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Published on: June 14, 2019
ISG15 drives cervical cancer progression by hyperactivating the NOD-like receptor signaling pathway
Zongyang Jia1, Junhua Zhang2, Xiaoli Liu2
1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Qingdao, Shandong 266035, PR China; Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China; Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, Shandong 250012, PR China.
Abstract:
The function of the interferon-stimulated gene ISG15 in cervical cancer (CC) is complex and remains unclear. We analyzed the expression and clinical significance of ISG15 in the TCGA-CESC cohort. Its function was investigated in Caski cells using RNA-seq, siRNA, and pharmacological inhibition methods, and validated in vivo in a xenograft model. ISG15 was significantly overexpressed in cervical cancer tissues (P < 0.001). However, high ISG15 expression was associated with better overall survival (HR=0.67, 95% CI: 0.48-0.94, p = 0.02). Gene set enrichment analysis (GSEA) indicated that high ISG15 expression was associated with the NOD-like receptor signaling pathway. Mechanistically, ISG15 binds to and stabilizes the NOD2 protein via ISGylation. This binding promotes cell proliferation and invasion. The RIPK2 inhibitor (GSK583) eliminated the oncogenic effects of ISG15. In vivo experiments showed that ISG15 knockdown or GSK583 treatment inhibited tumor growth by approximately 50%. Our study reveals the dual nature of ISG15: it is both a prognostic biomarker and a functional oncoprotein in cervical cancer cells. Its pro-tumorigenic effect is mediated by the overactivation of the NLR pathway through ISGylation. The ISG15-NOD2/RIPK2 axis is a targetable vulnerability, suggesting that treatment strategies should be decoupled from its prognostic association.
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