Huang Zixiong, Du Yiqing, Yin Huaqi, Wang Gongwei, Xu Tao
Department of Urology, Peking University People's Hospital, Beijing, China.
Department of Urology, Michigan Medicine, Ann Arbor, MI, United States.
Protein Pept Lett. 2025;32(5):327-334. doi: 10.2174/0109298665357331250416081850.
Canonical Wnt (Wnt/β-catenin) signaling maintains bone homeostasis by promoting osteoblastic activities. The inhibitory factor, Dickkopf-1 (DKK1), enhances bone resorption in malignant diseases. Low-density lipoprotein-related protein (LRP) 5 is antagonized by DKK1. This study aimed to investigate the expression of DKK1 and LRP5 in renal cell carcinoma bone metastasis (RCC-BM).
RCC-BM patients with paired samples of primary and metastatic lesions were selected for the study (RCC-BM group). RCC patients without any metastasis served as the control group (RCC-only group). Immunohistochemical staining with monoclonal anti-DKK1 and polyclonal anti- LRP5 antibody was conducted on paraffin-embedded slides. The staining results were recorded using scoring according to staining intensity in the renal tissue adjacent to the tumor, primary RCC lesions, and RCC-BM lesions.
DKK1 was differently expressed among normal renal tissues, primary RCC, and RCC- BM tissues (p<0.001). The DKK1 expression in primary RCC was significantly lower than that in normal renal tissues (p<0.001) without a difference between the RCC-BM and RCC-only groups. DKK1 expression in bone metastasis was significantly higher than that in primary tumors (p<0.001). For RCC-BM patients, the expression of LRP5 in the primary tumor was significantly lower than that in adjacent renal tissues (p<0.01). The tendency of lower expression was found in primary RCC from RCC-BM patients compared to RCC without metastasis (p=0.073).
A "rebound" pattern of DKK1 expression in bone metastasis lesions and the decreasing LRP5 expression in primary lesions of RCC-BM patients suggested that Wnt/β-catenin signaling was inhibited in RCC-BM. The overexpression of DKK1 and reduced expression of LRP5 suggest that these markers may be useful for the early prediction of RCC-BM.
经典Wnt（Wnt/β-连环蛋白）信号通路通过促进成骨细胞活性维持骨稳态。抑制因子Dickkopf-1（DKK1）在恶性疾病中增强骨吸收。低密度脂蛋白相关蛋白（LRP）5受到DKK1的拮抗。本研究旨在探讨DKK1和LRP5在肾细胞癌骨转移（RCC-BM）中的表达。
选取有原发性和转移性病变配对样本的RCC-BM患者进行研究（RCC-BM组）。无任何转移的RCC患者作为对照组（单纯RCC组）。用单克隆抗DKK1抗体和多克隆抗LRP5抗体对石蜡包埋切片进行免疫组织化学染色。根据肿瘤邻近肾组织、原发性RCC病变和RCC-BM病变中的染色强度评分记录染色结果。
DKK1在正常肾组织、原发性RCC和RCC-BM组织中的表达存在差异（p<0.001）。原发性RCC中DKK1的表达显著低于正常肾组织（p<0.001），RCC-BM组与单纯RCC组之间无差异。骨转移中DKK1的表达显著高于原发性肿瘤（p<0.001）。对于RCC-BM患者，原发性肿瘤中LRP5的表达显著低于邻近肾组织（p<0.01）。与无转移的RCC相比，RCC-BM患者原发性RCC中存在表达降低的趋势（p=0.073）。
RCC-BM患者骨转移病变中DKK1表达的“反弹”模式以及原发性病变中LRP5表达的降低表明RCC-BM中Wnt/β-连环蛋白信号通路受到抑制。DKK1的过表达和LRP5的表达降低表明这些标志物可能有助于RCC-BM的早期预测。
