Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
Chinese PLA Medical School, Beijing, China.
Cell Death Dis. 2024 Oct 10;15(10):739. doi: 10.1038/s41419-024-07085-8.
Primary cilia are present on renal tubules and are implicated to play a pivotal role in transducing signals during development; however, the oncogenic role of cilia in clear cell renal cell carcinoma (ccRCC) has not been examined. Here we show that VHL wild-type ccRCC cell lines have a high incidence of primary cilia, and a high frequency of primary cilia is positively correlated with VHL expression and poor prognosis. Besides, the depletion of KIF3A and IFT88, genes required for ciliogenesis, significantly inhibited tumor proliferation and metastasis in vitro and in vivo. Further analysis found that mutations of key genes in hedgehog signaling are enriched in VHL wild ccRCC, its downstream signaling activation depends on ciliogenesis. Moreover, depletion of primary cilia or suppression of hedgehog pathway activation with inhibitor-induced robust autophagic cell death. Collectively, our findings revealed that primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of VHL wild-type ccRCC progression. Targeting the primary cilia-hedgehog pathway may represent an effective therapeutic strategy for VHL wild-type ccRCC.
初级纤毛存在于肾小管中，被认为在发育过程中传递信号中发挥关键作用;然而，纤毛在透明细胞肾细胞癌（ccRCC）中的致癌作用尚未被研究。在这里，我们表明 VHL 野生型 ccRCC 细胞系具有高发生率的初级纤毛，并且初级纤毛的高频率与 VHL 表达和不良预后呈正相关。此外，纤毛发生所必需的基因 KIF3A 和 IFT88 的耗竭，显著抑制了体外和体内肿瘤的增殖和转移。进一步的分析发现， hedgehog 信号通路中的关键基因的突变在 VHL 野生型 ccRCC 中富集，其下游信号转导的激活依赖于纤毛发生。此外，初级纤毛耗竭或用抑制剂诱导的强烈自噬性细胞死亡来抑制 hedgehog 通路的激活。总之，我们的研究结果表明，初级纤毛可以作为一种诊断工具，并为 VHL 野生型 ccRCC 的发病机制提供新的见解。靶向初级纤毛- hedgehog 通路可能代表一种针对 VHL 野生型 ccRCC 的有效治疗策略。
