Wang Yiqiu, Zhao Ding, Lu Jiayi, Hou Naiqiao, Wu Qianyun, Zhou Sian, Xu Junyao, Xue Wei, Cui Wenguo, Zheng Junhua, Wang Fei, Zhai Wei
Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Oncogene. 2025 Jul 11. doi: 10.1038/s41388-025-03476-z.
Bone metastasis, which is associated with adverse outcomes, is a serious health concern for renal cell carcinoma (RCC) patients, especially considering the limited therapeutic options. In this study, we investigated the expression profiling of circRNAs in five primary RCC samples and RCC-bone metastases (Bone Met) using high-throughput screening and identified an upregulated circRNA in Bone Met (hsa_circ_0016459, circKCNK2). Notably, overexpression of circKCNK2 could promote osteoclast differentiation and accelerate the destruction of osteolytic bone metastasis by stimulating IL-11 secretion. Additionally, we observed that RCC with a high circKCNK2 expression could benefit from an anti-IL-11 strategy rather than a denosumab-based therapeutic regimen. At the molecular level, circKCNK2 is competitively bound to EDC4 (a scaffold protein of P-bodies). The interaction between circKCNK2 and EDC4α-helical disrupted the combination of DCP1 and DCP2, which weakened the function of P-bodies and resulted in an increased level of IL-11 mRNA and finally activated STAT-3 signaling in osteoclast precursors (OPs). This axis could be blocked with a mutation of EDC4α-helical. Further experiments revealed that increased circKCNK2 production in bone metastases was attributed to decreasing expression of heterogeneous nuclear ribonucleoprotein U (hnRNPU) under an acidic microenvironment. Our findings suggest that circKCNK2 could have a critical role in linking P-bodies to IL-11/STAT-3 signaling. Developing a secure and effective gene delivery system targeted at circKCNK2 is promising for RCC therapy.
骨转移与不良预后相关，是肾细胞癌（RCC）患者严重的健康问题，尤其是考虑到治疗选择有限的情况下。在本研究中，我们使用高通量筛选研究了5个原发性RCC样本和RCC骨转移样本（骨转移）中环状RNA的表达谱，并在骨转移样本中鉴定出一种上调的环状RNA（hsa_circ_0016459，circKCNK2）。值得注意的是，circKCNK2的过表达可促进破骨细胞分化，并通过刺激IL-11分泌加速溶骨性骨转移的破坏。此外，我们观察到circKCNK2高表达的RCC患者可能从抗IL-11策略中获益，而不是基于地诺单抗的治疗方案。在分子水平上，circKCNK2与EDC4（P小体的一种支架蛋白）竞争性结合。circKCNK2与EDC4α螺旋之间的相互作用破坏了DCP1和DCP2的结合，削弱了P小体的功能，导致IL-11 mRNA水平升高，最终激活破骨细胞前体（OPs）中的STAT-3信号。该轴可通过EDC4α螺旋的突变来阻断。进一步的实验表明，骨转移中circKCNK2产生增加归因于酸性微环境下异质性核糖核蛋白U（hnRNPU）表达的降低。我们的研究结果表明，circKCNK2在将P小体与IL-11/STAT-3信号联系起来方面可能起关键作用。开发一种针对circKCNK2的安全有效的基因递送系统有望用于RCC治疗。
