Liu Yingting, Xing Zhaoyu, Yuan Maoling, Xu Bin, Chen Lujun, Zhang Dachuan, Zhou You, Huang Hao, Zheng Xiao, Zhang Jinping, Jiang Jingting
Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu 213003, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210023, China.
Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China.
Pathol Res Pract. 2022 Oct;238:154069. doi: 10.1016/j.prp.2022.154069. Epub 2022 Aug 10.
Clear cell renal cell carcinoma (ccRCC) is known as the most aggressive subtype of genitourinary cancers. The lack of effective therapies has prompted us to further explore the complex network of genes involved in ccRCC tumor progression and metastasis and to seek new biomarkers and therapeutic strategies to improve clinical outcomes. Interleukin-1 receptor type 2 (IL1R2), a decoy receptor of IL-1, is found to be differentially expressed in various tumors types recently. However, the role of IL1R2 in ccRCC has not been documented. Herein, we found that the expression of IL1R2 in ccRCC tissues was significantly increased as the tumor's Furman pathological grade was elevated. Compared to lower IL1R2 expression, ccRCC patients with high IL1R2 expression had a significantly worse OS rate. IL1R2 could serve as an independent prognostic predictor for ccRCC patients. Depletion of IL1R2 could inhibit cell proliferation, migration, invasion, and cell cycle arrest at the G1 phase, while overexpression of IL1R2 could reverse this effect. Moreover, depletion of IL1R2 led to changes and enrichment of several signaling pathways, as shown by RNA sequencing. We subsequently verified that Janus kinase 2 / signal transducer and activator of transcription 3 (JAK2/STAT3) pathway was involved in the IL1R2 mediated regulation of cellular functions of ccRCC cells and these functions were acted by the intracellular domain of IL1R2, not the extracellular domain. Our findings suggested that IL1R2 could serve as a potential therapeutic target for ccRCC progression and metastasis via its regulation of the JAK2/STAT3 signaling pathway.
透明细胞肾细胞癌（ccRCC）是泌尿生殖系统癌症中最具侵袭性的亚型。缺乏有效的治疗方法促使我们进一步探索参与ccRCC肿瘤进展和转移的复杂基因网络，并寻找新的生物标志物和治疗策略以改善临床结局。白细胞介素-1受体2型（IL1R2）是白细胞介素-1的诱饵受体，最近发现在各种肿瘤类型中存在差异表达。然而，IL1R2在ccRCC中的作用尚未见报道。在此，我们发现随着肿瘤的富曼病理分级升高，ccRCC组织中IL1R2的表达显著增加。与IL1R2低表达相比，IL1R2高表达的ccRCC患者的总生存率显著更差。IL1R2可作为ccRCC患者的独立预后预测指标。IL1R2的缺失可抑制细胞增殖、迁移、侵袭，并使细胞周期停滞在G1期，而IL1R2的过表达可逆转这种效应。此外，如RNA测序所示，IL1R2的缺失导致多种信号通路的变化和富集。我们随后证实，Janus激酶2/信号转导子和转录激活子3（JAK2/STAT3）通路参与了IL1R2介导的ccRCC细胞功能调节，且这些功能是由IL1R2的胞内结构域而非胞外结构域发挥作用。我们的研究结果表明，IL1R2可能通过调节JAK2/STAT3信号通路成为ccRCC进展和转移的潜在治疗靶点。
