Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, 430022, Wuhan, China.
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, 430022, Wuhan, China.
Cell Death Dis. 2020 Jul 8;11(7):515. doi: 10.1038/s41419-020-2713-8.
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.
肾细胞癌（RCC）是泌尿系统中最常见的恶性肿瘤之一，其靶向药物耐药性相当常见。长链非编码 RNA SNHG12（lncRNA SNHG12）已成为许多人类癌症中的关键分子，但它在肾细胞癌（RCC）舒尼替尼耐药中的作用尚不清楚。在这项研究中，我们发现 SNHG12 在 RCC 组织和舒尼替尼耐药的 RCC 细胞中高表达，与不良的临床预后相关。SNHG12 通过 CDCA3 在体外促进 RCC 的增殖、迁移、侵袭和舒尼替尼耐药。在机制上，SNHG12 与 SP1 结合，防止 SP1 的泛素化依赖性蛋白水解。稳定的 SP1 结合到 CDCA3 启动子的特定区域，增加 CDCA3 的表达。此外，体内实验表明 SNHG12 增加了肿瘤的生长，而敲低 SNHG12 可以逆转 RCC 对舒尼替尼的耐药性。我们的研究揭示了 lncRNA SNHG12/SP1/CDCA3 轴促进了 RCC 的进展和舒尼替尼耐药，这为舒尼替尼耐药的 RCC 提供了一个新的治疗靶点。
