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lncRNA和雄激素受体（AR）如何驱动Hedgehog通路促进肾细胞癌肿瘤血管生成的新机制。我们发现lncRNA HOTAIR在RCC中的高表达与不良预后相关。而且，HOTAIR和AR形成反馈循环，促进彼此的表达。有趣的是，我们通过生物信息学分析还发现，在RCC中，HOTAIR与Hedgehog通路尤其是GLI2相关。此外，HOTAIR 在 AR 存在的情况下促进 GLI2 表达。从机制上讲，HOTAIR 与 AR 相互作用，它们协同结合GLI2启动子并增加其转录活性。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表达，发现HOTAIR和AR协同增强GLI2下游基因，如VEGFA、PDGFA和癌症干细胞转录因子的表达，促进肿瘤血管生成以及体外和肿瘤异种移植物中 RCC 细胞的癌症干性。总体而言，这些发现表明 HOTAIR 和 GLI2 可能成为 RCC 的新治疗靶点。