Black Seed Derivative Thymoquinone Suppresses Pancreatic Ductal Adenocarcinoma Associated Oncogenic circRNAs: A Pilot Study

[摘要] ObjectivesPancreatic cancer is projected to become the second leading cause of cancer-related deaths worldwide underscoring the urgent need for the identification of novel therapies. Circular RNAs (circRNAs) are closed loop small non-coding RNAs that are formed from back splicing and play a significant role in regulating the transcription of genes. Nevertheless, to date there are no studies that have evaluated whether circRNAs could be modulated using natural agent derivatives for therapeutic benefit.MethodsWe performed pilot circRNA-seq profiling and molecular analysis to identify circRNAs modulated by black seed derivative Thymoquinone (TQ) in PDAC models.ResultsTQ treatment resulted in the downregulation of PDAC associated oncogenic circRNAs, along with the inhibition of cell growth, CSC self-renewal capacity, clonogenic capacity. RT-PCR demonstrated that TQ suppressed the expression of five of the sequencing identified circRNAs (hsa_circ_0054853, hsa_circ_0012152, hsa_circ_0001495, hsa_circ_0006877, and hsa_circ_0000567) that were inherently elevated in PDAC cell lines and not in normal HPNE cells. CircR-0054853 was found to bind to specific tumor suppressor miRNAs, miR-1248 and miR-1287. Re-expression of these miRNAs result in the inhibition of cell growth and more pronounced sensitivity to TQ. TQ treatment also increased the expressions of these miRNAs. These findings suggest that circR-0054853 may act as an oncogenic circRNA by sponging tumor-suppressive miRNAs, thereby promoting PDAC growth, a process that can be reversed by TQ. Notably, circR-0054853 contains 22 binding sites for AGO2, and RNA immunoprecipitation assays confirmed that its binding to AGO2 was downregulated by TQ. Our novel results for the first time suggest that TQ exerts its inhibitory effects on cell signaling through the regulation of circRNA and RBP interactions.ConclusionsThese results provide a strong rationale for the future development of circRNA-targeted therapeutic strategies and biomarker-driven clinical studies evaluating TQ or related natural compounds in PDAC.

[发布日期] 2026-07-01

[关键词] circular RNAs;ncRNA;thymoquinone;TQ;pancreatic cancer