Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan; Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Am J Pathol. 2024 Oct;194(10):1967-1985. doi: 10.1016/j.ajpath.2024.07.003. Epub 2024 Jul 26.
Wnt-5a is a protein encoded by the WNT5A gene and is a ligand for the receptor tyrosine kinase-like orphan receptor 2 (ROR2). However, its biological impact on clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, the prognostic significance of concurrent WNT5A and ROR2 expression levels was observed to predict unfavorable overall survival and disease-specific survival. High Wnt-5a expression was detected in a ccRCC cell line panel but not in HK-2 cells, a normal proximal tubular cell line. Inhibition of DNA methyltransferase by 5-azacytidine in 786-O and Caki-2 cells resulted in Wnt-5a up-regulation, indicating potential epigenetic modification. Furthermore, there was a repression of cell movement in vitro and metastatic colonization in vivo on WNT5A and ROR2 knockdown. Suppressions of angiogenesis in vivo and tubular-like structure formation in endothelial cells in vitro were also observed after silencing WNT5A and ROR2 expression. In addition, alteration in the downstream gene signature of the Wnt-5a-ROR2 signaling was similar to that in metastasis-associated gene 1-β-catenin axis. Moreover, prunetin treatment reversed the gene signature derived from Wnt-5a-ROR2 signaling activation and to abolish ccRCC cell migration and proliferation. Overall, this study demonstrates the clinical and functional significance of the Wnt-5a-ROR2 axis and identifies prunetin as a potential precision medicine for patients with ccRCC harboring aberrant Wnt-5a-ROR2 signaling pathways.
Wnt-5a 是由 WNT5A 基因编码的蛋白质，是受体酪氨酸激酶样孤儿受体 2（ROR2）的配体。然而，其对透明细胞肾细胞癌（ccRCC）的生物学影响尚不清楚。在这项研究中，观察到同时表达 WNT5A 和 ROR2 的预后意义，以预测不利的总生存期和疾病特异性生存期。在 ccRCC 细胞系面板中检测到高 Wnt-5a 表达，但在正常近端肾小管细胞系 HK-2 细胞中未检测到。在 786-O 和 Caki-2 细胞中，通过 5-氮杂胞苷抑制 DNA 甲基转移酶导致 Wnt-5a 上调，表明存在潜在的表观遗传修饰。此外，在 WNT5A 和 ROR2 敲低时，体外细胞运动受到抑制，体内转移定植受到抑制。在沉默 WNT5A 和 ROR2 表达后，还观察到体内血管生成抑制和体外内皮细胞管状样结构形成。此外，Wnt-5a-ROR2 信号下游基因特征的改变与转移相关基因 1-β-连环蛋白轴相似。此外，补骨脂素处理逆转了源自 Wnt-5a-ROR2 信号激活的基因特征，并消除了 ccRCC 细胞的迁移和增殖。总的来说，这项研究表明了 Wnt-5a-ROR2 轴的临床和功能意义，并确定补骨脂素作为携带异常 Wnt-5a-ROR2 信号通路的 ccRCC 患者的潜在精准医学治疗方法。
