Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, Xi'an, Shaanxi, China.
Cancer Lett. 2021 Feb 1;498:70-79. doi: 10.1016/j.canlet.2020.10.031. Epub 2020 Nov 4.
Tumor angiogenesis is a major characteristic of renal cell carcinoma (RCC). Herein, we report a novel mechanism of how lncRNA and androgen receptor (AR) drive the Hedgehog pathway to promote tumor angiogenesis in RCC. We found that the high expression of lncRNA HOTAIR in RCC is associated with poor prognosis. Moreover, HOTAIR and AR form a feedback loop to promote the expression of each other. Interestingly, we also found that in RCC, HOTAIR is associated with the Hedgehog pathway, especially GLI2, via bioinformatics analysis. Furthermore, HOTAIR promotes GLI2 expression in the presence of AR. Mechanistically, HOTAIR interacts with AR and they cooperatively bind to GLI2 promoter and increase its transcription activity. We further confirmed how HOTAIR-AR axis regulates GLI2 expression by analyzing its function in RCC cells and found that HOTAIR and AR synergistically enhanced the expression of GLI2 downstream genes, such as VEGFA, PDGFA, and cancer stem cell transcription factors, and promoted tumor angiogenesis and cancer stemness in RCC cells both in vitro and in tumor xenografts. Overall, these findings suggest that HOTAIR and GLI2 could be novel therapeutic targets against RCC.
肿瘤血管生成是肾细胞癌 (RCC) 的主要特征。在此，我们报告了一个长非编码 RNA (lncRNA) 和雄激素受体 (AR) 如何驱动 Hedgehog 通路促进 RCC 肿瘤血管生成的新机制。我们发现，RCC 中 lncRNA HOTAIR 的高表达与预后不良有关。此外，HOTAIR 和 AR 形成一个反馈回路来促进彼此的表达。有趣的是，我们还通过生物信息学分析发现，在 RCC 中，HOTAIR 与 Hedgehog 通路有关，特别是 GLI2。此外，HOTAIR 在 AR 的存在下促进 GLI2 的表达。在机制上，HOTAIR 与 AR 相互作用，它们共同结合到 GLI2 启动子上并增加其转录活性。我们通过分析其在 RCC 细胞中的功能进一步证实了 HOTAIR-AR 轴如何调节 GLI2 的表达，发现 HOTAIR 和 AR 协同增强了 GLI2 下游基因的表达，如 VEGFA、PDGFA 和癌症干细胞转录因子，并促进了 RCC 细胞在体外和肿瘤异种移植中的肿瘤血管生成和癌症干性。总的来说，这些发现表明 HOTAIR 和 GLI2 可能成为针对 RCC 的新的治疗靶点。
