and was associated with a poor clinical prognosis. SNHG12 promoted RCC proliferation, migration, invasion and sunitinib resistance via CDCA3 in vitro. Mechanically, SNHG12 bound to SP1 and prevented the ubiquitylation-dependent proteolysis of SP1. Stabilised SP1 bound to a specific region in the promoter of CDCA3 and increased CDCA3 expression. Furthermore, in vivo experiments showed that SNHG12 increased tumour growth and that knocking down SNHG12 could reverse RCC sunitinib resistance. Our study revealed that the lncRNA SNHG12/SP1/CDCA3 axis promoted RCC progression and sunitinib resistance, which could provide a new therapeutic target for sunitinib-resistant RCC.