The molecular axis hnRNPU/circKCNK2/EDC4/IL-11 aggravates osteolytic bone metastasis of RCC

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.