National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, China.
Mol Carcinog. 2023 Jun;62(6):882-893. doi: 10.1002/mc.23532. Epub 2023 Mar 29.
Renal cell carcinoma (RCC) is the second commonest urological malignant neoplasm and mortality rate of patients with RCC appears to be increasing each year. Thus, further understanding of the molecular mechanisms responsible for the development and progression of RCC is of particular importance. Here, we report that atypical chemokine receptor 3 (ACKR3) orchestrates the Hedgehog (Hh)-GLI1 signaling to promote RCC progression. The expression of ACKR3 is elevated in RCC tissues, which is associated with malignant and clinical outcomes of RCC, and ACKR3 expression is positively correlated with GLI1 expression in RCC tissues. Mechanically, Hh promotes RCC progression through GLI1-mediated ACKR3 transcription by the directly binding of GLI1 to ACKR3 gene, while CXCL12-ACKR3 axis simultaneously enhances Hh activation via the binding of ACKR3 to Smoothened (SMO), a receptor in Hh pathway, resulting in the upregulation of SMO phosphorylation that potentiates downstream signal activity and consequently contributes to RCC progression. Thus, our findings may provide with the evidence of developing a novel treatment method with specific target for RCC.
肾细胞癌（RCC）是第二常见的泌尿生殖系统恶性肿瘤，RCC 患者的死亡率似乎每年都在增加。因此，进一步了解导致 RCC 发生和发展的分子机制尤为重要。在这里，我们报告非典型趋化因子受体 3（ACKR3）协调 Hedgehog（Hh）-GLI1 信号通路促进 RCC 进展。ACKR3 在 RCC 组织中的表达上调，与 RCC 的恶性和临床结局相关，并且 ACKR3 的表达与 RCC 组织中 GLI1 的表达呈正相关。在机制上，Hh 通过 GLI1 直接结合 ACKR3 基因，促进 GLI1 介导的 ACKR3 转录，从而促进 RCC 进展，而 CXCL12-ACKR3 轴通过 ACKR3 与 Hh 通路中的受体 Smoothened（SMO）结合，同时增强 Hh 激活，导致 SMO 磷酸化上调，增强下游信号活性，从而促进 RCC 进展。因此，我们的研究结果可能为开发针对 RCC 的新型治疗方法提供依据。
